Search

Background: In patients with HIV, conventional tests are of low sensitivity; therefore, a new diagnostic test with hydrogel nanoparticles with reactive blue dye is proposed, which allows the capture, conservation and concentration of ESAT-6 in urine. NIPAs are copolymers that capture low molecular weight proteins and protect against enzymatic degradation. Using an immunoassay, it is possible to detect and quantify ESAT-6 present in urine as a possible marker of active TB. Design/Methods: Study in Lima, Peru, HIV+ participants, ≥18 years with and without tuberculosis (TB). Smear microscopy, culture in solid medium and urine immunoassay were performed. The reference was the diagnosis of TB by radiological or clinical microbiological criteria (indication for TB treatment). There were 2 preanalytical processes: untreated and treated urine (centrifuged, heated), then incubation with NIPAm. After washing, elution, sonication, heat and centrifugation, the final eluate was obtained. This was placed on nitrocellulose membranes, which by means of fixation and incubation processes with anti-ESAT-6 and anti-IgG antibodies, revelation with C-DiGit&reg Blot Scanner and FluorChem R FR0001. Calibration curves were included in the membranes, density was measured using Image J software. ROC curves, sensitivity and specificity were obtained. Results: The result by groups was HIV+ patient: ROC: 0.75, cut-off point ≥24.06 ng/ml, sensitivity 76.32%, specificity 68.89%, patients ≤200 cells CD4 mm3/ml, ROC: 0.78, cutoff point ≥26.20 ng/ml, sensitivity 75.86%, specificity 71.88%, patients >200 CD4 mm3 cells/ml, ROC: 0.73, cutoff point ≥24.6 CD4 mm3/ml, sensitivity 73.68%, specificity 73.68%. Conclusions: The ESAT-6 detection assay using NIPAm was effective, with higher rates in patients with ≤200 CD4 cells/mm3, the test being more sensitive than smear and culture, but less specific.

Summary Background Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment. Methods This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670. Findings Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen [placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29–98) in the delamanid group and 57 days (43–85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91–1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid. Interpretation The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care. Funding Otsuka Pharmaceutical.

espanolEn paises con elevada endemia tuberculosa, las personas estan muy cerca a esta enfermedad a lo largo de toda su vida. Sea porque algun familiar o amigo desarrolla la enfermedad o porque en el devenir de la vida experimenta la infeccion o la enfermedad. En el caso del medico o profesional de la salud, seguramente su cercania sera mayor, y preferentemente si se dedica a actividades de prevencion y control en tuberculosis. En este articulo se exponen las experiencias cercanas con la tuberculosis desde nuestra infancia, como estudiante de medicina, medico, investigador, salubrista y docente universitario, donde el profesional pasa situaciones afectivas personales, temas de limitaciones de conocimiento, limitaciones en el diagnostico, hasta ejecucion de investigaciones sobre problemas locales y generando respuestas en la prevencion y control. Seguramente es una experiencia comun en profesionales de salud que en el dia a dia enfrentan esta endemia, de la cual cada vez conocemos mas, pero se nos hace muy dificil su control EnglishIn countries with high tuberculosis endemicity, people are very close to this disease throughout their lives. This may be because a relative or friend develops the disease, or because in the course of their lives they themselves acquire the infection or illness. In the event, that the person is a doctor or a health professional their contact with tuberculosis will be greater, and even more so if they are involved in activities relating to its prevention and control. This article discusses my experiences with tuberculosis since childhood, as a medical student, doctor, researcher, health professional and university professor, where the professional navigates situations of a personal or emotional nature, knowledge limitations, diagnostic constraints, and even undertaking research on local problems and generating responses in prevention and control. It is surely, a common experience among health professionals who each day face this endemic which we increasingly know more about, yet it remains very difficult to control.

Background There are limited data on influenza vaccine effectiveness (IVE) in preventing laboratory-confirmed influenza illness among healthcare personnel (HCP). Methods HCP with direct patient contact working full-time in hospitals were followed during three influenza seasons in Israel (2016–2017 to 2018–2019) and Peru (2016 to 2018). Trivalent influenza vaccines were available at all sites, except during 2018–2019 when Israel used quadrivalent vaccines; vaccination was documented by electronic medical records, vaccine registries, and/or self-report (for vaccinations outside the hospital). Twice-weekly active surveillance identified acute respiratory symptoms or febrile illness (ARFI); self-collected respiratory specimens were tested by real-time reverse transcription polymerase chain reaction (PCR) assay. IVE was 100 × 1-hazard ratio (adjusted for sex, age, occupation, and hospital). Results Among 5,489 HCP who contributed 10,041 person-seasons, influenza vaccination coverage was 47% in Israel and 32% in Peru. Of 3,056 ARFIs in Israel and 3,538 in Peru, A or B influenza virus infections were identified in 205 (7%) in Israel and 87 (2.5%) in Peru. IVE against all viruses across seasons was 1% (95% confidence interval [CI] = −30%, 25%) in Israel and 12% (95% CI = −61%, 52%) in Peru. Conclusion Estimates of IVE were null using person-time models during six study seasons in Israel and Peru.

Background Tuberculosis (TB) has been linked to an increased risk of atherosclerotic cardiovascular disease (ASCVD). We assessed whether latent TB infection (LTBI) is associated with subclinical coronary atherosclerosis in 2 TB-prevalent areas. Methods We analyzed cross-sectional data from studies conducted in Lima, Peru, and Kampala, Uganda. Individuals ≥40 years old were included. We excluded persons with known history of ASCVD events or active TB. Participants underwent QuantiFERON-TB (QFT) testing to define LTBI and computed tomography angiography to examine coronary atherosclerosis. A Coronary Artery Disease–Reporting Data System (CAD-RADS) score ≥3 defined obstructive CAD (plaque causing ≥50% stenosis). Results 113 and 91 persons with and without LTBI, respectively, were included. There were no significant differences between LTBI and non-LTBI participants in terms of age (median [interquartile range]; 56 [51–62] vs 55 [49–64] years; P = .829), male sex (38% vs 42%; P = .519), or 10-year ASCVD risk scores (7.1 [3.2–11.7] vs 6.1 [2.8–1.8]; P = .533). CAD prevalence (any plaque) was similar between groups (29% vs 24%; P = .421). Obstructive CAD was present in 9% of LTBI and 3% of non-LTBI individuals (P = .095). LTBI was associated with obstructive CAD after adjusting for ASCVD risk score, HIV status, and study site (adjusted OR, 4.96; 95% CI, 1.05–23.44; P = .043). Quantitative QFT TB antigen minus Nil interferon-γ responses were associated with obstructive CAD (adjusted OR, 1.2; 95% CI, 1.03–1.41; P = .022). Conclusions LTBI was independently associated with an increased likelihood of subclinical obstructive CAD. Our data indicate that LTBI is a nontraditional correlate of ASCVD risk.

The COVID-19, in the scant six months of its presence, has caused a global health crisis, with greater impact inthe poorest countries. Currently, there is a better understanding of the clinic of this disease and its relationshipwith physiopathological phenomena; however, given the high lethality, the major focus of its management hasbeen oriented towards the hospitalized or critical patient. This information and experience is shared in orderto achieve and strengthen better care for people affected by COVID-19 from their first symptoms at home,especially at these times of extensive community transmission, where health services are seriously limited inhuman and material resources. The aim is to (i) avoid complications beyond those caused by the evolution ofthe disease itself; (ii) determine the appropriate time for patient referral to the hospital and reduce lethality;(iii) reinforce the isolation of cases; and (iv) possibly, decrease the progression to severe disease. It includesoutpatient management after hospital discharge, as well as recommendations to consider if health servicescollapse; indications for when to discharge the patient for return to work, and highlights the importance oftelemonitoring for the success of this practice in the current epidemiological context., La COVID-19, en los escasos seis meses de su presencia, ha provocado una crisis sanitaria mundial, conmayor impacto en los países más pobres. En la actualidad, existe un mejor conocimiento de la clínica deesta enfermedad y su relación con los fenómenos fisiopatológicos; sin embargo, dada la alta letalidad, elmayor enfoque de su manejo se ha orientado hacia el paciente hospitalizado o crítico. Esta información yexperiencia se comparte con el fin de lograr reforzar una mejor atención a las personas afectadas por laCOVID-19 desde sus primeros síntomas en el hogar, especialmente en estos momentos de amplia transmisiónen la comunidad, donde los servicios de salud están seriamente limitados en recursos humanos y materiales.El objetivo es: i) evitar complicaciones más allá de las causadas por la propia evolución de la enfermedad;ii) determinar el momento adecuado para la referencia del paciente al hospital y reducir la letalidad; iii)reforzar el aislamiento de los casos; y iv) posiblemente, disminuir la progresión a una enfermedad severa.Incluye el manejo luego del alta hospitalaria, así como recomendaciones para considerar si los servicios desalud colapsan; indicaciones sobre cuándo dar de alta al paciente para que regrese al trabajo, y destaca laimportancia del telemonitoreo para el éxito de este manejo en el contexto epidemiológico actual.

Multicenter collaborative networks are essential for advancing research and improving clinical care for a variety of conditions. Research networks are particularly important for central nervous system infections, which remain difficult to study due to their sporadic occurrence and requirement for collection and testing of cerebrospinal fluid. Establishment of long-term research networks in resource-limited areas also facilitates diagnostic capacity building, surveillance for emerging pathogens, and provision of appropriate treatment where needed. We review our experience developing a research network for encephalitis among twelve hospitals in five Peruvian cities since 2009. We provide practical suggestions to aid other groups interested in advancing research on central nervous system infections in resource-limited areas., Highlights • This report provides a comprehensive review of implementing a research network at twelve hospitals in five Peruvian cities. • The network helped build testing capacity, provide education about clinical procedures, and gather data about CNS infections. • Lessons learned offer guidance to others wishing to build similar networks for CNS infections or other unrelated disorders.

The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis.International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1-infected antiretroviral therapy-naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms.For DTG (n = 69), the baseline HIV-1 RNA was100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65-86%) for DTG and 82% (36/44, 95% CI 70-93%) for EFV. The DTG nonresponses were driven by non-treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS.Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated.NCT02178592.

Access to nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line antiretroviral therapy (ART) for HIV has been increasing in Peru since a national ART program was initiated in 2004. Between 2007 and 2009, we found a 1% prevalence of pre-ART HIV drug resistance (PDR) among antiretroviral (ARV)-naive Peruvians. Given that PDR has been associated with virologic failure (VF) of ART, in 2014–2015 we enrolled a follow-up cohort at the same institution to determine whether the rate of transmitted resistance had increased and compared virologic outcomes of those with and without PDR. Blood specimens from ARV-naive individuals were assessed for PDR to NNRTI-based ART by an oligonucleotide ligation assay (OLA) sensitive to 2% mutant within an individual's HIV quasispecies at reverse transcriptase codons M41L, K65R, K103N, Y181C, M184V, and G190A, and by Sanger consensus sequencing (CS). Rates of VF (plasma HIV RNA >200 copies/mL) were compared between those with and without PDR. Among 122 ARV-naive adults, PDR was detected by OLA in 17 (13.9%) adults. Compared with the 2007–2009 cohort, the proportion with PDR at OLA codons was significantly increased (p

Background To evaluate the mortality in hospitalized patients with tuberculous meningitis and describe factors associated with an increased risk of mortality. Methods Retrospective study of hospitalized patients with tuberculous meningitis between 2006 and 2015 in Peru performing a generalized linear regression to identify factors predictive of in-hospital mortality. Results Of 263 patients, the median age was 35 years, 72.6% were men, 38% were positive for HIV upon admission, 24% had prior TB infections and 2.3% had prior MDR-TB infections. In-hospital mortality was 30.4% of all study patients with a final diagnosis of TBM. When multivariable analysis was applied, significant associations with in-hospital mortality were seen among patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44–2.94), BMRC II (RR 1.78; 95% CI 1.07–2.97), BMRC III (RR 3.11; 95% CI 1.78–5.45) and positive CSF cultures (RR 1.95; 95% CI 1.39–2.74). Conclusions In-hospital mortality is higher among patients with HIV infections, age over 40 years, positive CSF TB culture and BMRC stage II or III.

Ascaris lumbricoides is considered the largest intestinal nematode with a higher incidence in the childhood, representing a truly medical and public health problem, principally in undeveloped countries. We present the case of an 83 year old man, born and coming from the amazon region, without any relevant previous history of disease, admitted in the emergency department of our hospital for presenting intestinal obstruction and also presumptive biliary obstruction due to multiple balls of parasites, requiring immediate surgical intervention. We emphasize the need of consider this etiologic possibility in the differential diagnosis, that in this particular case, wasn't suspected in the first place.

SUMMARYHerpes simplex virus (HSV) is one of the most commonly identified infectious aetiologies of encephalitis in North America and Europe. The epidemiology of encephalitis beyond these regions, however, is poorly defined. During 2009–2012 we enrolled 313 patients in a multicentre prospective study of encephalitis in Peru, 45 (14·4%) of whom had confirmed HSV infection. Of 38 patients with known HSV type, 84% had HSV-1 and 16% had HSV-2. Patients with HSV infection were significantly more likely to present in the summer months (44·4% vs. 20·0%, P = 0·003) and have nausea (60·0% vs. 39·8%, P = 0·01) and rash (15·6% vs. 5·3%, P = 0·01) compared to patients without HSV infection. These findings highlight differences in the epidemiology and clinical presentation of HSV encephalitis outside of the Northern Hemisphere that warrant further investigation. Furthermore, there is an urgent need for improved HSV diagnostic capacity and availability of intravenous acyclovir in Peru.

Multidrug-resistant tuberculosis (MDRTB) rates in a human immunodeficiency virus (HIV) care facility increased by the year 2000—56% of TB cases, eight times the national MDRTB rate. We reported the effect of tuberculosis infection control measures that were introduced in 2001 and that consisted of 1) building a respiratory isolation ward with mechanical ventilation, 2) triage segregation of patients, 3) relocation of waiting room to outdoors, 4) rapid sputum smear microscopy, and 5) culture/drug–susceptibility testing with the microscopic-observation drug-susceptibility assay. Records pertaining to patients attending the study site between 1997 and 2004 were reviewed. Six hundred and fifty five HIV/TB–coinfected patients (mean age 33 years, 79% male) who attended the service during the study period were included. After the intervention, MDRTB rates declined to 20% of TB cases by the year 2004 (P = 0.01). Extremely limited access to antiretroviral therapy and specific MDRTB therapy did not change during this period, and concurrently, national MDRTB prevalence increased, implying that the infection control measures caused the fall in MDRTB rates. The infection control measures were estimated to have cost US$91,031 while preventing 97 MDRTB cases, potentially saving US$1,430,026. Thus, this intervention significantly reduced MDRTB within an HIV care facility in this resource-constrained setting and should be cost-effective.

Background Persons with active tuberculosis (TB) have increased immune activation, which declines with TB treatment. Whether residual immune activation is present after completion of TB treatment is unknown. We conducted immunophenotyping of T cells and monocytes from individuals who had completed TB treatment, and compared them to controls without history of active TB. Methods Cross-sectional study of HIV-uninfected individuals 40 to 70 years old recruited in Lima, Peru. For this analysis, we included 6 individuals who had completed treatment for pulmonary TB within the past year, and 10 healthy controls without history of active TB (6 QuantiFERON®-TB positive; 4 QuantiFERON®-TB negative). Participants provided blood for T cell and monocyte immunophenotyping using multi-parameter flow cytometry, including expression of cell surface activation markers. Results There were no significant differences in age, sex, or comorbidities between patients previously treated for TB and controls without history of active TB. Median time since TB treatment completion was 4 months (range, 2 – 9) for the previously treated group. Compared to controls, persons previously treated for TB had increased CD4+ to CD8+ ratio (2.4 vs. 1.3; p=0.03), increased proportion of CD4+ T cells co-expressing HLA-DR and CD38 activation markers (5.8% vs. 3.1%; p=0.02), increased CD4+ T cell ICAM-1 expression (56.3% vs. 33.2%; p=0.03), as well as increased density of HLA-DR in monocytes (HLA-DR MFI; 7572 vs. 3917; p=0.03). Conclusion In this pilot study, individuals who recovered from pulmonary TB exhibited increased CD4+ T cell and monocyte activation phenotypes within one year of TB treatment completion. These results suggest residual immune activation after clinical TB cure. Disclosures Carl Fichtenbaum, MD, Amgen (Grant/Research Support, outside the submitted work)Clinical Care Options (Other Financial or Material Support, outside the submitted work)Cytodyn (Grant/Research Support, outside the submitted work)Gilead Sciences (Grant/Research Support, outside the submitted work)Janssen (Grant/Research Support, outside the submitted work)Merck (Grant/Research Support, outside the submitted work)ViiV Healthcare (Research Grant or Support, outside the submitted work)

Cough is a characteristic symptom of tuberculosis, is the main cause of transmission, and is used to assess treatment response. We aimed to identify the best measure of cough severity and characterize changes during initial tuberculosis therapy. We conducted a prospective cohort of recently diagnosed ambulatory adult patients with pulmonary tuberculosis in two tertiary hospitals in Lima, Peru. Pre-treatment and five times during the first two months of treatment, a vibrometer was used to capture 4-hour recordings of involuntary cough. A total of 358 recordings from 69 participants were analyzed using a computer algorithm. Total time spent coughing (seconds per hour) was a better predictor of microbiologic indicators of disease severity and treatment response than the frequency of cough episodes or cough power. Patients with prior tuberculosis tended to cough more than patients without prior tuberculosis, and patients with tuberculosis and diabetes coughed more than patients without diabetes co-morbidity. Cough characteristics were similar regardless of HIV co-infection and for drug-susceptible versus drug-resistant tuberculosis. Tuberculosis treatment response may be meaningfully assessed by objectively monitoring the time spent coughing. This measure demonstrated that cough was increased in patients with TB recurrence or co-morbid diabetes, but not because of drug resistance or HIV co-infection.

Objective: During effective antiretroviral therapy (ART), low-level plasma viremias (LLV) (HIV RNA >30–1000 copies/ml) can be detected intermittently. We hypothesized that systemic inflammation is associated with LLV either as the cause or result of the production of virions from clonally expanded cells. Methods: Prospective cohort study of HIV-infected ART-naive Peruvians enrolled prior to ART and followed for 2 years. Plasma HIV RNA and peripheral blood mononuclear cell (PBMC) HIV DNA concentrations were quantified pre-ART from individuals whose plasma HIV RNA was ART-suppressed. Inflammatory biomarker concentrations were measured pre and during ART. Single-genome amplification (SGA) derived HIV env and pol genotypes from pre-ART and LLV specimens. Antiretroviral levels during ART assessed adherence. Statistical associations and phylogenetic relationships were examined. Results: Among 82 participants with median plasma HIV RNA less than 30 copies/ml, LLV were detected in 33 of 82 (40%), with a LLV median HIV RNA of 73 copies/ml. Participants with vs. without LLV had significantly higher pre-ART plasma HIV RNA (P

Pneumonia is one of the most common acute respiratory infections among pediatric populations worldwide. Ultrasound is becoming increasingly important in the diagnosis of lung diseases as a more portable and safer alternative to X-ray imaging. In the current work, we present a new automatic system for detection of B-lines, one of the distinctive features of pneumonic ultrasound scans, using amplitude modulation-frequency modulation (AM-FM). Features are evaluated on 109 videos obtained from 100 pediatric patients using a Verasonics V1 scanner. Further, the results were compared to the ones obtained with a previously published spectral feature (SF) method. Sensitivities of 92% and 83% and specificities of 91% and 70% were obtained on zone-1 and zone-2 of the lungs, respectively. In contrast, the SF method provided sensitivities of 72% and 68% in zone-1 and zone-2, respectively, and specificities of 68% and 46% in zone-1 and zone-2, respectively. In addition, the AM-FM method allowed increasing the F1-score when compared to the SF method from 70% to 87% and from 61% to 78% in zone-1 and zone-2, respectively. The results suggest the proposed method may be useful for the computer assisted diagnosis of pneumonia.

To reduce transmission of tuberculosis (TB) in resource-limited countries where TB remains a major cause of mortality, novel diagnostic tools are urgently needed. We evaluated the fractional concentration of exhaled nitric oxide (FeNO) as an easily measured, noninvasive potential biomarker for diagnosis and monitoring of treatment response in participants with pulmonary TB including multidrug resistant–TB in Lima, Peru. In a longitudinal study however, we found no differences in baseline median FeNO levels between 38 TB participants and 93 age-matched controls (13 parts per billion [ppb] [interquartile range (IQR) = 8–26] versus 15 ppb [IQR = 12–24]), and there was no change over 60 days of treatment (15 ppb [IQR = 10–19] at day 60). Taking this and previous evidence together, we conclude FeNO is not of value in either the diagnosis of pulmonary TB or as a marker of treatment response.

Background: Concurrent treatment of tuberculosis and HIV is challenging owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir were assessed in adults with HIV and drug-susceptible tuberculosis. Methods: INSPIRING (NCT02178592) is a Phase 3b, non-comparative, active-control, randomised, open-label study in HIV-1-infected ARTcells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomised (3:2) to receive dolutegravir (50mg twice-daily during and 2 weeks post-tuberculosis therapy, then 50mg once-daily) or efavirenz (600mg once-daily), with two NRTI for 52 weeks. The primary endpoint was the proportion of dolutegravir-arm participants with plasma HIV-1-RNA 100,000 c/mL in 64%, with median CD4 208 c/µL; for efavirenz (N=44), 55% had HIV-1-RNA >100,000 c/mL, median CD4 count was 202 c/µL. Week 48 response rate was 75% (52/69) (95%CI: 65%, 86%) for dolutegravir and 82% (36/44) (70%, 93%) for efavirenz. Dolutegravir non-response was driven by non-treatmentrelated discontinuations, mostly loss-to-follow-up following initial virologic suppression. There were no deaths or study drug switches in either arm; there were two discontinuations for toxicity (efavirenz).There were three protocol-defined virological failures (2 dolutegravir with no emergence of resistance, 1 efavirenz with NRTI and NNRTI emergent resistance detected). Tuberculosis treatment success was high. TBassociated IRIS was uncommon, with no discontinuations for IRIS. Interpretation: Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily dolutegravir was effective and well-tolerated. Clinical Trial Number: NCT02178592 Funding Statement: This study was funded by ViiV Healthcare. Declaration of Interests: MAK, MA, RS, CLT, KA, AT, DB and MRK are employed by and own shares in GSK. KED received salary support through her university for research effort devoted to this study. Ethics Approval Statement: The trial was approved by local ethics committees at each site, and participants gave written informed consent.

Background We previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru. Methods We analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay. Participants with a positive QFT test were defined as having LTBI, whereas participants with a negative QFT test were defined as non-LTBI. Unstimulated interferon-gamma was quantified via enzyme-linked immunosorbent assay in the QFT nil-tube, which does not contain antigens. We compared unstimulated interferon-gamma levels between LTBI and non-LTBI groups using the Wilcoxon rank sum test. We used proportional odds modeling for multivariable analysis. Results Data from 214 participants were included in this analysis. Of those, 120 (56%) had LTBI. There were no significant differences in age, sex and comorbidities between LTBI and non-LTBI participants, except for recent AMI that was more frequent in LTBI. LTBI participants had higher unstimulated interferon-gamma levels compared to non-LTBI participants (median, interquartile range; 14 pg/mL, 6.5–52.8 vs. 6.5 pg/mL, 4.5–15; P

Background Meningitis caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. We evaluated the performance of cerebrospinal fluid (CSF) testing with the GeneXpert MTB/RIF assay versus traditional approaches for diagnosing tuberculosis meningitis (TBM). Methods Patients were adults (n = 37) presenting with suspected TBM to the Hospital Nacional Dos de Mayo, Lima, Peru, during 12 months until 1st January 2015. Each participant had a single CSF specimen that was divided into aliquots that were concurrently tested for M. tuberculosis using GeneXpert, Ziehl-Neelsen smear and culture on solid and liquid media. Drug susceptibility testing used Mycobacteria Growth Indicator Tube (MGIT 960) and the proportions method. Results 81% (30/37) of patients received a final clinical diagnosis of TBM, of whom 63% (19/30, 95% confidence intervals, CI: 44–80%) were HIV-positive. 22% (8/37, 95%CI: 9.8–38%), of patients had definite TBM. Because definite TBM was defined by positivity in any laboratory test, all laboratory tests had 100% specificity. Considering the 30 patients who had a clinical diagnosis of TBM: diagnostic sensitivity was 23% (7/30, 95%CI: 9.9–42%) for GeneXpert and was the same for all culture results combined; considerably greater than 7% (2/30, 95%CI: 0.82–22%) for microscopy; whereas all laboratory tests had poor negative predictive values (20–23%). Considering only the 8 patients with definite TBM: diagnostic sensitivity was 88% (7/8, 95%CI: 47–100%) for GeneXpert; 75% (6/8, 95%CI: 35–97%) for MGIT culture or LJ culture; 50% (4/8, 95%CI 16–84) for Ogawa culture and 25% (2/8, 95%CI: 3.2–65%) for microscopy. GeneXpert and microscopy provided same-day results, whereas culture took 20–56 days. GeneXpert provided same-day rifampicin-susceptibility results, whereas culture-based testing took 32–71 days. 38% (3/8, 95%CI: 8.5–76%) of patients with definite TBM with data had evidence of drug-resistant TB, but 73% (22/30) of all clinically diagnosed TBM (definite, probable, and possible TBM) had no drug-susceptibility results available. Conclusions Compared with traditional culture-based methods of CSF testing, GeneXpert had similar yield and faster results for both the detection of M. tuberculosis and drug-susceptibility testing. Including use of the GeneXpert has the capacity to improve the diagnosis of TBM cases.

The presence of a cavitary lesion is a radiographic hallmark of pulmonary tuberculosis (TB). The sizes of the cavitary lesion and its proximity to the bronchial tree have been associated with mycobacterial burden. However, the task of evaluating the size of a cavitary lesion is problematic due to differences in reporting methods (e.g., uni-dimensional maximum in the axial plane vs. bi-dimensional) and inter-observer variance. The evaluation of a cavitary lesion is often complicated by their irregular shape, thus the radiographic reporting of the lesion (e.g., spherical volume) might underestimate or overestimate its actual size. The problem with having several methods of reporting is that global communication becomes impaired, and results from different groups more difficult to compare. A computer-aided algorithm would help to diminish the inter-rater differences in reporting, and provide a more precise evaluation of the size of a lesion and its distance from the bronchial tree...

Hospital infection control measures are crucial to tuberculosis (TB) control strategies within settings caring for human immunodeficiency virus (HIV)-positive patients, as these patients are at heightened risk of developing TB. Pyrazinamide (PZA) is a potent drug that effectively sterilizes persistent Mycobacterium tuberculosis bacilli. However, PZA resistance associated with mutations in the nicotinamidase/pyrazinamidase coding gene, pncA, is increasing. A total of 794 patient isolates obtained from four sites in Lima, Peru, underwent spoligotyping and drug resistance testing. In one of these sites, the HIV unit of Hospital Dos de Mayo (HDM), an isolation ward for HIV/TB coinfected patients opened during the study as an infection control intervention: circulating genotypes and drug resistance pre- and postintervention were compared. All other sites cared for HIV-negative outpatients: genotypes and drug resistance rates from these sites were compared with those from HDM. HDM patients showed high concordance between multidrug resistance, PZA resistance according to the Wayne method, the two most common genotypes (spoligotype international type [SIT] 42 of the Latino American-Mediterranean (LAM)-9 clade and SIT 53 of the T1 clade), and the two most common pncA mutations (G145A and A403C). These associations were absent among community isolates. The infection control intervention was associated with 58-92% reductions in TB caused by SIT 42 or SIT 53 genotypes (odds ratio [OR] = 0.420, P = 0.003); multidrug-resistant TB (OR = 0.349, P < 0.001); and PZA-resistant TB (OR = 0.076, P < 0.001). In conclusion, pncA mutation typing, with resistance testing and spoligotyping, was useful in identifying a nosocomial TB outbreak and demonstrating its resolution after implementation of infection control measures.

Objetivos.Determinar el nivel de estigma relacionado a VIH/SIDA y su asociación con la adherencia al tratamientoantirretroviral (TARV) en pacientes de un hospital nacional de Lima, Perú. Materiales y métodos. Estudio transversal que incluyó a pacientes adultos que seguían el programa de TARV con un mínimo de seis meses. Se consideró el estigma como la desvalorización de la persona por tener la infección de VIH y se midió con la escala de Berger para estigma relacionado a VIH, la adherencia a la toma adecuada de los medicamentos fue medida con la encuesta Simplified medication adherence questionaire (SMAQ). Para evaluar los factores asociados a estigma se calcularon razones de prevalencia (RP) usando la regresión de Poisson. Resultados. Se analizaron 339 encuestas, la mediana de edad fue 39 años (RIC: 16) donde 74,0% eran hombres. Se halló un estigma alto en 25,4% y moderado en 47,5% de los encuestados. Una reducción de 10 puntos en la escala de estigma relacionado a VIH/SIDA se asoció a un aumento de 5% de adherencia al TARV en hombres (RPa 0,95, IC95%: 0,91-0,99) y un aumento del 7% en mujeres (RPa 0,93, IC95%: 0,87-0,98). Conclusiones. Existe un alto nivel de estigma relacionado a VIH/SIDA y se asocia a la falta de adherencia al tratamiento con diferencias de acuerdo al sexo. Se recomiendan intervenciones dirigidas a reducir el estigma relacionado a divulgación de estatus en las mujeres y el relacionado a actitudes públicas en hombres. Objectives. To determine the level of stigma related to HIV/AIDS and its association with adherence to antiretroviral therapy (HAART). Materials and methods. A cross-sectional study that included adult patients which were part of the HAART program during at least 6 months. Stigma was defined as the loss of value of the person infected with HIV according to Berger scale and treatment adherence as the correct consume of medications which were measured with the Simplified Medication Adherence Questionnaire. Poisson regression test was used to calculate the prevalence ratios (PR) of associated factors. Results. The results of 339 surveys were analyzed. 74% were male and the median age was 39 years (Interquartile Range [IQR]: 16). High stigma was found in 25,4% of respondents, moderate in 47,5%. A reduction of 10 points in the Berger scale was associated with an increase of 5% in adherence to HAART in men (adjusted PR [aPR]: 0.95; 95% confidence interval [CI]: 0.91-0.99), and 7% in women (aPR: 0.92; 95% CI: 0.87-0.98). Conclusions. There is a high level of stigma related to HIV/AIDS and is associated with the lack of adherence to HAART according to gender. We recommend interventions aimed at reducing stigma related to status disclosure in women and related to public attitudes in men.

We report the case of a male newborn, product of a 36 week pregnancy, with diagnosis of congenital pneumonia and with a confirmatory test for influenza A (H1N1) virus, without any other suspicious contact. The mother was admitted to the hospital with respiratory failure and the history of a flu-like episode of 5 days of evolution, during the first days of the pandemic in Peru. Due to the severe evolution of the respiratory process, assisted ventilation was given to her and then a cesarean section was performed due to acute fetal distress and oligoamnios. The mother was later confirmed as a case of epidemic influenza A (H1N1) and pulmonary tuberculosis.

Summary Objectives To describe the mycologic and clinical outcomes and factors associated with failure in Peruvian patients with AIDS-associated cryptococcal meningitis (CM) treated with amphotericin B deoxycholate (Amph B) followed by fluconazole. Methods Patients were treated with intravenous Amph B 0.7mg/kg/day for 2 or 3 weeks followed by oral fluconazole 400mg/day for 7 or 8 weeks. Clinical and laboratory evaluations including cerebrospinal fluid (CSF) studies were performed at baseline and at weeks 2 and 10. Results The CSF cultures were negative in 25% and 68% of 47 patients at weeks 2 and 10, respectively. In the univariate analysis, baseline low body mass index (BMI), hyponatremia, low serum albumin, positive blood culture and CSF antigen titers ≥1024 were associated with a positive CSF culture at week 2. Baseline positive urine culture, positive blood culture, any positive extraneural culture and CSF opening pressure at week 2 ≥300mm H2O were associated with a positive CSF culture at week 10. In the multivariate analysis no association was found. Conclusions Therapy with Amph B and fluconazole, combined with aggressive management of elevated intracranial pressure (ICP), results in low CSF sterilization rates at week 2 and acceptable CSF sterilization rates at week 10 when compared with other series.

We performed a cross-sectional study to determine the epidemiology of Cryptosporidium in human immunodeficiency virus (HIV)-infected persons at 3 diagnostic levels: microscopy, genotypes of Cryptosporidium, and subtype families of C. hominis and C. parvum. The study enrolled 2,490 HIV-infected persons in Lima, Peru, and 230 were microscopy positive for Cryptosporidium infection. Specimens from 193 participants were available for genotyping. They had C. hominis (141 persons), C. parvum (22 persons), C. meleagridis (17 persons), C. canis (6 persons), C. felis (6 persons), and C. suis (1 person) infection. Although microscopy results showed that Cryptosporidium infections were associated with diarrhea, only infections with C. canis, C. felis, and subtype family Id of C. hominis were associated with diarrhea, and infection with C. parvum was associated with chronic diarrhea and vomiting. These results demonstrate that different Cryptosporidium genotypes and subtype families are linked to different clinical manifestations.

The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics. Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, subsets of mycobacteria actively replicate during latent tuberculosis infection (LTBI), and recent studies suggest that LTBI is associated with persistent chronic inflammation that may lead to CVD. Recent epidemiologic work has shown that the risk of CVD in persons who develop tuberculosis is higher than in persons without a history of tuberculosis, even several years after recovery from tuberculosis. Together, these data suggest that tuberculosis may play a role in the pathogenesis of CVD. Further research to investigate a potential link between tuberculosis and CVD is warranted.

OBJECTIVE Inflammatory biomarkers associated with cardiovascular disease are elevated in HIV-infected persons. These biomarkers improve with antiretroviral therapy (ART) but do not normalize to values observed in HIV-uninfected adults. Little is known regarding biomarkers of inflammation in HIV-infected Peruvians, in whom an increased burden of infectious diseases may exacerbate inflammation, and women, in whom sex difference may alter inflammation compared with men. METHODS Peruvians initiating first-line ART were enrolled in a prospective observational study. Individuals with suppression of HIV RNA plasma loads to less than 30 copies/ml when determined quarterly over 24 months of ART, had biomarkers of inflammation and cellular activation measured pre-ART and at 24-months of ART, and evaluated for associations with sex and clinical parameters. RESULTS Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0 mg/l) more frequently compared with women (P = 0.02); most women's values were in the low/average-risk categories. At 24 months of suppressive ART, hsCRP concentrations decreased in men (P = 0.03), but tended to increase in women, such that the proportion with high-risk hsCRP did not differ by sex. Pre-ART, soluble CD163 concentrations were higher in women compared with men (P = 0.02), and remained higher after 24 months of suppressive ART (P = 0.02). All other inflammatory biomarkers (P

Tuberculosis causes an enormous burden of morbidity and mortality worldwide [1]. Increasing rates of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis pose a serious threat to ongoing efforts in controlling the epidemic, particularly in low- and middle-income countries [2]. Screening all comers able to provide a sputum sample increased TB detection in an emergency department in Peru

The effects of HIV co-infection and multi-drug resistant tuberculosis (MDRTB) on tuberculosis prognosis are poorly defined. Therefore, we studied infectiousness and mortality of 287 tuberculosis patients treated with standard, directly observed, short-course therapy in the Peruvian community. During 6-17 months of treatment, 49 (18%) of patients died, of whom 48 (98%) had AIDS and 28 (57%) had MDRTB; 17/31 (55%) of MDRTB-patients with AIDS died within 2 months of diagnosis, before traditional susceptibility testing would have identified their MDRTB. Most non-MDRTB became smear- and culture-negative within 6 weeks of therapy, whereas most MDRTB remained sputum-culture-positive until death or treatment completion. HIV-negative patients with non-MDRTB had good outcomes. However, MDRTB was associated with prolonged infectiousness and HIV co-infection with early mortality, indicating a need for greater access to anti-retroviral therapy. Furthermore, early and rapid tuberculosis drug-susceptibility testing and infection control are required so that MDRTB can be appropriately treated early enough to reduce mortality and transmission.

Summary Aim: To determine efficacy and safety of intravenous micafungin vs. intravenous fluconazole in the treatment of oesophageal candidiasis. Methods: A total of 523 patients ≥16 years with documented oesophageal candidiasis were randomized (1:1) in this controlled, non-inferiority study to receive either micafungin (150 mg/day) or fluconazole (200 mg/day). Response was evaluated clinically and endoscopically. Post-treatment assessments were performed at 2 and 4 weeks after discontinuation of therapy. Results: Median duration of therapy was 14 days. For the primary end-point of endoscopic cure, treatment difference was −0.3% (micafungin 87.7%, fluconazole 88.0%). Documented persistent invasive disease at the end of therapy was reported in 2.7% and 3.9% of patients, respectively. Both 84.8% of micafungin and 88.7% of fluconazole patients remained recurrence free at 4-weeks post-treatment. The overall therapeutic response rate was 87.3% for micafungin and 87.2% for fluconazole. The incidence of drug-related adverse events was 27.7% for micafungin and 21.3% for fluconazole. Six (2.3%) micafungin- and two (0.8%) fluconazole-treated patients discontinued therapy; rash was the most common event leading to discontinuation. Conclusion: Intravenous micafungin (150 mg daily) is well tolerated and as efficacious as intravenous fluconazole (200 mg daily) in the primary treatment of oesophageal candidiasis, achieving high rates of clinical and endoscopic cure.

We conducted a phase 2, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)- gamma 1b in patients with acquired immunodeficiency syndrome and acute cryptococcal meningitis. Patients received 100 or 200 microg of rIFN- gamma 1b or placebo, thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin B, with or without flucytosine, followed by therapy with fluconazole. End points included conversion of cerebrospinal fluid fungal cultures from positive to negative at 2 weeks, resolution of symptoms, and survival. Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN- gamma 1b (100 microg) recipients, and 32% of rIFN- gamma 1b (200 microg) recipients. There was a trend toward improved combined mycologic and clinical success in rIFN- gamma 1b recipients (26% vs. 8%; P=.078). Therapy with rIFN- gamma 1b was well tolerated, and there was no apparent influence on serial CD4 cell counts and human immunodeficiency virus load measurements. Adjunctive therapy with rIFN- gamma 1b holds promise for patients with acute cryptococcal meningitis and warrants further study.

Cholera is a disease of poverty that remains prevalent in resource-limited countries. The abrupt emergence of an epidemic frequently takes communities and health systems by surprise. Spread is rapid and initial mortality high: delays in organizing an appropriate response, lack of health worker training, and high patient numbers contribute to high rates of complications and deaths.

Accidents caused by urticating or poisonous setae from lepidoptera caterpillars are known as erucism. These accidents are produced by accidental contact, especially in children, with bristles on the insect's body surface, connected to venom glands. Symptoms may be local or systemic, with deadly clinical presentations. The accident caused by Lonomia spp. caterpillars can trigger bleeding disorders, which is considered the most severe type of erucism. The case of a 5-year-old girl is reported. She was from the town of Villarondos, in the Peruvian Amazon, department of Huanuco, who accidentally knelt down on caterpillar bristles, and subsequently experienced hemolytic anemia, plateletopenia, and coagulation disorder. The diagnosis was made based on the medical history, clinical manifestation, laboratory examination results, and response to antilonomic serum. The clinical, laboratory, and therapeutic aspects of erucism due to Lonomia spp. are discussed.

Diarrhea and wasting are among the most debilitating and deadly manifestations of AIDS, yet only limited information is available regarding the etiology, clinical consequences, and immunologic effects of infection with diarrheal agents. Peruvian AIDS patients presenting with and without diarrhea were followed prospectively to examine the relations among diarrheal pathogens, clinical presentations, CD4 lymphocyte count, weight loss, and survival. Patients with chronic diarrhea had lower CD4 lymphocyte counts (P = .001) and lost more weight (P < .001). Weight loss and a decreased CD4 lymphocyte count were associated with increased mortality (P = .011 and P = .003, respectively). Mean CD4 lymphocyte count varied significantly by diarrheal agent. Clostridium difficile was the most prevalent pathogen and was associated with significantly increased mortality before and after adjustment for coinfection, length of follow-up, CD4 lymphocyte count, and weight loss (P = .006). C. difficile may be a more important and more prevalent etiologic agent in AIDS than previously recognized and may represent a preventable cause of death in patients with immunosuppression.

Background Institutional tuberculosis (TB) transmission is an important public health problem highlighted by the HIV/AIDS pandemic and the emergence of multidrug- and extensively drug-resistant TB. Effective TB infection control measures are urgently needed. We evaluated the efficacy of upper-room ultraviolet (UV) lights and negative air ionization for preventing airborne TB transmission using a guinea pig air-sampling model to measure the TB infectiousness of ward air. Methods and Findings For 535 consecutive days, exhaust air from an HIV-TB ward in Lima, Perú, was passed through three guinea pig air-sampling enclosures each housing approximately 150 guinea pigs, using a 2-d cycle. On UV-off days, ward air passed in parallel through a control animal enclosure and a similar enclosure containing negative ionizers. On UV-on days, UV lights and mixing fans were turned on in the ward, and a third animal enclosure alone received ward air. TB infection in guinea pigs was defined by monthly tuberculin skin tests. All guinea pigs underwent autopsy to test for TB disease, defined by characteristic autopsy changes or by the culture of Mycobacterium tuberculosis from organs. 35% (106/304) of guinea pigs in the control group developed TB infection, and this was reduced to 14% (43/303) by ionizers, and to 9.5% (29/307) by UV lights (both p < 0.0001 compared with the control group). TB disease was confirmed in 8.6% (26/304) of control group animals, and this was reduced to 4.3% (13/303) by ionizers, and to 3.6% (11/307) by UV lights (both p < 0.03 compared with the control group). Time-to-event analysis demonstrated that TB infection was prevented by ionizers (log-rank 27; p < 0.0001) and by UV lights (log-rank 46; p < 0.0001). Time-to-event analysis also demonstrated that TB disease was prevented by ionizers (log-rank 3.7; p = 0.055) and by UV lights (log-rank 5.4; p = 0.02). An alternative analysis using an airborne infection model demonstrated that ionizers prevented 60% of TB infection and 51% of TB disease, and that UV lights prevented 70% of TB infection and 54% of TB disease. In all analysis strategies, UV lights tended to be more protective than ionizers. Conclusions Upper-room UV lights and negative air ionization each prevented most airborne TB transmission detectable by guinea pig air sampling. Provided there is adequate mixing of room air, upper-room UV light is an effective, low-cost intervention for use in TB infection control in high-risk clinical settings., Using a guinea-pig detection model, Rod Escombe and colleagues find that upper-room UV lamps in hospital rooms can substantially reduce airborne transmission ofMycobacterium tuberculosis., Editors' Summary Background. Tuberculosis—a contagious infection, usually of the lungs—kills nearly 2 million people annually. It is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with tuberculosis cough or sneeze. Most people infected with M. tuberculosis do not become ill—their immune system contains the infection. However, the bacteria remain dormant within the body and can cause disease years later if immunity declines because of, for example, infection with human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). The symptoms of tuberculosis include a persistent cough, weight loss, and night sweats. Infection with M. tuberculosis is diagnosed using the tuberculin skin test. Tests for tuberculosis itself include chest X-rays and sputum cultures (in which bacteriologists try to grow M. tuberculosis from mucus brought up from the lungs by coughing). Tuberculosis can usually be cured by taking several powerful antibiotics daily for several months. Drug-resistant tuberculosis is much harder to cure, requiring multiple second-line antibiotics for up to two years or more. Tuberculosis transmission can be reduced by, for example, hospitalizing people with tuberculosis in isolation wards in which negative-pressure mechanical ventilation is used to reduce the concentration of infectious airborne droplets. Why Was This Study Done? After the development of antibiotics capable of killing M. tuberculosis in the mid 20th century, it seemed that tuberculosis would become a disease of the past. But in the mid 1980s, drug-resistant M. tuberculosis strains began to emerge, the HIV/AIDS epidemic took hold, and tuberculosis resurged to today's worrying levels. New ways of reducing tuberculosis transmission, particularly in health care settings and in resource-limited settings, are now urgently needed. The need for effective infection control measures is especially urgent in HIV care programs where highly susceptible individuals frequently mix with people with tuberculosis. In this study, the researchers use a guinea pig air-sampling model (which was first used in the 1950s to show that tuberculosis is an airborne infection) to investigate whether upper-room ultraviolet (UV) lights in patient rooms and negative air ionization can prevent airborne tuberculosis transmission. UV light kills M. tuberculosis; negative ionization gives airborne particles a charge that makes them stick to surfaces. What Did the Researchers Do and Find? The researchers exposed a group of control guinea pigs kept in a special air-sampling enclosure to untreated air from an HIV–TB ward in Lima (Perú). Another group of animals (the UV group) breathed air from the same ward, but only on the days that UV lights suspended near the ward's ceiling were turned on, together with mixing fans to mix up the room air. The “ionizer group” had a negative ionizer switched on in their enclosure when they were exposed to ward air (each group of animals was exposed to ward air every other day). The animals were tested monthly with the tuberculin skin test and all were examined for tuberculosis disease when they became infected with tuberculosis or at the end of the 535-day experiment. 35% of the control animals, 14% of the ionizer group animals, and 9.5% of the UV group animals developed M. tuberculosis infections. Tuberculosis disease was found in 8.6% of the control animals but in only 4.3% and 3.6% of the animals in the ionizer and UV groups, respectively. A “time-to-event analysis” also showed that UV lights and ionizers reduced tuberculosis infection and disease. Finally, an analysis of the data using an airborne infection model indicated that ionizers and UV lights prevented 60% and 70% of tuberculosis infections, respectively. What Do These Findings Mean? These findings indicate that upper-room UV lights, combined with adequate air mixing, or negative air ionization with special large-scale ionizers can prevent most airborne tuberculosis transmission to guinea pigs exposed to hospital room air. The effectiveness of these approaches in reducing tuberculosis transmission between people is likely to be similar, although remains to be tested. Nevertheless, this first study of the effect of upper-air UV light and of negative air ionization on airborne transmission in a clinical setting suggests that both approaches could be potentially important tuberculosis infection control measures. Furthermore, the UV light approach might provide a relatively low-cost intervention for possible use in waiting rooms and other overcrowded settings where patients with undiagnosed, untreated tuberculosis—individuals who tend to be highly infectious—are likely to come into contact with other susceptible patients, health care workers, and visitors. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000043. The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis, including multidrug-resistance tuberculosis, and on tuberculosis and HIV The US Centers for Disease Control and Prevention provide several fact sheets and other information resources about all aspects of tuberculosis, including Guidelines for preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 2005 (some information in Spanish is also available) The World Health Organization's 2008 report “Global Tuberculosis Control—Surveillance, Planning, Financing” provides a snapshot of the current state of the global tuberculosis epidemic and links to information about all aspects of tuberculosis and its control (in several languages) Tuberculosis Infection-Control in the Era of Expanding HIV Care and Treatment is another report from the World Health Organization HIVInsite provides detailed information about the combination of HIV infection and tuberculosis Avert, an international AIDS charity, also provides information about the interaction between HIV and tuberculosis GHD (Global Health Delivery) Online is an online resource dedicated to TB infection control, and is moderated by world experts

Background The current understanding of airborne tuberculosis (TB) transmission is based on classic 1950s studies in which guinea pigs were exposed to air from a tuberculosis ward. Recently we recreated this model in Lima, Perú, and in this paper we report the use of molecular fingerprinting to investigate patient infectiousness in the current era of HIV infection and multidrug-resistant (MDR) TB. Methods and Findings All air from a mechanically ventilated negative-pressure HIV-TB ward was exhausted over guinea pigs housed in an airborne transmission study facility on the roof. Animals had monthly tuberculin skin tests, and positive reactors were removed for autopsy and organ culture for M. tuberculosis. Temporal exposure patterns, drug susceptibility testing, and DNA fingerprinting of patient and animal TB strains defined infectious TB patients. Relative patient infectiousness was calculated using the Wells-Riley model of airborne infection. Over 505 study days there were 118 ward admissions of 97 HIV-positive pulmonary TB patients. Of 292 exposed guinea pigs, 144 had evidence of TB disease; a further 30 were tuberculin skin test positive only. There was marked variability in patient infectiousness; only 8.5% of 118 ward admissions by TB patients were shown by DNA fingerprinting to have caused 98% of the 125 characterised cases of secondary animal TB. 90% of TB transmission occurred from inadequately treated MDR TB patients. Three highly infectious MDR TB patients produced 226, 52, and 40 airborne infectious units (quanta) per hour. Conclusions A small number of inadequately treated MDR TB patients coinfected with HIV were responsible for almost all TB transmission, and some patients were highly infectious. This result highlights the importance of rapid TB drug-susceptibility testing to allow prompt initiation of effective treatment, and environmental control measures to reduce ongoing TB transmission in crowded health care settings. TB infection control must be prioritized in order to prevent health care facilities from disseminating the drug-resistant TB that they are attempting to treat., Using a guinea pig detection system above an HIV-tuberculosis ward, Rod Escombe and colleagues found that most transmitted tuberculosis originated from patients with inadequately treated multidrug-resistant tuberculosis., Editors' Summary Background. Every year, more than nine million people develop tuberculosis—a contagious infection usually of the lungs—and nearly two million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis. These bacteria are spread in airborne droplets when people with the disease cough or sneeze. Most people infected with M. tuberculosis never become ill—their immune system contains the infection. However, the bacteria remain dormant within the body and can cause tuberculosis years later if host immunity declines. The symptoms of tuberculosis include a persistent cough, weight loss, and night sweats. Diagnostic tests for the disease include chest X-rays, the tuberculin skin test, and sputum cultures (in which bacteriologists try to grow M. tuberculosis from mucus brought up from the lungs by coughing). Tuberculosis can usually be cured by taking several powerful antibiotics daily for several months. Why Was This Study Done? Scientists performed definitive experiments on airborne tuberculosis transmission in the 1950s by exposing guinea pigs to the air from a tuberculosis ward. They found that a minority of patients actually transmit tuberculosis, that the infectiousness of transmitters varies greatly, and that effective antibiotic treatment decreases infectiousness. Since the 1950s, however, multidrug-resistant (MDR) and more recently extensively drug-resistant (XDR) strains of M. tuberculosis have become widespread. Treatment of drug-resistant tuberculosis is much more difficult than normal tuberculosis, requiring even more antibiotics, and for long periods, up to 2 years and beyond. In addition, HIV (the virus that causes AIDS) has emerged. HIV weakens the immune system so HIV-positive people are much more likely to develop active tuberculosis (and to die from the disease, which also speeds the development of HIV/AIDS) than people with a healthy immune system. Have these changes altered tuberculosis transmission between people? The answer to this question might help to optimize the control of tuberculosis infection, particularly in hospitals. In this study, the researchers investigate current patterns of tuberculosis infectiousness among HIV-positive patients by recreating the 1950s guinea pig model for tuberculosis transmission in a hospital in Lima, Perú. What Did the Researchers Do and Find? The researchers passed all the air from an HIV–tuberculosis ward over guinea pigs housed in an animal facility on the hospital's roof. The guinea pigs were tested monthly with tuberculin skin tests, and tissues from positive animals were examined for infection with M. tuberculosis. Sputum was also collected daily from the patients on the ward. The researchers then used the timing of patient admissions and guinea pig infections, together with the drug susceptibility patterns and DNA fingerprints of the M. tuberculosis strains isolated from the animals and the patients, to identify which patients had infected which guinea pigs. Finally, they used a mathematical equation to calculate the relative infectiousness of each patient in airborne infectious units (“quanta”) per hour. During the 505 study days, although 97 HIV-positive patients with tuberculosis were admitted to the ward, just ten patients were responsible for virtually all the characterized cases of tuberculosis among the guinea pigs. Six of these patients had MDR tuberculosis that had been suboptimally treated. The average patient infectiousness over the entire study period was 8.2 quanta per hour—six times greater than the average infectiousness recorded in the 1950s. Finally, the three most infectious patients (all of whom had suboptimally treated MDR tuberculosis) produced 226, 52, and 40 quanta per hour. What Do These Findings Mean? These findings show that a few inadequately treated HIV-positive patients with MDR tuberculosis caused nearly all the tuberculosis transmission to guinea pigs during this study. They also show for the first time that tuberculosis infectiousness among HIV-positive patients is very variable. The increase in the average patient infectiousness in this study compared to that seen in the 1950s hints at the possibility that HIV infection might increase tuberculosis infectiousness. However, studies that directly compare the tuberculosis infectiousness of HIV-positive and HIV-negative patients are needed to test this possibility. More importantly, this study demonstrates the potentially high infectiousness of inadequately treated MDR TB patients and their importance in ongoing TB transmission. These findings suggest that rapid, routine testing of antibiotic susceptibility should improve tuberculosis control by ensuring that patients with MDR TB are identified and treated effectively and quickly. Finally, they re-emphasize the importance of implementing environmental control measures (for example, adequate natural or mechanical ventilation of tuberculosis wards, or crowded waiting rooms or emergency departments where tuberculosis patients may be found) to prevent airborne tuberculosis transmission in health-care facilities, particularly in areas where many patients are HIV positive and/or where MDR tuberculosis is common. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050188. The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis, including multidrug-resistance tuberculosis, and on tuberculosis and HIV The US Centers for Disease Control and Prevention provide several fact sheets and other information resources about all aspects of tuberculosis (in English and Spanish) The World Health Organization's 2008 report on global tuberculosis control—surveillance, planning, financing provides a snapshot of the current state of the global tuberculosis epidemic and links to information about all aspects of tuberculosis and its control (in several languages) HIVInsite provides detailed information about coinfection with HIV and tuberculosis • Avert, an international AIDS charity, also provides information about the interaction between HIV and tuberculosis Tuberculosis Infection-Control in the Era of Expanding HIV Care and Treatment is a report from the World Health Organization

BACKGROUND: Institutional transmission of airborne infections such as tuberculosis (TB) is an important public health problem, especially in resource-limited settings where protective measures such as negative-pressure isolation rooms are difficult to implement. Natural ventilation may offer a low-cost alternative. Our objective was to investigate the rates, determinants, and effects of natural ventilation in health care settings. METHODS AND FINDINGS: The study was carried out in eight hospitals in Lima, Peru; five were hospitals of "old-fashioned" design built pre-1950, and three of "modern" design, built 1970-1990. In these hospitals 70 naturally ventilated clinical rooms where infectious patients are likely to be encountered were studied. These included respiratory isolation rooms, TB wards, respiratory wards, general medical wards, outpatient consulting rooms, waiting rooms, and emergency departments. These rooms were compared with 12 mechanically ventilated negative-pressure respiratory isolation rooms built post-2000. Ventilation was measured using a carbon dioxide tracer gas technique in 368 experiments. Architectural and environmental variables were measured. For each experiment, infection risk was estimated for TB exposure using the Wells-Riley model of airborne infection. We found that opening windows and doors provided median ventilation of 28 air changes/hour (ACH), more than double that of mechanically ventilated negative-pressure rooms ventilated at the 12 ACH recommended for high-risk areas, and 18 times that with windows and doors closed (p < 0.001). Facilities built more than 50 years ago, characterised by large windows and high ceilings, had greater ventilation than modern naturally ventilated rooms (40 versus 17 ACH; p < 0.001). Even within the lowest quartile of wind speeds, natural ventilation exceeded mechanical (p < 0.001). The Wells-Riley airborne infection model predicted that in mechanically ventilated rooms 39% of susceptible individuals would become infected following 24 h of exposure to untreated TB patients of infectiousness characterised in a well-documented outbreak. This infection rate compared with 33% in modern and 11% in pre-1950 naturally ventilated facilities with windows and doors open. CONCLUSIONS: Opening windows and doors maximises natural ventilation so that the risk of airborne contagion is much lower than with costly, maintenance-requiring mechanical ventilation systems. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection. Natural ventilation costs little and is maintenance free, and is particularly suited to limited-resource settings and tropical climates, where the burden of TB and institutional TB transmission is highest. In settings where respiratory isolation is difficult and climate permits, windows and doors should be opened to reduce the risk of airborne contagion.

There is a paucity of HIV autopsy data from South America and none that document the postmortem findings in patients with HIV/AIDS in Peru. The purpose of this autopsy study was to determine the spectrum of opportunistic infections and the causes of mortality in HIV-positive patients at a public hospital in Lima. Clinico-epidemiological information regarding HIV infection in Peru is also reviewed. Sixteen HIV-related hospital postmortems, performed between 1999 and 2004, were included in this retrospective analysis. The primary cause of death was established in 12 patients: one died of neoplasia and 11 of infectious diseases, including 3 from pulmonary infection, 7 from disseminated infection, and 2 from central nervous system infection (one case had dual pathology). Opportunistic infections were identified in 14 cases, comprising cytomegalovirus, histoplasmosis, cryptococcosis, toxoplasmosis, Pneumocystis pneumonia, aspergillosis, tuberculosis, varicella zoster virus, and cryptosporidiosis. Fourteen patients had at least one AIDS-related disease that had been neither clinically suspected nor diagnosed premortem. Moreover, 82% of the diagnoses considered to be of important clinical significance had not been suspected antemortem. The spectrum and frequency of certain opportunistic infections differed from other South American autopsy studies, highlighting the importance of performing HIV/AIDS postmortems in resource-limited countries where locally specific disease patterns may be observed.

Sputum induction, bronchoalveolar lavage, or gastric aspiration are often needed to produce adequate diagnostic respiratory samples from people with HIV in whom tuberculosis is suspected. Since these procedures are rarely appropriate in less-developed countries, we compared the performances of a simple string test and the gold-standard sputum induction. 160 HIV-positive adults under investigation for tuberculosis, and 52 asymptomatic HIV-positive control patients underwent the string test followed by sputum induction. The string test detected tuberculosis in 14 patients in whom this disease was suspected; sputum induction detected only eight of them (McNemar's test, p=0.03). These preliminary data suggest that the string test is safe and effective for retrieval of useful clinical specimens for diagnosis of pulmonary tuberculosis, and is at least as sensitive as sputum induction.

There is an urgent need for new tools to improve our ability to diagnose tuberculosis (TB) and multidrug-resistant TB (MDR-TB) in resource-poor settings. In a retrospective analysis undertaken in a region with a high incidence of TB, we evaluated the performance of the microscopic observation drug susceptibility assay (MODS), a novel assay developed in Perú which uses an inverted light microscope and culture in Middlebrook 7H9 broth to detect mycobacterial growth. MODS detected 94.0% of 1,908 positive sputum cultures, whereas Löwenstein-Jensen (LJ) culture detected only 86.9% ( P < 0.001). The median time to culture positivity was 8 days (compared to 16 days for the same 208 samples by LJ culture; P < 0.001, Wilcoxon signed rank test). The results obtained by direct susceptibility testing using MODS demonstrated excellent concordance for isoniazid and rifampin and the detection of multidrug resistance with those obtained by indirect colorimetric methods: the microplate Alamar Blue assay (MABA) and the tetrazolium microplate assay (TEMA) (agreement, 95, 98, and 94%; kappa values, 0.8, 0.7, and 0.7, respectively). The concordance of the susceptibility testing results for ethambutol and streptomycin was poor. MODS is a novel assay which can detect the organisms responsible for TB and MDR-TB directly from sputum inexpensively, rapidly, and effectively. A comprehensive prospective evaluation of MODS is under way in Perú, and independent validation in nonresearch laboratories should be undertaken at the earliest opportunity.

During 1999 to 2000, we identified HIV-infected persons with new episodes of tuberculosis (TB) at 10 hospitals in Lima-Peru and a random sample of other Lima residents with TB. Multidrug-resistant (MDR)-TB was documented in 35 (43%) of 81 HIV-positive patients and 38 (3.9%)of 965 patients who were HIV-negative or of unknown HIV status (p < 0.001). HIV-positive patients with MDR-TB were concentrated at three hospitals that treat the greatest numbers of HIV-infected persons with TB. Of patients with TB, those with HIV infection differed from those without known HIV infection in having more frequent prior exposure to clinical services and more frequent previous TB therapy or prophylaxis. However, MDR-TB in HIV-infected patients was not associated with previous TB therapy or prophylaxis. MDR-TB is an ongoing problem in HIV-infected persons receiving care in public hospitals in Lima and Callao; they represent sentinel cases for a potentially larger epidemic of nosocomial MDR-TB.

To determine the prevalence of sexually transmitted diseases (STDs), we screened 107 human immunodeficiency virus-positive patients in Peru, where the virus is predominantly sexually transmitted. Patients had multiple risk factors for STDs, and 38% of women and 50% of men had at least 1 STD (gonorrhea, trichomoniasis, herpes simplex, anogenital warts, or syphilis seropositivity). No chlamydial infection was detected, even though infection rates in the general population are 5%-12%. Patients receiving trimethoprim-sulfamethoxazole (TMP-SMZ) for prophylaxis or treatment of respiratory infections were least likely to have cervicitis and/or urethritis (odds ratio, 0.37; 95% confidence interval, 0.15-0.89). Although not optimal treatment, administration of TMP-SMZ is effective against chlamydial infection. We speculate that the use of concomitant medications, such as TMP-SMZ, may be inadvertently preventing chlamydial infection in this population. Another finding was the presence of Trichomonas vaginalis in pharyngeal specimens of 3 men with histories of orogenital activity. This has not been previously reported and requires further study.