Publications by authors named "Maria Elvira Balcells"

16 Publications

  • Page 1 of 1

Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial.

PLoS Med 2021 03 3;18(3):e1003415. Epub 2021 Mar 3.

Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Background: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.

Methods And Findings: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.

Conclusions: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.

Trial Registration: NCT04375098.
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http://dx.doi.org/10.1371/journal.pmed.1003415DOI Listing
March 2021

Insights into neutralizing antibody responses in individuals exposed to SARS-CoV-2 in Chile.

Sci Adv 2021 02 12;7(7). Epub 2021 Feb 12.

SARS-CoV-2 Research Group, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.

Chile has one of the worst numbers worldwide in terms of SARS-CoV-2 positive cases and COVID-19-related deaths per million inhabitants; thus, characterization of neutralizing antibody (NAb) responses in the general population is critical to understanding of immunity at the local level. Given our inability to perform massive classical neutralization assays due to the scarce availability of BSL-3 facilities in the country, we developed and fully characterized an HIV-based SARS-CoV-2 pseudotype, which was used in a 96-well plate format to investigate NAb responses in samples from individuals exposed to SARS-CoV-2 or treated with convalescent plasma. We also identified samples with decreased or enhanced neutralization activity against the D614G spike variant compared with the wild type, indicating the relevance of this variant in host immunity. The data presented here represent the first insights into NAb responses in individuals from Chile, serving as a guide for future studies in the country.
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http://dx.doi.org/10.1126/sciadv.abe6855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880587PMC
February 2021

[Identification of mycobacteria species through mass spectrometry (MALDI-TOF)].

Rev Chilena Infectol 2020 Jun;37(3):252-256

Departamento de Laboratorios Clínicos, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Background: Mycobacterial diseases are very important both clinically and epidemiologically. Mycobacterium tuberculosis complex (MTBc) infections confer higher morbidity and mortality rate than non-tuberculous mycobacteria (NTM) infections. Traditional species identification techniques are based on phenotypic characteristics which take a long time by laborious processes and in occasions are no conclusive. Currently, most used techniques are based on molecular methods, which are accurate but are expensive and complex. Matrix Assisted Laser Desorption/Ionization Time-of-Flight mass spectrometry (MALDI-TOF MS) is a simple, cheap and fast identification method based on comparing protein spectra with a reference database.

Aim: To assess the performance of MALDI-TOF MS in the identification of MTBc and NTM, compared with molecular methods.

Methods: For that purpose, 28 isolates of 9 different species were analyzed through MALDI-TOF MS.

Results: 78.5% (22/28) of isolates were correctly identified, 100% (9/9) of rapidly growers NTM, 60% (9/15) of slow growing NTM and 100% (4/4) of MTBc. Every unidentified isolate (6/6) corresponded to M. avium/intracellulare complex.

Conclusion: MALDI-TOF MS is fast, simple and cheaper than molecular methods and also has adequate accuracy.
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http://dx.doi.org/10.4067/s0716-10182020000300252DOI Listing
June 2020

[The importance of the BCG vaccine in the prevention of childhood tuberculosis].

Rev Chil Pediatr 2019 12;90(6):579-580

Departamento de Enfermedades Infecciosas del Adulto, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile.

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http://dx.doi.org/10.32641/rchped.v90i6.1379DOI Listing
December 2019

Unraveling the Role of MicroRNAs in Mycobacterium tuberculosis Infection and Disease: Advances and Pitfalls.

Infect Immun 2020 02 20;88(3). Epub 2020 Feb 20.

Departamento de Enfermedades Infecciosas del Adulto, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Tuberculosis (TB) is an infectious disease of extremely high epidemiological burden worldwide that is easily acquired through the inhalation of infected respiratory droplets. The complex pathogenesis of this infection spans from subjects never developing this disease despite intense exposure, to others in which immune containment fails catastrophically and severe or disseminated forms of disease ensue. In recent decades, microRNAs (miRNAs) have gained increasing attention due to their role as gene silencers and because of their altered expression in diverse human diseases, including some infections. Recent research regarding miRNAs and TB has revealed that the expression profile for particular miRNAs clearly changes upon infection and also varies in the different stages of this disease. However, despite the growing number of studies-some of which have even proposed some miRNAs as potential biomarkers-methodological variations and key differences in relevant factors, such as sex and age, cell type analyzed, strain, and antimicrobial therapy status, strongly hinder the comparison of data. In this review, we summarize and discuss the literature and highlight the role of selected miRNAs that have specifically and more consistently been associated with infection, together with a discussion of the possible gene and immune regulation pathways involved.
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http://dx.doi.org/10.1128/IAI.00649-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035921PMC
February 2020

The lung microbiome, vitamin D, and the tuberculous granuloma: A balance triangle.

Microb Pathog 2019 Jun 3;131:158-163. Epub 2019 Apr 3.

Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA. Electronic address:

Mycobacterium tuberculosis (Mtb) has the extraordinary ability to persist for decades within granulomas in the human host. These histopathological structures involved in both protection and pathogenesis, are subject to various influences from the host systemically and through micro-niche environments. Despite the fact that vitamin D (VD) has a key role in macrophage activation and mycobacterial clearance in the early stages of Mtb infection, the overall role of VD in granuloma maintenance or functionality has been scarcely studied. VD deficiency has long time been known to influence on gut microbiota composition, and recent studies have shown that it can also impact on respiratory microbiome. The human microbiota plays an important role in pathogen colonization resistance, and it has been proposed to play a potential role in TB pathogenesis. In this article, we have reviewed current knowledge on the interaction between VD, the lung microbiome and TB, and propose mechanisms by which the tuberculous granuloma's outcome could be modulated by these two factors. The determinants of the final fate of lung granulomas are still unclear, and deciphering the underlying drivers of Mtb infection outcome within those structures is of critical importance.
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http://dx.doi.org/10.1016/j.micpath.2019.03.041DOI Listing
June 2019

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

Diagnostic performance of GM-CSF and IL-2 in response to long-term specific-antigen cell stimulation in patients with active and latent tuberculosis infection.

Tuberculosis (Edinb) 2018 09 13;112:110-119. Epub 2018 Aug 13.

Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago, Chile. Electronic address:

Background: A simple blood test for detecting active tuberculosis (TB) could be key to this epidemic containment, given that a large proportion of patients are unable to produce sputum for testing. Currently available interferon-γ release assays (IGRAs) are inadequate to diagnose active TB, with reported pooled sensitivity and specificity both under 81%.

Objective: To explore whether cytokines/chemokines other than interferon-γ in response to long-term cell stimulation could improve the ability to distinguish between different TB infection status.

Methods: We prospectively enrolled subjects with newly diagnosed pulmonary TB and their household contacts in Santiago. All contacts were tested with IGRA. Peripheral blood mononuclear cells were obtained and antigen-specific stimulated for 72 h before collecting their culture supernatants.

Results: Subjects with active TB displayed markedly low cytokines/chemokines secretion upon PBMC stimulation, with lower GM-CSF being the best differentiator from IGRA(+) contacts, with 71% (95% CI 53-85) sensitivity, 86% (95% CI 65-97) specificity and AUC = 0.79 (p = 0.0003). On the other hand, when compared to the uninfected IGRA(-) contacts, higher level of IL-2 secretion was the best indicator of active TB, with 73.5% (95% CI 56-87) sensitivity, 85% (95% CI 66-96) specificity and AUC = 0.79 (p = 0.0001). No single cytokine/chemokine released upon stimulation could accurately differentiate between active TB and all TB contacts grouped together.

Conclusion: GM-CSF and IL-2 provided the best yield to differentiate active TB from latent TB and from TB uninfected, respectively, with higher specificities than that reported for IGRAs. However, none of both resulted sensitive enough to be used as a stand-alone biomarker for active TB.
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http://dx.doi.org/10.1016/j.tube.2018.08.006DOI Listing
September 2018

Association of vitamin D deficiency, season of the year, and latent tuberculosis infection among household contacts.

PLoS One 2017 12;12(4):e0175400. Epub 2017 Apr 12.

Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Objectives: Vitamin D (VD) enhances the immune response against Mycobacterium tuberculosis in vitro, and VD deficiency has been described in patients with active tuberculosis (TB). However, the role of hypovitaminosis D in the pathogenesis of early TB infection acquisition is unclear. We aimed to evaluate the association of VD deficiency, season of the year, and latent TB infection in household contacts (HHC), given that this is a potentially modifiable condition often related to nutritional deficiencies and lack of sun exposure.

Methods: We prospectively enrolled new pulmonary TB cases (n = 107) and their HHC (n = 144) over a 2-year period in Santiago, Chile. We compared plasma 25-hydroxycholecalciferol (25OHD) levels and examined the influence of season, ethnic background, living conditions, and country of origin.

Results: Over 77% of TB cases and 62.6% of HHC had VD deficiency (<20 ng/ml). Median 25OHD concentration was significantly lower in TB cases than in HHC (11.7 vs. 18.2 ng/ml, p<0.0001). Migrants HHC had lower 25OHD levels than non-migrants (14.6 vs. 19.0 ng/ml, p = 0.026), and a trend towards a higher burden of latent TB infection (52.9% vs. 35.2%, p = 0.066). Multivariate analysis found VD deficiency in HHC was strongly associated with being sampled in winter/spring (adOR 25.68, 95%CI 7.35-89.7), corresponding to the seasons with lowest solar radiation exposure. Spring enrollment-compared with other seasons-was the chief risk factor for latent TB infection in HHC (adOR 3.14, 95%CI 1.28-7.69).

Conclusions: Hypovitaminosis D was highly prevalent in TB cases and also in HHC. A marked seasonality was found for both VD levels and latent TB in HHC, with winter being the season with lowest VD levels and spring the season with the highest risk of latent TB infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389794PMC
April 2017

In reply.

Int J Tuberc Lung Dis 2016 10;20(10):1416

Infectious Diseases Department, Pontificia Universidad Católica de Chile, Santiago, Chile.

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http://dx.doi.org/10.5588/ijtld.16.0459-2DOI Listing
October 2016

Microbiome Changes during Tuberculosis and Antituberculous Therapy.

Clin Microbiol Rev 2016 10 8;29(4):915-26. Epub 2016 Sep 8.

Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA

The critical role of commensal microbiota in the human body has been increasingly recognized, and our understanding of its implications in human health and disease has expanded rapidly. The lower respiratory tract contains diverse communities of microbes known as lung microbiota, which are present in healthy individuals and in individuals with respiratory diseases. The dysbiosis of the airway microbiota in pulmonary tuberculosis (TB) may play a role in the pathophysiological processes associated with TB disease. Recent studies of the lung microbiome have pointed out changes in lung microbial communities associated with TB and other lung diseases and have also begun to elucidate the profound effects that antituberculous drug therapy can have on the human lung microbiome composition. In this review, the potential role of the human microbiome in TB pathogenesis and the changes in the human microbiome with Mycobacterium tuberculosis infection and TB therapy are presented and discussed.
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http://dx.doi.org/10.1128/CMR.00096-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010754PMC
October 2016

A first insight on the population structure of Mycobacterium tuberculosis complex as studied by spoligotyping and MIRU-VNTRs in Santiago, Chile.

PLoS One 2015 11;10(2):e0118007. Epub 2015 Feb 11.

WHO Supranational TB Reference Laboratory, Institut Pasteur de la Guadeloupe, Abymes, Guadeloupe, France.

Tuberculosis (TB) remains a significant public health problem worldwide, but the ecology of the prevalent mycobacterial strains, and their transmission, can vary depending on country and region. Chile is a country with low incidence of TB, that has a geographically isolated location in relation to the rest of South American countries due to the Andes Mountains, but recent migration from neighboring countries has changed this situation. We aimed to assess the genotypic diversity of Mycobacterium tuberculosis complex (MTBC) strains in Santiago, Chile, and compare with reports from other Latin-American countries. We analyzed MTBC isolates from pulmonary tuberculosis cases collected between years 2008 and 2013 in Central Santiago, using two genotyping methods: spoligotyping and 12-loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTRs). Data obtained were analyzed and compared to the SITVIT2 database. Mean age of the patients was 47.5 years and 61% were male; 11.6% were migrants. Of 103 strains (1 isolate/patient) included, there were 56 distinct spoligotype patterns. Of these, 16 strains (15.5%) corresponded to orphan strains in the SITVIT2 database, not previously reported. Latin American and Mediterranean (LAM) (34%) and T (33%) lineages were the most prevalent strains, followed by Haarlem lineage (16.5%). Beijing family was scarcely represented with only two cases (1.9%), one of them isolated from a Peruvian migrant. The most frequent clustered spoligotypes were SIT33/LAM3 (10.7%), SIT53/T1 (8.7%), SIT50/H3 (7.8%), and SIT37/T3 (6.8%). We conclude that LAM and T genotypes are the most prevalent genotypes of MTBC in Santiago, Chile, and together correspond to almost two thirds of analyzed strains, which is similar to strain distribution reported from other countries of Latin America. Nevertheless, the high proportion of SIT37/T3, which was rarely found in other Latin American countries, may underline a specific history or demographics of Chile related to probable human migrations and evolutions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118007PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324903PMC
January 2016

A comparative study of two different methods for the detection of latent tuberculosis in HIV-positive individuals in Chile.

Int J Infect Dis 2008 Nov 4;12(6):645-52. Epub 2008 Jun 4.

School of Medicine, Pontificia Universidad Católica de Chile, Lira 44, Santiago, Chile.

Objective: To compare the performance of two tests for diagnosing latent tuberculosis (TB) infection in the HIV-positive population in Chile, in order to better identify the subjects who might benefit from TB chemoprophylaxis.

Design: This was a cross-sectional study among individuals attending three HIV outpatient clinics in Santiago, tested with a 2-TU purified protein derivative, QuantiFERON((R))-TB Gold 'in-tube' (QFT-G), and a chest X-ray.

Results: A total of 116 subjects were enrolled in the study, having a mean CD4 count of 393cells/microl (range 100-977). The tuberculin skin text (TST; 5mm cutoff) and QFT-G results were positive in 10.9% and 14.8% of the individuals, respectively, with moderate agreement between both tests (kappa=0.59). A history of both known TB exposure (odds ratio (OR) 3.46, 95% confidence interval (CI) 1.02-11.22) and past TB (OR 4.31, 95% CI 1.13-15.5) were associated with a positive QFT-G result. Only past TB was significantly associated with a positive TST result (OR 6.63, 95% CI 1.62-26.3). Among the subjects with TST<5mm, 8.2% were positive by QFT-G test. These individuals had a lower mean CD4 cell count than those detected positive by both tests (328cells/microl and 560cells/microl, respectively, p=0.03).

Conclusions: In this population of HIV-infected individuals, QFT-G and TST showed an acceptable level of agreement, although QFT-G appears less affected by more advanced immunosuppression.
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http://dx.doi.org/10.1016/j.ijid.2008.03.005DOI Listing
November 2008

Isoniazid preventive therapy and risk for resistant tuberculosis.

Emerg Infect Dis 2006 May;12(5):744-51

Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom.

In the context of tuberculosis (TB) resurgence, isoniazid preventive therapy (IPT) is increasingly promoted, but concerns about the risk for development of isoniazid-resistant tuberculosis may hinder its widespread implementation. We conducted a systematic review of data published since 1951 to assess the effect of primary IPT on the risk for isoniazid-resistant TB. Different definitions of isoniazid resistance were used, which affected summary effect estimates; we report the most consistent results. When all 13 studies (N = 18,095 persons in isoniazid groups and N = 17,985 persons in control groups) were combined, the summary relative risk for resistance was 1.45 (95% confidence interval 0.85-2.47). Results were similar when studies of HIV-uninfected and HIV-infected persons were considered separately. Analyses were limited by small numbers and incomplete testing of isolates, but findings do not exclude an increased risk for isoniazid-resistant TB after IPT. The diagnosis of active TB should be excluded before IPT. Continued surveillance for isoniazid resistance is essential.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374455PMC
http://dx.doi.org/10.3201/eid1205.050681DOI Listing
May 2006