T-cell immune responses in patients with cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML)were studied during the active disease, at the end of therapy, and 1 to 17 years posttherapy (long-term follow-up). Lymphocyte proliferative responses, phenotypic characterization of CD4 ؉ and CD8 ؉ Leishmaniareactive T cells, and cytokine production were assayed. Patients with active ML and CL showed higher proportions of CD4 ؉ than CD8 ؉ T cells. In CL, the healing process was associated with a decrease of CD4؉ and an increase of CD8 ؉ , leading to similar CD4 ؉ and CD8 ؉ proportions. This pattern was only seen in ML after long-term therapy. Long-term follow-up of patients with CL showed a positive CD4؉ /CD8 ؉ ratio as observed during the active disease, although the percentages of these T cell subsets were significantly lower. Patients with CL did not show significant differences between gamma interferon (IFN-␥) and interleukin-5 (IL-5) production during the period of study. Patients with active ML presented higher IFN-␥ and IL-5 levels compared to patients with active CL. IL-4 was only detected during active disease. Patients long term after cure from ML showed increasing production of IFN-␥, significant decrease of IL-5, and no IL-4 production. Two apparently beneficial immunological parameters were detected in tegumentary leishmaniasis: (i) decreasing proportions of CD4 ؉ Leishmania-reactive T cells in the absence of IL-4 production associated with cure of CL and ML and (ii) decreasing levels of IL-5 long after cure, better detected in patients with ML. The observed T-cell responses maintained for a long period in healed patients could be relevant for immunoprotection against reinfection and used as a parameter for determining the prognosis of patients and selecting future vaccine preparations.
Background
The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates’ drugs. Nitazoxanide (NTZ) has a broad antiviral effect.
Methods
This was a randomized, double-blind pilot clinical trial comparing NTZ 600 mg BID versus Placebo for seven days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency from May 20
th
, 2020, to September 21
st
, 2020 (ClinicalTrials.gov NCT04348409). Clinical and virologic endpoints and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used.
Findings
Two patients died in the NTZ arm compared to 6 in the placebo arm (
p
= 0.564). NTZ was superior to placebo when considering SSD (
p
< 0001), the mean time for hospital discharge (6.6 vs. 14 days,
p
= 0.021), and negative PCR at day 21 (
p
= 0.035), whereas the placebo group presented more adverse events (
p
= 0.04). Among adverse events likely related to the study drug, 14 were detected in the NTZ group and 22 in placebo (
p
= 0.24). Among the 30 adverse events unlikely related, 21 occurred in the placebo group (
p
= 0.04). A decrease from baseline was higher in the NTZ group for
d
-Dimer (
p
= 0.001), US-RCP (
p
< 0.002), TNF (
p
< 0.038), IL-6 (
p
< 0.001), IL-8 (
p
= 0.014), HLA DR. on CD4
+
T
lymphocytes (
p
< 0.05), CD38 in CD4
+
and CD8
+
T
(both
p
< 0.05), and CD38 and HLA-DR. on CD4+ (
p
< 0.01)
Interpretation
Compared to placebo in clinical and virologic outcomes and improvement of inflammatory outcomes, the superiority of NTZ warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms.
Giardia lamblia is a pathogen transmitted by water and food that causes infection worldwide. Giardia genotypes are classified into 8 assemblages (A-H). Assemblages A and B are detected in humans, but they are potentially zoonotic because they infect other mammalian hosts. Giardia in samples from 44 children was genotyped. Conserved fragments of the genes encoding β-giardin and glutamate dehydrogenase were sequenced and their alignment were carried out with sequences deposited in GenBank. As expected for Rio de Janeiro, the majority of samples were related to assemblage A. Surprisingly, assemblage E was detected in 15 samples. Detection of assemblage E in humans suggests a new zoonotic route of Giardia transmission.
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