Imported Malaria in Countries where Malaria Is Not Endemic: a Comparison of Semi-immune and Nonimmune Travelers.

The continuous increase in long-distance travel and recent large migratory movements have changed the epidemiological characteristics of imported malaria in countries where malaria is not endemic (here termed non-malaria-endemic countries). While malaria was primarily imported to nonendemic countries by returning travelers, the proportion of immigrants from malaria-endemic regions and travelers visiting friends and relatives (VFRs) in malaria-endemic countries has continued to increase. VFRs and immigrants from malaria-endemic countries now make up the majority of malaria patients in many nonendemic countries. Importantly, this group is characterized by various degrees of semi-immunity to malaria, resulting from repeated exposure to infection and a gradual decline of protection as a result of prolonged residence in non-malaria-endemic regions. Most studies indicate an effect of naturally acquired immunity in VFRs, leading to differences in the parasitological features, clinical manifestation, and odds for severe malaria and clinical complications between immune VFRs and nonimmune returning travelers. There are no valid data indicating evidence for differing algorithms for chemoprophylaxis or antimalarial treatment in semi-immune versus nonimmune malaria patients. So far, no robust biomarkers exist that properly reflect anti-parasite or clinical immunity. Until they are found, researchers should rigorously stratify their study results using surrogate markers, such as duration of time spent outside a malaria-endemic country.

One and a half years into the COVID-19 pandemic - exit strategies and efficacy of SARS-CoV-2 vaccines for holistic management and achieving global control

One and a half years into the pandemic, SARS-CoV-2 is still here to stay. Whilst rapid several effective COVID-19 vaccines have been developed and are being rolled out, the critical questions remain whether vaccines provide widespread protection against infection and reinfection, and what the duration of protection is. Community wide control cannot be obtained until almost everyone is immune. Vaccine production must be ramped up to cover the world population. The price of herd immunity through natural infection is high mortality in the elderly and morbidity in other age groups including children and Long-COVID. We must expect a new wave in the coming winter. The severity will depend on the proportion of the population with immunity from natural infections or immunisation. Therefore, control rests on a population wide immunisation including children, which may or may not need to be repeated if new SARS-CoV-2 variants evolve that can escape immunity from either previous infections or immunisations. Preventing long term sequelae of COVID-19 also remains a priority.

Transmission of respiratory tract infections at mass gathering events.

PURPOSE OF REVIEW: Mass gathering events bring people from across all continents increasing the risk of spread of aerosol transmissible respiratory tract infections. Respiratory tract infections for instance in pilgrims attending the world's largest recurring annual pilgrimage, the Hajj are common. We review recent literature on viral and bacterial infectious diseases with special focus on the Hajj. RECENT FINDINGS: The prevalence of bacterial and viral infections continue to increase, because of the acquisition of rhinovirus, coronaviruses (229E, HKU1, OC43), influenza A H1N1, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus during Hajj. Whilst MERS-CoV continues to circulate in the Middle East, no cases of MERS-CoV have yet been identified in pilgrims during Hajj. SUMMARY: Respiratory tract infections are a major cause of morbidity in pilgrims attending mass gathering events. The management of severe respiratory infections should consider investigation and empirical coverage for the most likely agents based on syndromic surveillance data from hosting country and /or other relevant exposure history during events. Pneumococcal and Pertussis vaccines should be recommended for Hajj pilgrims.

SARS-CoV-2 epidemiology and control, different scenarios for Turkey

Background/aim: Coronavirus Infectious Disease 2019 (COVID-19) is now a pandemic spreading in most countries including Turkey. Materials and methods: The current knowledge of COVID-19 and the virus causing it, SARS-CoV-2, was reviewed. The epidemiology and control in different countries was compared and the differences discussed. Results: The population attack rates and case fatality rates vary from country to country with Lombardy in northern Italy reporting an attack rate in the general population of 0.37% compared to 0.004% in Hong Kong. The differences are caused by different testing strategies and reporting systems. Conclusion: Turkey is early in the outbreak. Different control strategies are available with South Korea, Hong Kong and Singapore being models to follow.

Genetic diversity of Plasmodium vivax metacaspase 1 and Plasmodium vivax multi-drug resistance 1 genes of field isolates from Mauritania, Sudan and Oman.

BACKGROUND: Plasmodium vivax is the second most important human malaria parasite, widely spread across the world. This parasite is associated with important issues in the process toward malaria elimination, including potential for relapse and increased resistance to chloroquine. Plasmodium vivax multi-drug resistant (pvmdr1) is suspected to be a marker of resistance although definitive evidence is lacking. Progress has been made in knowledge of biological factors affecting parasite growth, including mechanisms of regulated cell death and the suspected role of metacaspase. Plasmodium vivax metacaspase1 (PvMCA1-cd) has been described with a catalytic domain composed of histidine (H372) and cysteine (C428) residues. The aim of this study was to test for a link between the conserved histidine and cysteine residues in PvMCA1-cd, and the polymorphism of the P. vivax multi-drug resistant gene (pvmdr1). RESULTS: Thirty P. vivax isolates were collected from Mauritania, Sudan, and Oman. Among the 28 P. vivax isolates successfully sequenced, only 4 samples showed the conserved His (372)-Cys (428) residues in PvMCA1-cd. Single nucleotide polymorphisms observed were H372T (46.4%), H372D (39.3%), and C428R (85.7%). A new polymorphic catalytic domain was observed at His (282)-Cys (305) residues. Sequences alignment analysis of pvmdr1 showed SNP in the three codons 958, 976 and 1076. A single SNP was identified at the codon M958Y (60%), 2 SNPs were found at the position 976: Y976F (13%) and Y976V (57%), and 3 SNPs were identified at the position 1076: F1076L (40%), F1076T (53%) and F1076I (3%). Only one isolate was wildtype in all three codons (MYF), 27% were single MYL mutants, and 10% were double MFL mutants. Three new haplotypes were also identified: the triple mutant YVT was most prevalent (53.3%) distributed in the three countries, while triple YFL and YVI mutants (3%), were only found in samples from Sudan and Mauritania. CONCLUSIONS: Triple or quadruple mutants for metacaspase genes and double or triple mutants for Pvmdr1 were observed in 24/28 and 19/28 samples. There was no difference in the frequency of mutations between PvMCA1-cd and Pvmdr1 (P > 0.2). Histidine and cysteine residues in PvMCA1-cd are highly polymorphic and linkage disequilibrium with SNPs of Pvmdr1 gene may be expected from these three areas with different patterns of P. vivax transmission.

Imported Talaromycosis in Oman in Advanced HIV: A Diagnostic Challenge Outside the Endemic Areas.

A 37-year-old male living in Oman was seen by his physician with complaints of cough, body aches with bilateral lower limb weakness and on and off fever. He was diagnosed with HIV infection and culture from blood and bone marrow grew Talaromyces marneffei. He had travelled to Malaysia on several occasions. Treatment with liposomal amphotericin B resulted in complete cure. This case is reported for its rarity and unusual presentation to alert clinicians and microbiologists to consider T. marneffei as an etiology in high risk individuals. Our case is the first recorded diagnosis of T. marneffei in Oman.

Co-administration of interleukins 7 and 15 with DNA vaccine improves protective immunity against Toxoplasma gondii.

Toxoplasma gondii is an obligatory intracellular parasite, which can infect all warm-blooded animals including humans. Cytokines, including IL-15 and IL-7, play a critical role in the regulation of the homeostasis of naive and memory T cells. Co-administration the DNA vaccine with cytokines may improve its efficacy. IL-7 and IL-15 from splenic tissues of Kunming mice were cloned, and eukaryotic plasmid pVAX-IL-7-IL-15 was constructed. Kunming mice were administrated with DNA vaccine expressing T. gondii calcium-dependent protein kinase 1 (TgCDPK1), pVAX-CDPK1, in the presence or absence of IL-7 and IL-15 plasmids (pVAX-IL-7-IL-15), immune responses were analyzed including lymphoproliferative assay, cytokine and serum antibody measurements, flow cytometric surface markers on lymphocytes, and thus protective immunity against acute and chronic T. gondii infection was estimated. Mice injected with pVAX-CDPK1 supplemented with pVAX-IL-7-IL-15 showed higher Toxoplasma-specific IgG2a titers, Th1 responses associated with the production of IFN-γ, IL-2 as well as cell-mediated cytotoxic activity where stronger frequencies of IFN-γ secreting CD8+ and CD4+ T cells (CD8+/CD4+ IFN-γ+ T cells) compared to controls. Co-administration of pVAX-IL-7-IL-15 and pVAX-CDPK1 significantly (P < 0.05) increased survival time (18.07 ± 5.43 days) compared with pVAX-CDPK1 (14.13 ± 3.85 days) or pVAX-IL-7-IL-15 (11.73 ± 1.83 days) alone, and pVAX-IL-7-IL-15 + pVAX-CDPK1 significantly reduced the number of brain cysts (73.5%) in contrast to pVAX-CDPK1 (46.0%) or pVAX-IL-7-IL-15 alone (45.0%). Our results indicate that supplementation of DNA vaccine with IL-7 and IL-15 would facilitate specific humoral and cellular immune responses elicited by DNA vaccine against acute and chronic T. gondii infection in mice.

Immunogenicity of twenty peptides representing epitopes of the hepatitis B core and surface antigens by IFN-γ response in chronic and resolved HBV.

BACKGROUND: Patients with chronic hepatitis B virus infection (CHB) usually mount a modest T cell response against HBV epitopes. In order to determine immunogenic epitopes of HBV recognized by HBV-specific T cells, previous studies focused on previously confirmed HBV epitopes and assessed the T cell response by the number of HBV-specific T cells by IFN-γ ELISPOT. METHODS: We studied T cell functionality by combined in silico methods predicting HBV-specific epitopes and experimental investigations on the recognition of these epitopes. 30 chronic CHB patients and 10 patients with resolved HBV (RHB) were included in the study. We identified epitopes from the literature and by in silico analysis. These were evaluated for immunogenicity by use of synthetic peptides representing the epitopes through exposure to PBMCs from patients with CHB or RHB by IFN-γ ELISPOT. The number of IFN-γ producing cells (SFC), mean spot size (MSS) and stimulation index (SI) were recorded. RESULTS: The frequency of HBV-specific T cells producing IFN-γ after stimulation with HBV epitopes was similar in CHB and RHB patients. CHB patients had a higher MSS SI than RHB patients. Patients not carrying the HLA-A2 genotype had higher SFC SI and MSS SI. Patients with HLA-A11 had higher MSS SI compared to non- HLA-A11 allele patients. HBeAg-positive patients had a lower MSS SI, and none of the HBeAg positive patients had the HLA-A11 genotype. We found 3 immunogenic epitopes not described previously. CONCLUSION: IFN-γ ELISPOT-determined MSS is an efficient marker for T cell recognition of epitopes. This experimental measure showed the in silico analysis for epitope prediction to be a valuable tool in future studies on HLA genotypes and HBV epitopes. This way our study now points to previously unappreciated consequences of carrying the HLA-A11 allele in terms of stronger immunity to HBV.

Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community-acquired pneumonia.

When antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (Cmax) and area under the free drug concentration-time curve from 0 to 24 h (fAUC0-24) values predicted for each patient were evaluated against epidemiological cutoff MIC values for Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila. PK-PD targets adopted were a Cmax/MIC of ≥12.2 for all pathogens, an fAUC0-24/MIC of >34 for S. pneumoniae, and an fAUC0-24/MIC of >75 for H. influenzae and L. pneumophila. Individual predicted estimates for Cmax/MIC and fAUC0-24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable for S. pneumoniae and H. influenzae but not for L. pneumophila. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused by L. pneumophila. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.).

Clinical findings in a multi-ethnic adult hepatitis B virus patient population in Denmark with emphasis on genotypic characteristics.

OBJECTIVE: Most knowledge about chronic hepatitis B virus (HBV) infection is based upon studies in high-endemic areas with one or two predominant genotype(s). The aim of the study was to describe clinical characteristics of a heterogeneous genotypic HBV patient population in a low-endemic European country. METHODS: Data from HBV patients currently followed in a Danish university hospital and affiliated regional clinics were reviewed in accordance to genotype status. RESULTS: Of 540 HBV patients, 462 (86%) were of non-Danish ethnicity originating from 43 different countries. HBV genotype was known in 37% of the patients: A (11%), B (25%), C (25%), D (37%) and E (2%). Logistic regression analysis of pre-treatment data among genotype A-D patients receiving nucleos(t)ide analogue (NA) therapy revealed a decreased HBeAg rate by age (OR = 0.93; CI: 0.89-0.97; p < 0.01) and an increased rate in genotype C patients (OR = 20.5; CI: 3.3-129; p < 0.01). Among untreated patients HBeAg rate was also significantly decreased by age (OR = 0.90 (0.85:0.95; p < 0.0001), whereas the rate was increased in both genotype B and C patients (OR = 7.5; CI: 1.8-30.5; p < 0.01 and OR = 12.2; CI: 3.2-46.6; p < 0.001, respectively). No significant variation was found in HBV DNA level in any of the two groups when adjusting for age, gender, genotype and HBeAg. Increased liver pathology prevalence was, irrespectively of treatment status, associated to age and male gender, but not to any genotype. CONCLUSION: In this study population, genotype B and C was found associated with higher HBeAg rate but not with increased liver pathology.

Outpatient parenteral antimicrobial therapy (OPAT) in patients with cystic fibrosis.

BACKGROUND: To determine complications during outpatient parenteral antimicrobial therapy (OPAT) administrated through a peripheral venous line, PICC-line or PORT-A-CATH (PAC). METHODS: Catheter related complications in patients with cystic fibrosis during OPAT were identified through a retrospective review of patient files supplemented by an interview. RESULTS: In 64 treatment episodes with a peripheral venous line, 51 (79.7 %) used bolus injection and 13 (20.3 %) used infusion pump. 27 out of 51 (53.0 %) bolus injection episodes experienced complications, which required removal. None were observed for infusion pump treatments. The infectious complications requiring removal of peripheral venous line were 9 out of 23 (39.1 %) for the PICC line and 11 out of 26 (42.3 %) for the PAC. No anaphylaxis was observed during the OPAT treatments. CONCLUSIONS: Our data indicate that using an infusion pump to administer the antibiotic treatment minimized peripheral venous line complications. The frequency of complications leading to removal of the catheter is about the same for PICC-lines and PACs, but the average life-time of the latter is much longer. Allergic reactions are not a major problem.

Protective efficacy of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) adjuvated with recombinant IL-15 and IL-21 against experimental toxoplasmosis in mice.

BACKGROUND: Toxoplasma gondii can infect all warm-blooded animals including humans. Infection with T. gondii is probably the leading cause of posterior uveitis in humans and the most comment route of transmission is raw and undercooked meat from infected animals. T. gondii calcium-dependent protein kinase 1 (TgCDPK1) plays a critical role in direct parasite motility, host-cell invasion, and egress. METHODS: We constructed a DNA vaccine expressing TgCDPK1 inserted into eukaryotic expression vector pVAX I and evaluated the immune protection induced by pVAX-CDPK1 in Kunming mice. Mice immunized with pVAX-CDPK1 intramuscularly and/or with a plasmid encoding IL-15 and IL-21 (pVAX-IL-21-IL-15). The immune responses were analyzed including lymphoproliferative assay, cytokine, antibody measurements, lymphocyte surface markers by flow cytometry and protective efficacy were measured as survival and cysts numbers after challenge 1 to 2 months post vaccination. RESULTS: Immunization with pVAX-CDPK1 or pVAX-IL-21-IL-15 alone developed strong humoral responses and Th1 type cellular immune responses, and the significantly (P < 0.05) increase of both the percentages of CD4+ and CD8+ T cells compared with all the controls (blank control, PBS, and pVAX). Co-injection of pVAX-IL-21-IL-15 significantly increased humoral and cellular immune responses compared to the group of pVAX-CDPK1 or pVAX-IL-21-IL-15. Challenge experiments showed that co-administration of pVAX-IL-21-IL-15 and pVAX-CDPK1 significantly (P < 0.05) increased survival time (19.2 ± 5.1 days) compared with pVAX-CDPK1 (17.3 ± 4.3 days) or pVAX-IL-21-IL-15 (12.0 ± 2.0 days) alone, and pVAX-IL-21-IL-15 + pVAX-CDPK1 significantly reduced the number of brain cysts (72.7%) in contrast to pVAX-ROP13 (45.7%) or pVAX-IL-21-IL-15 alone (43.6%). CONCLUSIONS: TgCDPK1 is identified to be a promising vaccine candidate for inducing a strong humoral and cellular response against T. gondii infection, and thus synergistic of mIL-21 and mIL-15 can induce non-specific immune responses, but also facilitate specific humoral as well as cellular immune responses elicited by DNA vaccine against acute and chronic T. gondii infection in mice.

Toxoplasma gondii: protective immunity induced by rhoptry protein 9 (TgROP9) against acute toxoplasmosis.

Toxoplasma gondii rhoptry protein 9 (ROP9) is involved in the early stages of host invasion, and contains B cell epitopes. The aim of this study was to evaluate the immune protective efficacy of a DNA vaccine encoding TgROP9 gene against acute T. gondii infection in mice. A DNA vaccine (pVAX-ROP9) encoding TgROP9 inserted into eukaryotic expression vector pVAX I was constructed, and the efficacy of intramuscular vaccination of Kunming mice with pVAX-ROP9 was analyzed. Mice immunized with pVAX-ROP9 induced a high level of specific anti-T. gondii antibodies, as well as a mixed IgG1/IgG2a response with predominance of IgG2a production. Also, injection of pVAX-ROP9 induced a specific lymphocyte proliferative responses and Th1-type cellular immune response with production of IFN-γ and interleukin-2. The percentages of CD4+ and CD8+ T cells were significantly increased in mice immunized with pVAX-ROP9, compared to empty vector, PBS or blank controls. Immunization with pVAX-ROP9 significantly (P<0.05) prolonged survival time (12.9±2.9days) after challenge infection with the virulent T. gondii RH strain (Type I), compared with the control groups which died within 6days. DNA vaccination with pVAX-ROP9 triggered strong humoral and cellular responses, and induced effective protection in mice against acute T. gondii infection, indicating that TgROP9 is a promising vaccine candidate against acute toxoplasmosis.