Results of phase 2 randomized multi-center study to evaluate the safety and efficacy of infusion of memory T cells as adoptive therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and/or lymphopenia (RELEASE NCT04578210).

BACKGROUND AIMS: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. METHODS: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA- memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA- memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. RESULTS: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. CONCLUSIONS: Adoptive cell therapy with off-the-shelf CD45RA- memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. TRIAL REGISTRATION: NCT04578210.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

[Treatment and prevention of monkeypox]. / Tratamiento y prevención de la viruela del mono.

Monkeypox is a zoonosis that is spread mainly through direct contact with fluids and skin lesions of infected people with vesicles still active. Although the virus was isolated for the first time in 1958 and the first human case was identified in a child in 1970, in the Democratic Republic of the Congo, the disease has progressively increased its incidence in Africa reaching in May 2022 sustained transmission outside this continent. As it is a newly introduced virus in our health system, it is necessary to learn the epidemiological pattern in a different environment from that of traditionally endemic areas and to know the available antiviral treatments, as well as the prophylactic measures that could be considered, knowing that as a virus emerging in our regions, scientific evidence is still limited. There are antivirals that have been shown, in animal models, to effectively combat the disease with very good clinical tolerance. This disease has also forced us to review the characteristics of smallpox vaccines, because they have shown a protective effect against monkeypox. For this reason, it is important to have a document that compiles all the scientific information published in this regard.

Autochthonous Crimean-Congo Hemorrhagic Fever in Spain.

Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, viral, tickborne disease. In Europe, cases have been reported only in the southeastern part of the continent. We report two autochthonous cases in Spain. The index patient acquired the disease through a tick bite in the province of Ávila - 300 km away from the province of Cáceres, where viral RNA from ticks was amplified in 2010. The second patient was a nurse who became infected while caring for the index patient. Both were infected with the African 3 lineage of this virus. (Funded by Red de Investigación Cooperativa en Enfermedades Tropicales [RICET] and Efficient Response to Highly Dangerous and Emerging Pathogens at EU [European Union] Level [EMERGE].).

Broad Neutralizing Activity Against Ebolaviruses Lacking the Mucin-Like Domain in Convalescent Plasma Specimens From Patients With Ebola Virus Disease.

Background: In Ebola virus (EBOV) infection, the specific neutralizing activity of convalescent plasma against other members of the Ebolavirus genus has not been extensively analyzed. Methods: We measured the neutralizing activity in plasma from 3 survivors of the recent outbreak due to the Makona variant of EBOV and tested its neutralizing potency against other variants of EBOV (ie, Mayinga and Kikwit) and against Sudan virus (SUDV), Bundibugyo virus (BDBV), and Reston virus (RESTV), using a glycoprotein (GP)-pseudotyped lentiviral system both with full-length GP and in vitro-cleaved GP (GPCL). Results: Convalescent plasma specimens from survivors of EBOV infection showed low neutralizing activity against full-length GPs of SUDV, BDBV, RESTV, and EBOV variants Mayinga and Kikwit. However, broad and potent neutralizing activity was observed against the GPCL forms of SUDV, BDBV, and RESTV. Discussion: Removal of the mucin-like domain and glycan cap from the GP of members of the Ebolavirus genus presumably exposes conserved epitopes in or in the vicinity of the receptor binding site and internal fusion loop that are readily amenable to neutralization. These types of broad neutralizing antibodies could be induced by using immunogens mimicking GPCL.

Evidence for Previously Unidentified Sexual Transmission of Protozoan Parasites.

Knowing the mode of transmission of a disease can affect its control and prevention. Here, we identify 5 protozoan parasites with demonstrated presence in seminal fluid, only 1 of which has been identified as a sexually transmitted disease among humans.

Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms.

Ceftazidime-avibactam (CAZ-AVI) is a recently approved ß-lactam-ß-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used the Wilcoxon rank sum test and Fisher's exact test to compare patients by treatment outcome. The sample included 36 patients infected with CRE and two with CRPa. The most common infections were intra-abdominal. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was nonresistant in vitro Twenty-eight patients (73.7%, 95% confidence interval [CI], 56.9 to 86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died (P = 0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.

A Multinational, Preregistered Cohort Study of ß-Lactam/ß-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae.

The spread of extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether ß-lactam/ß-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.).

Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational pre-registered cohort study.

OBJECTIVES: Data about the efficacy of ertapenem for the treatment of bloodstream infections (BSI) due to ESBL-producing Enterobacteriaceae (ESBL-E) are limited. We compared the clinical efficacy of ertapenem and other carbapenems in monomicrobial BSI due to ESBL-E. METHODS: A multinational retrospective cohort study (INCREMENT project) was performed (ClinicalTrials.gov identifier: NCT01764490). Patients given monotherapy with ertapenem or other carbapenems were compared. Empirical and targeted therapies were analysed. Propensity scores were used to control for confounding; sensitivity analyses were performed in subgroups. The outcome variables were cure/improvement rate at day 14 and all-cause 30 day mortality. RESULTS: The empirical therapy cohort (ETC) and the targeted therapy cohort (TTC) included 195 and 509 patients, respectively. Cure/improvement rates were 90.6% with ertapenem and 75.5% with other carbapenems (P = 0.06) in the ETC and 89.8% and 82.6% (P = 0.02) in the TTC, respectively; 30 day mortality rates were 3.1% and 23.3% (P = 0.01) in the ETC and 9.3% and 17.1% (P = 0.01) in the TTC, respectively. Adjusted ORs (95% CI) for cure/improvement with empirical and targeted ertapenem were 1.87 (0.24-20.08; P = 0.58) and 1.04 (0.44-2.50; P = 0.92), respectively. For the propensity-matched cohorts it was 1.18 (0.43-3.29; P = 0.74). Regarding 30 day mortality, the adjusted HR (95% CI) for targeted ertapenem was 0.93 (0.43-2.03; P = 0.86) and for the propensity-matched cohorts it was 1.05 (0.46-2.44; P = 0.90). Sensitivity analyses were consistent except for patients with severe sepsis/septic shock, which showed a non-significant trend favouring other carbapenems. CONCLUSIONS: Ertapenem appears as effective as other carbapenems for empirical and targeted therapy of BSI due to ESBL-E, but further studies are needed for patients with severe sepsis/septic shock.

[Ebola virus disease: Update]. / Enfermedad por virus ebola: actualización.

The first known Ebola outbreak occurred in 1976. Since then, 24 limited outbreaks had been reported in Central Africa, but never affecting more than 425 persons. The current outbreak in Western Africa is the largest in history with 28,220 reported cases and 11,291 deaths. The magnitude of the epidemic has caused worldwide alarm. For the first time, evacuated patients were treated outside Africa, and secondary cases have occurred in Spain and the United States. Since the start of the current epidemic, our knowledge about the epidemiology, clinical picture, laboratory findings, and virology of Ebola virus disease has considerably expanded. For the first time, experimental treatment has been tried, and there have been spectacular advances in vaccine development. A review is presented of these advances in the knowledge of Ebola virus disease.

Uncoupling between core genome and virulome in extraintestinal pathogenic Escherichia coli.

Extraintestinal pathogenic Escherichia coli (ExPEC) are among the most frequently isolated bacterial pathogens in hospitals. They are considered opportunistic pathogens and are found mostly in urinary and bloodstream infections. They are genetically diverse, and many studies have sought associations between genotypes or virulence genes and infection site, severity, or outcome, with varied, often contradictory, results. To understand these difficulties, we have analyzed the diversity patterns in the core genomes and virulomes of more than 500 ExPEC isolates from 5 different collections. The core genome was analyzed using a multilocus sequence type-based single-nucleotide polymorphism (SNP) pyrosequencing approach, while the virulence gene content (the virulome) was studied by polymerase chain reaction detection of 25 representative genes. SNP typing showed a similar population structure in the different collections: half of the isolates belong to a few sequence types (5 to 8), while the other half is composed of a large diversity of sequence types that are found once or twice. Sampling analysis by rarefaction plots of SNP profiles showed saturation curves indicative of a limited diversity. Contrary to this, the virulome shows an extremely high diversity, with almost as many gene profiles as isolates, and linear, nonsaturating, rarefaction plots, even within sequence types. These data show that genetic exchange rates are very heterogeneous along the chromosome, being much higher in the virulome fraction of the genome than in the core genome.

Infections caused by OXA-48-producing Klebsiella pneumoniae in a tertiary hospital in Spain in the setting of a prolonged, hospital-wide outbreak.

OBJECTIVES: We describe clinical and microbiological features of infections caused by OXA-48-producing Klebsiella pneumoniae (O48KP) in the setting of a prolonged, hospital-wide outbreak detected in January 2011. METHODS: Clinical, demographic and microbiological data of patients with growth of O48KP in clinical specimens were collected until December 2011. PCR was used to detect carbapenemase and ß-lactamase genes. The genetic relationships were determined by automated repetitive-sequence-based PCR. RESULTS: Seventy-one patients with clinically guided cultures showing growth of O48KP were identified. Nine were considered to be colonizing rather than causing infection. The most frequent source of infection was the urinary tract (22/62), followed by surgical site infections (17/62). Blood cultures were positive in 23/62 patients. Many patients had significant comorbidity and prolonged hospital stays. In-hospital mortality among patients with O48KP infections was 43.5%. The MIC(90)s of ertapenem, imipenem and meropenem were >32, 16 and 16 mg/L, respectively. No single antimicrobial was active against all the isolates. The antibiotics most active against O48KP were amikacin (97.2% susceptible), colistin (90.1%), tigecycline (73%) and fosfomycin (66.2%). Although eight clones were identified, a predominant clone caused 73.2% of the infections. Multilocus sequence typing (MLST) of the predominant clone gave sequence type (ST) 405 and bla(TEM-1), bla(SHV-76), bla(CTX-M-15) and bla(OXA-1) genes and the insertion sequence IS1999 of the Tn1999 transposon were associated with bla(OXA-48) in this clone. CONCLUSIONS: To our knowledge, this is the largest reported series of infections caused by O48KP in the setting of a single-centre outbreak and provides further input on the clinical relevance of infections caused by O48KP and the difficulties associated with its detection and control.

How to assist clinicians in improving antimicrobial prescribing: tools and interventions provided by stewardship programs.

In the last decade, there has been an exponential increase in the microorganisms resistant to antimicrobials and a significant increase in the cost of these types of drugs. This phenomenon has increased interest in the development of interventions for counseling on and control of the use of antimicrobials, referred to as stewardship programs. In this article we review, from various points of view, the tools that have been developed with this purpose. First, we highlight the value of locally adapted guidelines and clinical pathways as an essential part of the operational process. Then we emphasize the importance of the relationship between microbiologists and clinicians for the accurate transmission of the information provided by blood cultures to make the most appropriate choice of antimicrobial for the patient's treatment. We also review the computerized tools that have facilitated the correct use of antimicrobials according to the controls established by the departments of pharmacy. Based on the previous tools, some programs based on "bedside recommendations" provided by multidisciplinary teams have been developed for optimizing the rational use of antimicrobials (PROA programs). Finally, we comment on the peculiarities of the programs targeting antifungals that have been developed in recent years.

A Comparison of the Efficacy of Treatment With Fidaxomicin Versus Vancomycin in Clostridioides difficile Infection.

Background Clostridioides difficile infection (CDI) is a major cause of diarrhea in hospitalized adult patients. This study aims to evaluate the clinical characteristics, clinical cure, recurrence and mortality in patients with CDI treated with either fidaxomicin or vancomycin. Methods A retrospective case-control study was conducted on patients with CDI treated with either fidaxomicin or vancomycin at a hospital from January 2019 to March 2022. Results We assessed 140 patients with CDI episodes, 70 patients treated with fidaxomicin and 70 with vancomycin. Seventy (50%) were male. Median age was 70 years old (IQR: 56-81). Fidaxomicin group had more recurrent CDI episodes within six months (59% vs 11%, p ≤ 0.001), more severity (43% vs 16%, p ≤ 0.001) and less treatment response (84% vs 100%, p ≤ 0.002) compared with vancomycin group. Recurrence and mortality rates in the follow-up period did not differ in both groups. Conclusions Our study found fidaxomicin treatment had worse outcomes due to restricted usage, potentially impacting its effectiveness in CDI. This finding is especially significant for patients with severe or recurrent CDI, as prescribing of the drug was limited until May 2022 in Spain with the lifting of this restriction, further research is necessary to better understand the potential benefits of fidaxomicin in treating CDI.

Treatment and prevention of monkeypox.

Monkeypox is a zoonosis that is spread mainly through direct contact with fluids and skin lesions of infected people with vesicles still active. Although the virus was isolated for the first time in 1958 and the first human case was identified in a child in 1970, in the Democratic Republic of the Congo, the disease has progressively increased its incidence in Africa reaching in May 2022 sustained transmission outside this continent. As it is a newly introduced virus in our health system, it is necessary to learn the epidemiological pattern in a different environment from that of traditionally endemic areas and to know the available antiviral treatments, as well as the prophylactic measures that could be considered, knowing that as a virus emerging in our regions, scientific evidence is still limited. There are antivirals that have been shown, in animal models, to effectively combat the disease with very good clinical tolerance. This disease has also forced us to review the characteristics of smallpox vaccines, because they have shown a protective effect against monkeypox. For this reason, it is important to have a document that compiles all the scientific information published in this regard.

Response to combined antiretroviral therapy according to gender and origin in a cohort of naïve HIV-infected patients: GESIDA-5808 study.

BACKGROUND: We analyzed differences in response to combined antiretroviral therapy (cART) according to sex and geographic origin in a retrospective comparative study of Spanish-born and immigrant patients initiating cART. METHODS: The primary endpoint was time to treatment failure (TTF), defined as virological failure, death, opportunistic infection, interruption of cART, or loss to follow-up. Late diagnosis was defined as a CD4+ cell count ≤ 200 cells/mm3 and/or AIDS at initiation of cART. Survival was analyzed using Kaplan-Meier analysis and Cox regression. RESULTS: We followed 1,090 patients, of whom 318 were women (45.6% immigrant women [IW]). At initiation of treatment, women had a higher CD4+ count than men (217 vs 190 cells/mm3), a lower viral load (4.7 vs 5 log), and fewer were late starters (49% vs 59%). The adjusted risk of TTF between women and men was not significantly different (hazard ratio [HR], 1.10; 95% CI, 0.79-1.53). TTF was shorter among IW than Spanish-born women (124 weeks [95% CI, 64-183] vs 151 [95% CI, 127-174]) and loss to follow-up was double that of Spanish-born women (25.5% vs 11.6%). CONCLUSIONS: Although response to cART was similar for both sexes, men started treatment later. IW were more frequently lost to follow-up and switched treatment. Measures to improve medical follow-up after initiation of cART should be promoted among this minority group.

[Monitoring activities and improvement in the use of antibiotics in Spanish hospitals: results of a national survey]. / Actividades de monitorización y mejora del uso de antibióticos en hospitales españoles: resultado de una encuesta nacional.

OBJECTIVES: To describe: 1) the main features of antimicrobial stewardship activities (ASA) in Spanish hospitals and 2) the perceptions of the Spanish Infectious Diseases (ID) community on ASA. METHODS: An online survey was designed and distributed through the e-mailing lists of several working groups of the Spanish Clinical Microbiology and Infectious Diseases Society. RESULTS: Between September 15 and November 23, 2009, surveys representing 78 hospitals were received. Most of the respondents were either ID physicians (30%) or microbiologists (29%), and 31/78 hospitals (40%) had ongoing ASA. These hospitals were concentrated in 4 of the 17 regions, particularly in Catalonia. Professionals belonging to 26/31 centres with ASA completed the survey. The most frequent principles of antibiotic (ABX) stewardship implemented in these programs were: 1) ABX streamlining (22/26) and 2) intravenous to oral switch (22/26) followed by 3) strategic monitoring of ABX (21/26). In 22/26 (86%) of the centres with ASA any physician could initially prescribe any of the antimicrobials included in the formulary. The most frequent activity carried out was ABX restriction, 69% (18/26) followed by conferences 61% (16/26) and therapeutic audit and feed-back 54% (14/26). When asked which antimicrobials that should be closely monitored, carbapenems were considered by all respondents in centres with ongoing ASA. CONCLUSIONS: 1) A minority (40%) of the surveyed hospitals in Spain has an ongoing ASA and large geographical variations were observed. 2) ASA were most commonly structured in the form of an integrated part-time multidisciplinary team of ID physicians and Pharmacists, and 3) Carbapenems were considered the ABX most required to be monitored.

COVID-19: Key Concepts for the Surgeon. / COVID-19: conceptos clave para el cirujano.

In view of the current pandemic by SARS-CoV-2 it deems essential to understand the key concepts about the infection: its epidemiological origin, presentation, clinical course, diagnosis and treatment (still experimental in many cases). The knowledge about the virus is still limited, but as the pandemic progresses and the physiopathology of the disease is understood, new evidence is being massively published. Surgical specialists are facing an unprecedented situation: they must collaborate in the ER or medical wards attending these patients, while still needing to make decisions about surgical patients with probable COVID-19. The present narrative review aims to summarize the most relevant aspects and synthetize concepts on COVID-19 for surgeons.

Absence of IgG antibodies among high-risk contacts of two confirmed cases of Crimean-Congo haemorrhagic fever in the autonomous region of Madrid (Spain).

Crimean-Congo haemorrhagic fever (CCHF) is a widely distributed tick-borne disease. In Spain, the disease has emerged as outbreak associated with high-risk exposures. Our goal was to evaluate the prevalence of antibodies against the CCHF virus (CCHFV) in high-risk contacts. A cross-sectional study was conducted. Three hundred eighty-six high-risk contacts were identified comprising family contacts and hospital workers who had attended the cases. Fifty-seven cases with closer exposure were selected. However, forty-nine cases participated in the study. IgG antibodies were detected by immunoenzymatic techniques. All determinations tested negative for anti-CCHFV IgG antibodies. Most of the responders were women (73.5%), and belong to the intensive care department (53.1%). In relation to other possible sources of exposures, 18.4% travelled to countries with CCHF transmission risk. No CCHF positivity was recorded among selected high-risk contacts. This highlights the importance of standard precautions which might have protected healthcare workers and care providers from CCHF infection.