Late-presenting Plasmodium falciparum Malaria in a Non-Endemic Setting During COVID-19 Travel Restrictions.

We report a case of febrile Plasmodium falciparum malaria in a 36-year-old male patient occurring 14 years after immigration from and more than 12 months since a return visit to the endemic area. The critical need for awareness regarding late presentations of P. falciparum is discussed.

First-in-human assessment of safety and immunogenicity of low and high doses of Plasmodium falciparum malaria protein 013 (FMP013) administered intramuscularly with ALFQ adjuvant in healthy malaria-naïve adults.

The global burden of malaria remains substantial. Circumsporozoite protein (CSP) has been demonstrated to be an effective target antigen, however, improvements that offer more efficacious and more durable protection are still needed. In support of research and development of next-generation malaria vaccines, Walter Reed Army Institute of Research (WRAIR) has developed a CSP-based antigen (FMP013) and a novel adjuvant ALFQ (Army Liposome Formulation containing QS-21). We present a single center, open-label, dose-escalation Phase 1 clinical trial to evaluate the safety and immunogenicity of the FMP013/ALFQ malaria vaccine candidate. In this first-in-human evaluation of both the antigen and adjuvant, we enrolled ten subjects; five received 20 µg FMP013 / 0.5 mL ALFQ (Low dose group), and five received 40 µg FMP013 / 1.0 mL ALFQ (High dose group) on study days 1, 29, and 57. Adverse events and immune responses were assessed during the study period. The clinical safety profile was acceptable and there were no serious adverse events. Both groups exhibited robust humoral and cellular immunological responses, and compared favorably with historical responses reported for RTS,S/AS01. Based on a lower reactogenicity profile, the 20 µg FMP013 / 0.5 mL ALFQ (Low dose) was selected for follow-on efficacy testing by controlled human malaria infection (CHMI) with a separate cohort. Trial Registration:Clinicaltrials.gov Identifier NCT04268420 (Registered February 13, 2020).

Risk of Acute Kidney Injury in Combat-Injured Patients Associated With Concomitant Vancomycin and Extended-Spectrum ß-Lactam Antibiotic Use.

BACKGROUND: Multidrug-resistant infections complicating combat-related trauma necessitate the use of broad-spectrum antimicrobials. Recent literature posits an association between vancomycin (VANC) and piperacillin-tazobactam (VPT) combination therapy and acute kidney injury (AKI). We examined whether therapy with VPT was associated with an increased risk of AKI compared to VANC and other broad-spectrum ß-lactam antibiotics (VBL) following combat-related injuries. METHODS: Patients within the Trauma Infectious Disease Outcomes Study (TIDOS) who received ≥48 hours concomitant VPT or VBL started within 24 hours of each other were assessed. Exclusion criteria were receipt of renal replacement therapy and baseline creatinine >1.5 mg/dL. Acute kidney injury was defined by meeting any of the Risk, Injury, Failure, Loss, End Stage Renal Disease (RIFLE), AKIN, or VANC consensus guidelines criteria 3 to 7 days after therapy initiation. Variables significantly associated with AKI were used in inverse probability treatment weighting to perform univariate and subsequent logistic regression multivariate modeling to determine significant risk factors for AKI. RESULTS: Sixty-one patients who received VPT and 207 who received VBL were included. Both groups had a median age of 24 years and initial median creatinine of 0.7 mg/dL. The VBL patients were more likely to have sustained blast injuries (P = .001) and received nephrotoxic agents (amphotericin [P = .002] and aminoglycosides [P < .001]). In the VBL group, AKI incidence was 9.7% compared to 13.1% in the VPT group (P = .438). Multivariate analysis identified a relative risk of 1.727 (95% CI: 1.027-2.765) for AKI associated with VPT exposure. Acute kidney injury severity generally met RIFLE Risk criteria and was 1 day in duration. Only 1 patient had persistent renal dysfunction 30 days after therapy completion. CONCLUSION: In this young and previously healthy, severely ill combat-injured population, VPT was associated with nearly twice the risk of AKI compared to VBL. Nevertheless, AKI was of low severity, short duration, and had high rates of renal recovery.

Multi-Drug-Resistant Organisms in Burn Infections.

Background: Infection is the most frequent complication after severe burns and remains the predominant cause of death. Burn patients may require multiple courses of antibiotics, lengthy hospitalizations, and invasive procedures that place burn patients at especially high risk for infections with multi-drug-resistant organisms (MDROs). Methods: The published literature on MDROs in burn patients was reviewed to develop a strategy for managing these infections. Results: Within a burn unit meticulous infection prevention and control measures and effective antimicrobial stewardship can limit MDRO propagation and decrease the antibiotic pressure driving the selection of MDROs from less resistant strains. Several new antimicrobial agents have been developed offering potential therapeutic options, but familiarity with their benefits and limitations is required for safe utilization. Successful management of MDRO burn infections is supported by a multifactorial approach. Novel non-antibiotic therapeutics may help combat MDRO infections and outbreaks. Conclusions: Multi-drug-resistant organisms are being identified with increasing frequency in burn patients. Effective sensitivity testing is essential to identify MDROs and to direct appropriate antibiotic choices for patient treatment.

Fever of Unknown Origin in US Soldier: Telemedical Consultation Limitations in a Deployment to West Africa.

OBJECTIVE: Review the application of telemedicine support for managing a patient with possible sepsis, suspected malaria, and unusual musculoskeletal symptoms. Clinical Context: Regionally Aligned Forces (RAF) supporting US Army Africa/Southern European Task Force (USARAF/ SETAF) in the Africa Command area of responsibility. Care provided by a small Role I facility on the compound. Organic Medical Expertise: Five 68W combat medics (one is the patient); one SOCM trained 68W combat medic. No US provider present in country. Closest Medical Support: Organic battalion physician assistant (PA) located in the USA; USARAF PA located in Italy; French Role II located in bordering West African country; medical consultation sought via telephone, WhatsApp® (communication with French physician) or over unclassified, encrypted e-mail. Earliest Evacuation: Estimated at 12 to 24 hours with appropriate country clearances and approval to fly from three countries including French forces support approval.

Infectious complications of damage control orthopedics in war trauma.

BACKGROUND: War-trauma, especially due to blast injury, can be associated with long bone fracture. Immediate external fixation of fractures, followed by internal fixation when the patient is medically stabilized (damage control orthopedics [DCO]), is the U.S. Army policy for war-related fractures. Data on infectious outcomes when DCO is used for war-trauma fractures are scant. METHODS: A retrospective review of U.S. war-trauma patients from 2003 to 2007 with femoral or tibial fractures treated by DCO was conducted. Fisher's Exact and Mann-Whitney tests were used for comparisons. RESULTS: Fifty-eight soldiers were identified. Fifty-five were males with a median age of 26 years (19-54 years) and a median time to internal fixation by intramedually nailing of 9 days (4-414 days). Eighty-eight percent of fractures were open, and 57% were femoral fractures. The median duration of follow-up was 447 days (20-1,340 days). Fracture site infection occurred in 40% (23 of 58), with suspected osteomyelitis in 17% (10 of 58). Of infected nails, fracture union occurred in 70% and nail retention in 57%. Median time to infection after nail placement was 15 days (0-717 days) with 75% of infections occurring by day 113. Multiple bacterial pathogens including Acinetobacter baumannii and Staphylococcus spp. were causative organisms. Blast injuries occurred in 91% of infected versus 47% of uninfected (p = 0.005). There was no difference between infections occurring in femoral (61%) versus tibial (39%) (p = 0.620) location. CONCLUSIONS: Infection was associated with 40% of DCO-associated intramedullary nails. Blast injury was a predictor of infection. Despite infection, fracture union and nail retention rates were high, suggesting a good outcome.

Atypical Q fever in US soldiers.

Q fever is an emerging infectious disease among US soldiers serving in Iraq. Three patients have had atypical manifestations, including 2 patients with acute cholecystitis and 1 patient with acute respiratory distress syndrome. Providers must be aware of Q fever's signs and symptoms to avoid delays in treatment.

Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis.

Circulating murine monocytes comprise two largely exclusive subpopulations that are responsible for seeding normal tissues (Gr-1-/CCR2-/CX3CR1high) or responding to sites of inflammation (Gr-1+/CCR2+/CX3CR1lo). Gr-1+ monocytes are recruited to the site of infection during the early stages of immune response to the intracellular pathogen Toxoplasma gondii. A murine model of toxoplasmosis was thus used to examine the importance of Gr-1+ monocytes in the control of disseminated parasitic infection in vivo. The recruitment of Gr-1+ monocytes was intimately associated with the ability to suppress early parasite replication at the site of inoculation. Infection of CCR2-/- and MCP-1-/- mice with typically nonlethal, low doses of T. gondii resulted in the abrogated recruitment of Gr-1+ monocytes. The failure to recruit Gr-1+ monocytes resulted in greatly enhanced mortality despite the induction of normal Th1 cell responses leading to high levels of IL-12, TNF-alpha, and IFN-gamma. The profound susceptibility of CCR2-/- mice establishes Gr-1+ monocytes as necessary effector cells in the resistance to acute toxoplasmosis and suggests that the CCR2-dependent recruitment of Gr-1+ monocytes may be an important general mechanism for resistance to intracellular pathogens.

Food- and waterborne pathogens: you are (infected by) what you eat!

Coccidia are protozoan parasites responsible for disease worldwide. The orally transmissible stages of coccidia make them food- and waterborne threats. The occurrence of multiple, human-infectious coccidia with diverse life cycles suggests that alterations in host range are a frequent occurrence, and can underlie the rapid emergence of pathogens.

Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype.

Three clonal strain types (I, II, and III) of Toxoplasma gondii predominate worldwide. The outcome of infection in mice is highly dependent on the parasite genotype with type I strains being uniformly virulent, while types II and III are nonvirulent. Interactions with the innate immune response play a major role in determining the outcome of infection in the murine model. To identify key early differences in the innate immune response that contribute to pathogenesis, we examined the cytokine production of macrophages after in vitro infection with parasites of virulent type I and nonvirulent type II genotypes. Infection with type II strain parasites stimulated the production of proinflammatory cytokines, and particularly high levels of the Th1-polarizing cytokine, IL-12. Infection with type II strain parasites stimulated NF-kappaB nuclear translocation at early time points and led to the up-regulation of mRNA levels of IL-12 and other proinflammatory cytokines that was dependent on the myeloid differentiation factor 88 signaling pathway. Induction of IL-12 required active invasion by live parasites and was not blocked by infection with virulent type I strain parasites, arguing against an active inhibition of signaling. Our findings suggest that early induction of high levels of IL-12 by macrophages infected with type II strain parasites may contribute to more effective control.

Genetic approaches to studying virulence and pathogenesis in Toxoplasma gondii.

Toxoplasma gondii is a common protozoan parasite that causes disease in immunocompromised humans. Equipped with a wide array of experimental tools, T. gondii has rapidly developed as a model parasite for genetic studies. The population structure of T. gondii is highly clonal, consisting of three distinct lineages that differ dramatically in virulence. Acute virulence is probably mediated by the genetic differences that distinguish strain types. We have utilized a combination of genetic approaches to investigate the acute virulence of toxoplasmosis using the mouse model. These studies reveal the surprising finding that pathogenicity is due to the over-stimulation of normally protective immune responses. Classical genetic linkage mapping studies indicate that genes that mediate acute virulence are linked to chromosome VII in the parasite. To increase the resolution of genetic mapping studies, single-nucleotide polymorphisms are being developed based on an extensive database of expressed sequence tags (ESTs) from T. gondii. Separately, DNA microarray studies are being used to examine the expression of parasite and host genes during infection. Collectively, these approaches should improve current understanding of virulence and pathogenicity in toxoplasmosis.