Screening tools for predicting mortality of adults with suspected sepsis: an international sepsis cohort validation study.

OBJECTIVES: We evaluated the performance of commonly used sepsis screening tools across prospective sepsis cohorts in the USA, Cambodia and Ghana. DESIGN: Prospective cohort studies. SETTING AND PARTICIPANTS: From 2014 to 2021, participants with two or more SIRS (Systemic Inflammatory Response Syndrome) criteria and suspected infection were enrolled in emergency departments and medical wards at hospitals in Cambodia and Ghana and hospitalised participants with suspected infection were enrolled in the USA. Cox proportional hazards regression was performed, and Harrell's C-statistic calculated to determine 28-day mortality prediction performance of the quick Sequential Organ Failure Assessment (qSOFA) score ≥2, SIRS score ≥3, National Early Warning Score (NEWS) ≥5, Modified Early Warning Score (MEWS) ≥5 or Universal Vital Assessment (UVA) score ≥2. Screening tools were compared with baseline risk (age and sex) with the Wald test. RESULTS: The cohorts included 567 participants (42.9% women) including 187 participants from Kumasi, Ghana, 200 participants from Takeo, Cambodia and 180 participants from Durham, North Carolina in the USA. The pooled mortality was 16.4% at 28 days. The mortality prediction accuracy increased from baseline risk with the MEWS (C-statistic: 0.63, 95% CI 0.58 to 0.68; p=0.002), NEWS (C-statistic: 0.68; 95% CI 0.64 to 0.73; p<0.001), qSOFA (C-statistic: 0.70, 95% CI 0.64 to 0.75; p<0.001), UVA score (C-statistic: 0.73, 95% CI 0.69 to 0.78; p<0.001), but not with SIRS (0.60; 95% CI 0.54 to 0.65; p=0.13). Within individual cohorts, only the UVA score in Ghana performed better than baseline risk (C-statistic: 0.77; 95% CI 0.71 to 0.83; p<0.001). CONCLUSIONS: Among the cohorts, MEWS, NEWS, qSOFA and UVA scores performed better than baseline risk, largely driven by accuracy improvements in Ghana, while SIRS scores did not improve prognostication accuracy. Prognostication scores should be validated within the target population prior to clinical use.

A three-antigen Plasmodium falciparum DNA prime-Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults.

BACKGROUND: A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection. METHODOLOGY: This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method. RESULTS: In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection. CONCLUSIONS: This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.

Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.

Importance: Myocarditis has been reported with COVID-19 but is not clearly recognized as a possible adverse event following COVID-19 vaccination. Objective: To describe myocarditis presenting after COVID-19 vaccination within the Military Health System. Design, Setting, and Participants: This retrospective case series studied patients within the US Military Health System who experienced myocarditis after COVID-19 vaccination between January and April 2021. Patients who sought care for chest pain following COVID-19 vaccination and were subsequently diagnosed with clinical myocarditis were included. Exposure: Receipt of a messenger RNA (mRNA) COVID-19 vaccine between January 1 and April 30, 2021. Main Outcomes and Measures: Clinical diagnosis of myocarditis after COVID-19 vaccination in the absence of other identified causes. Results: A total of 23 male patients (22 currently serving in the military and 1 retiree; median [range] age, 25 [20-51] years) presented with acute onset of marked chest pain within 4 days after receipt of an mRNA COVID-19 vaccine. All military members were previously healthy with a high level of fitness. Seven received the BNT162b2-mRNA vaccine and 16 received the mRNA-1273 vaccine. A total of 20 patients had symptom onset following the second dose of an appropriately spaced 2-dose series. All patients had significantly elevated cardiac troponin levels. Among 8 patients who underwent cardiac magnetic resonance imaging within the acute phase of illness, all had findings consistent with the clinical diagnosis of myocarditis. Additional testing did not identify other etiologies for myocarditis, including acute COVID-19 and other infections, ischemic injury, or underlying autoimmune conditions. All patients received brief supportive care and were recovered or recovering at the time of this report. The military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period. While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose. Conclusions and Relevance: In this case series, myocarditis occurred in previously healthy military patients with similar clinical presentations following receipt of an mRNA COVID-19 vaccine. Further surveillance and evaluation of this adverse event following immunization is warranted. Potential for rare vaccine-related adverse events must be considered in the context of the well-established risk of morbidity, including cardiac injury, following COVID-19 infection.

Recovering Coronavirus Disease Patients in the Active Duty Military Population: A Review of Current Evidence and Special Considerations for Uniformed Providers.

Patients acutely infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease (COVID-19) may continue to have symptoms well beyond 2 weeks. The range of symptoms and physiological sequelae can impact medical readiness even in a relatively young and healthy cohort of service members. It is important to monitor, document, and investigate symptoms from all service members recovering from COVID-19. Military medicine must be prepared to support and manage cases of patients who are recovered from acute COVID-19 but are suffering from post-COVID-19 complications.

When upper respiratory tract infections go rogue: A case report of Arcanobacterium haemolyticum Cerebral Abscess.

Arcanobacterium haemolyticum is an extremely rare cause of cerebral abscess. We present a unique case of Arcanobacterium haemolyticum sinusitis complicated by preseptal cellulitis and cerebral abscess. The patient initially presented with pharyngitis and then developed sinus congestion, headache and facial pain. Computed tomography and magnetic resonance imaging revealed a right gyrus rectus cerebral abscess and paranasal sinus infection. The patient underwent endoscopic sinus surgery and cultures revealed Arcanobacterium haemolyticum. Repeat imaging revealed maturation and progression of intracranial abscess. The abscess was drained and patient was treated with parenteral and oral antibiotics until complete clinical and radiological remission. This case highlights the importance of recognizing Arcanobacterium haemolyticum as a cause of invasive disease in immunocompetent hosts.

Antimicrobial resistance (AMR) and molecular characterization of Neisseria gonorrhoeae in Ghana, 2012-2015.

Neisseria gonorrhoeae antimicrobial resistance (AMR) surveillance is essential for tracking the emergence and spread of AMR strains in local, national and international populations. This is crucial for developing or refining treatment guidelines. N. gonorrhoeae multiantigen sequence typing (NG-MAST) is beneficial for describing the molecular epidemiology of gonococci at national and international levels. Elucidation of AMR determinants to ß-lactam drugs, is a means of monitoring the development of resistance. In Ghana, little is known about the current gonococcal AMR prevalence and no characterization of gonococcal isolates has been previously performed. In this study, gonococcal isolates (n = 44) collected from five health facilities in Ghana from 2012 to 2015, were examined using AMR testing, NG-MAST and sequencing of penA. High rates of resistance were identified to tetracycline (100%), benzylpenicillin (90.9%), and ciprofloxacin (81.8%). One isolate had a high cefixime MIC (0.75 µg/ml). Twenty-eight NG-MAST sequence types (STs) were identified, seventeen of which were novel. The isolate with the high cefixime MIC contained a mosaic penA-34 allele and belonged to NG-MAST ST1407, an internationally spreading multidrug-resistant clone that has accounted for most cefixime resistance in many countries. In conclusion, AMR testing, NG-MAST, and sequencing of the AMR determinant penA, revealed high rates of resistance to tetracycline, benzylpenicillin, and ciprofloxacin; as well as a highly diverse population of N. gonorrhoeae in Ghana. It is imperative to continue with enhanced AMR surveillance and to understand the molecular epidemiology of gonococcal strains circulating in Ghana and other African countries.

Antigenicity and immune correlate assessment of seven Plasmodium falciparum antigens in a longitudinal infant cohort from northern Ghana.

The current global malaria control and elimination agenda requires development of additional effective disease intervention tools. Discovery and characterization of relevant parasite antigens is important for the development of new diagnostics and transmission monitoring tools and for subunit vaccine development. This study assessed the natural antibody response profile of seven novel Plasmodium falciparum pre-erythrocytic antigens and their potential association with protection against clinical malaria. Antigen-specific antibody levels in plasma collected at six time points from a longitudinal cohort of one-to-five year old children resident in a seasonal malaria transmission area of northern Ghana were assessed by ELISA. Antibody levels were compared between parasite-positive and parasite-negative individuals and the association of antibody levels with malaria risk assessed using a regression model. Plasma antibody levels against five of the seven antigens were significantly higher in parasite-positive children compared to parasite-negative children, especially during low transmission periods. None of the antigen-specific antibodies showed an association with protection against clinical malaria. The study identified five of the seven antigens as markers of exposure to malaria, and these will have relevance for the development of disease diagnostic and monitoring tools. The vaccine potential of these antigens requires further assessment.

Risk factors associated with gonorrhea and chlamydia transmission in selected health facilities in Ghana.

BACKGROUND: Understanding the underlying epidemiology that shapes Neisseria gonorrhoeae (GC), and Chlamydia trachomatis (CT) infections can contribute to data driven policies directed towards curbing the proliferation of these pathogens in Ghana. Information on the symptoms and risk factors for STIs will help to identify high-risk individuals which will in turn inform STI syndromic management and tailor the use of public health resources. METHODS: Participants were from 4 military clinics and 1 civilian STI clinic in Ghana and eligible if they had symptoms suggestive of STI. First void urine samples were collected and tested with Nucleic Acid Amplification Test (NAAT). A structured questionnaire was administered to all participants. Multivariate logistic regression identified factors associated with infection, separately for NG and for CT and for men and women. RESULTS: A total of 950 patients, 58% of whom were females were enrolled, 28% had gonorrhea and 11% had chlamydia with more males testing positive than females. Reported symptoms that were more common among patients who tested positive for gonorrhea were painful urination and urethral discharge (all P values < 0.05). Additionally, multiple sexual partners and alcohol use were statistically associated with higher rates of gonorrhea in males while only the frequency of condom use was associated with gonorrhea for females. None of the symptoms or risk factors except marital status was associated with testing positive for chlamydia. CONCLUSION: Identifying these symptoms and risk factors help inform health care delivery systems for STIs in Ghana. Furthermore, men and women presenting with these symptoms and risk factors are a prime target for public health education campaigns, aimed at curbing the spread of gonorrhea and chlamydia infections.

Prevalence and factors associated with asymptomatic gonococcal and chlamydial infection among US Navy and Marine Corps men infected with the HIV: a cohort study.

OBJECTIVES: Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) can facilitate transmission of HIV. Men who have sex with men (MSM) may harbour infections at genital and extragenital sites. Data regarding extragenital GC and CT infections in military populations are lacking. We examined the prevalence and factors associated with asymptomatic GC and CT infection among this category of HIV-infected military personnel. DESIGN: Cross-sectional cohort study (pilot). SETTING: Infectious diseases clinic at a single military treatment facility in San Diego, CA. PARTICIPANTS: Ninety-nine HIV-positive men were evaluated-79% men who had sex with men, mean age 31 years, 36% black and 33% married. INCLUSION CRITERIA: male, HIV-infected, Department of Defense beneficiary. EXCLUSION CRITERIA: any symptom related to the urethra, pharynx or rectum. PRIMARY OUTCOME MEASURES: GC and CT screening results. RESULTS: Twenty-four per cent were infected with either GC or CT. Rectal swabs were positive in 18% for CT and 3% for GC; pharynx swabs were positive in 8% for GC and 2% for CT. Only one infection was detected in the urine (GC). Anal sex (p=0.04), male partner (OR 7.02, p=0.04) and sex at least once weekly (OR 3.28, p=0.04) were associated with infection. Associated demographics included age <35 years (OR 6.27, p=0.02), non-Caucasian ethnicity (p=0.03), <3 years since HIV diagnosis (OR 2.75, p=0.04) and previous sexually transmitted infection (STI) (OR 5.10, p=0.001). CONCLUSIONS: We found a high prevalence of extragenital GC/CT infection among HIV-infected military men. Only one infection was detected in the urine, signalling the need for aggressive three-site screening of MSM. Clinicians should be aware of the high prevalence in order to enhance health through comprehensive STI screening practices.