Prevalence of anti-lymphocyte IgM autoantibodies driving complement activation in COVID-19 patients.

Introduction: COVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have. Methods: We evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients' lymphocytes and examined its correlation with lymphocyte numbers during acute disease. Results: Compared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients' CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients. Discussion: IgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients.

Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients.

The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus may vary from asymptomatic to severe infection with multi-organ failure and death. Increased levels of circulating complement biomarkers have been implicated in COVID-19-related hyperinflammation and coagulopathy. We characterized systemic complement activation at a cellular level in 49-patients with COVID-19. We found increases of the classical complement sentinel C1q and the downstream C3 component on circulating blood monocytes from COVID-19 patients when compared to healthy controls (HCs). Interestingly, the cell surface-bound complement inhibitor CD55 was also upregulated in COVID-19 patient monocytes in comparison with HC cells. Monocyte membrane-bound C1q, C3 and CD55 levels were associated with plasma inflammatory markers such as CRP and serum amyloid A during acute infection. Membrane-bounds C1q and C3 remained elevated even after a short recovery period. These results highlight systemic monocyte-associated complement activation over a broad range of COVID-19 disease severities, with a compensatory upregulation of CD55. Further evaluation of complement and its interaction with myeloid cells at the membrane level could improve understanding of its role in COVID-19 pathogenesis.

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16- Monocytes From COVID-19 Patients.

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1ß secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.

Use of whole-genome sequencing to guide a Clostridioides difficile diagnostic stewardship program.

Whole-genome sequencing (WGS) has yielded new insights into the transmission patterns of healthcare facility-onset Clostridioides difficile infection (HO-CDI). WGS results prompted a focused diagnostic stewardship program, which was associated with a significant and sustained decrease in HO-CDI at large, urban hospital.

Unusual effects of common antibiotics.

Antibiotics are widely prescribed and have a generally favorable safety profile. Common adverse effects such as rash and diarrhea are well recognized, but less common ones may go unrecognized. This review highlights rare but potentially lethal complications associated with antibiotics.

Middle East respiratory syndrome: SARS redux?

Middle East respiratory syndrome (MERS) is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). Although predominantly affecting countries across the Arabian Peninsula, the infection has been exported by travelers to countries around the world, including the United States. The virus has caused several healthcare-related outbreaks, so prompt recognition and patient isolation are critical to containing the spread of infection. Healthcare providers are urged to stay current on the evolving outbreak, and to screen at-risk travelers for possible MERS.

Care of the aging HIV patient.

Thanks to antiretroviral therapy, human immunodeficiency virus (HIV) infection has become a controllable chronic disease, and many infected patients are now living into their 60s and beyond. In addition, many patients with newly diagnosed HIV infection are over age 50. The subsequent rising prevalence of HIV infection in older adults presents several challenges for primary care clinicians. This article promotes increased HIV screening in older adults and highlights the need to recognize polypharmacy and the various comorbidities inherent in the aging HIV population.

A case report and literature review of "Chiclero's ulcer".

An 86-year-old man with history of travel to Guatemala presented with a 4-month history of an enlarging ulcerative lesion on his right ear. After several weeks of empiric treatment for otitis externa, histopathology, culture, and PCR analysis of a biopsy specimen confirmed the diagnosis of localized cutaneous leishmaniasis secondary to Leishmania mexicana. Known as "Chiclero's ulcer" in southeast Mexico and Latin America, this unique presentation of cutaneous leishmaniasis is caused mainly by the L. mexicana complex. Infection results in a single ulcerative lesion, most commonly involving the ear pinna, without a tendency for cutaneous metastasis, lymphatic or mucosal involvement. The majority of cases of "Chiclero's ulcer" spontaneously re-epithelialize without treatment within 3-9 months. This patient's lesion completely resolved without therapy after 11 months. "Chiclero's ulcer" should be considered in the differential diagnosis of a patient presenting with a chronic ulcerative lesion and history of travel to an endemic area.

Invasive mold infections following combat-related injuries.

BACKGROUND: Major advances in combat casualty care have led to increased survival of patients with complex extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, complication following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity. METHODS: The patient population includes US military personnel injured during combat from June 2009 through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and pathologist review of histopathology specimens. RESULTS: A total of 37 cases were identified: proven (angioinvasion, n=20), probable (nonvascular tissue invasion, n=4), and possible (positive fungal culture without histopathological evidence, n=13). In the last quarter surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n=16; Aspergillus spp, n=16; Fusarium spp, n=9), commonly with multiple mold species among infected wounds (28%). Clinical outcomes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions (58%). CONCLUSIONS: IFIs are an emerging trauma-related infection leading to significant morbidity. Early identification, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending mycology results) among patients with suspicious wounds.

Invasive fungal infections following combat-related injury.

Invasive mold infections are a rare complication of traumatic wounds. We examined the incidence and outcomes of these infections in combat wounds. A retrospective chart review from March 2002 through July 2008 of U.S. soldiers returning from Iraq and Afghanistan with traumatic wounds was performed. A confirmed fungal wound infection was defined as growth of a known pathogenic mold and visualization of fungal elements on histopathology. Six cases were identified for an incidence of 0.4 cases/1,000 admissions. The incidence of invasive mold infections increased over time (p = 0.008) with a peak of 5.2 cases/1,000 admissions in 2007. Isolated molds included Aspergillus (n = 4), Bipolaris (n = 2), and 1 each Mucor and Absidia. All patients were male with a mean age of 22. Blast (n = 5) and gunshot wound (n = 1) were the sources of injury. All patients had fever (mean 39.4 degrees C) and leukocytosis (mean white blood cell count 25 x 10(3)/microL). The average acute physiology and chronic health evaluation II score was 22. All patients received antifungal agents, surgical debridement, and 3 required amputation revision. Average length of stay was 97 days. There were no deaths. Invasive mold infections are a rare complication of combat wounds but are associated with significant morbidity and may be increasing in frequency.

Executive summary: Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society.

Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat-related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight.

Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society.

Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat-related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications, and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight.

Prevention of infections associated with combat-related central nervous system injuries.

Combat-related injuries to the central nervous system (CNS) are of critical importance because of potential catastrophic outcomes. Although the overall infection rate of combat-related CNS injuries is between 5% and 10%, the development of an infectious complication is associated with a very high morbidity and mortality. This review focuses on the prevention of infections related to injuries to the brain or the spinal cord and provides evidence-based medicine recommendations from military and civilian data for the prevention of infection from combat-related CNS injuries. Prevention strategies emphasize the importance of expert evaluation and management by a neurosurgeon as expeditiously as possible. Areas of focus include elimination of cerebrospinal fluid leaks, wound coverage, postinjury antimicrobial therapy, irrigation, and debridement. Given that these recommendations are not supported by randomized control trials or adequate cohort studies in a military population, further efforts are needed to determine the best treatment strategies. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma.

High incidence of multidrug-resistant gram-negative bacteria recovered from Afghan patients at a deployed US military hospital.

OBJECTIVE: To investigate potential sources and risks associated with multidrug-resistant (MDR) bacteria in a deployed US military hospital. DESIGN: Retrospective analysis of factors associated with recovery of MDR bacteria, supplemented by environmental sampling. SETTING: The largest US military hospital in Afghanistan. PATIENTS: US and Afghan patients with positive bacterial culture results, from September 2007 through August 2008. METHODS: Microbiologic, demographic, and clinical data were analyzed. Potential risk factors included admission diagnosis or mechanism of injury, length of stay, gender, age, and nationality (US or Afghan). Environmental sampling of selected hospital high-touch surfaces and equipment was performed to help elucidate whether environmental MDR bacteria were contributing to nosocomial spread. RESULTS: A total of 266 patients had 411 bacterial isolates that were identified during the study period, including 211 MDR bacteria (51%). Gram-negative bacteria were common among Afghan patients (241 [76%] of 319), and 70% of these were classified as MDR. This included 58% of bacteria recovered from Afghan patients within 48 hours of hospital admission. The most common gram-negative bacteria were Escherichia coli (53% were MDR), Acinetobacter (90% were MDR), and Klebsiella (63% were MDR). Almost one-half of potential extended-spectrum ß-lactamase (ESBL) producers were community acquired. Of 100 environmental swab samples, 18 yielded MDR bacteria, including 10 that were Acinetobacter, but no potential ESBL-producing bacteria. CONCLUSIONS: Gram-negative bacteria from Afghan patients had high rates of antimicrobial resistance. Patients experiencing complex trauma and prolonged hospital stays likely contribute to the presence of MDR bacteria in this facility. However, many of these patients had community-acquired cases, which implies high rates of colonization prior to hospital admission.

Multidrug-resistant bacterial colonization of combat-injured personnel at admission to medical centers after evacuation from Afghanistan and Iraq.

BACKGROUND: Multidrug-resistant organism (MDRO) infections, including those secondary to Acinetobacter (ACB) and extended spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (Escherichia coli and Klebsiella species) have complicated the care of combat-injured personnel during Operations Iraqi Freedom and Enduring Freedom. Data suggest that the source of these bacterial infections includes nosocomial transmission in both deployed hospitals and receiving military medical centers (MEDCENs). Admission screening for MDRO colonization has been established to monitor this problem and effectiveness of responses to it. METHODS: Admission colonization screening of injured personnel began in 2003 at the three US-based MEDCENs receiving the majority of combat-injured personnel. This was extended to Landstuhl Regional Medical Center (LRMC; Germany) in 2005. Focused on ACB initially, screening was expanded to include all MDROs in 2009 with a standardized screening strategy at LRMC and US-based MEDCENs for patients evacuated from the combat zone. RESULTS: Eighteen thousand five hundred sixty of 21,272 patients admitted to the 4 MEDCENs in calendar years 2005 to 2009 were screened for MDRO colonization. Average admission ACB colonization rates at the US-based MEDCENs declined during this 5-year period from 21% (2005) to 4% (2009); as did rates at LRMC (7-1%). In the first year of screening for all MDROs, 6% (171 of 2,989) of patients were found colonized at admission, only 29% (50) with ACB. Fifty-seven percent of patients (98) were colonized with ESBL-producing E. coli and 11% (18) with ESBL-producing Klebsiella species. CONCLUSIONS: Although colonization with ACB declined during the past 5 years, there seems to be replacement of this pathogen with ESBL-producing Enterobacteriaceae.

Response to infection control challenges in the deployed setting: Operations Iraqi and Enduring Freedom.

BACKGROUND: Infections caused by multidrug-resistant organisms (MDROs), including Acinetobacter, have complicated the care of military personnel injured in Operations Iraqi and Enduring Freedom. Cumulative data suggest that nosocomial transmission of MDROs in deployed medical treatment facilities (MTFs) has contributed to these infections. A 2008 review of deployed MTFs identified multiple factors impeding the performance of infection prevention and control (IC) practices. In response, efforts to emphasize IC basics, improve expertise, and better track MDRO colonization were pursued. METHODS: Efforts to increase awareness and enhance IC in deployed MTFs were focused on educating leaders and deploying personnel, producing deployed IC resources, and standardizing level IV and V admission screening for MDRO colonization. A repeat mission in 2009 reviewed interval progress. RESULTS: Increased awareness and the need for emphasis on basic IC practice, including hand hygiene, use of transmission-based (isolation) precautions, and cohorting of patients, were imparted to leaders and deploying personnel through briefings, presentations, and an All Army Activities message. Enhancement of IC expertise was implemented through increased standardization of IC practice, establishment of a predeployment IC short course, an IC teleconsultation service, and dedicated Internet resources. Standardization of admission colonization screening of personnel evacuated from the combat theater was established to better define and respond to the MDRO problem. A repeat review of the deployed MTFs found overall improvement in IC practice, including clear command emphasis in the Iraqi theater of operations. CONCLUSIONS: Maintaining a strong IC effort in the deployed setting, even in a stabilized operational environment, is difficult. Use of innovative strategies to enhance expertise and practice were implemented to reduce MDRO infections.

Outcomes of highly active antiretroviral therapy in the context of universal access to healthcare: the U.S. Military HIV Natural History Study.

BACKGROUND: To examine the outcomes of highly-active antiretroviral therapy (HAART) for individuals with free access to healthcare, we evaluated 2327 patients in a cohort study composed of military personnel and beneficiaries with HIV infection who initiated HAART from 1996 to the end of 2007. METHODS: Outcomes analyzed were virologic suppression (VS) and failure (VF), CD4 count changes, AIDS and death. VF was defined as never suppressing or having at least one rebound event. Multivariate (MV) analyses stratified by the HAART initiation year (before or after 2000) were performed to identify risk factors associated with these outcomes. RESULTS: Among patients who started HAART after 2000, 81% had VS at 1 year (N = 1,759), 85% at 5 years (N = 1,061), and 82% at 8 years (N = 735). Five years post-HAART, the median CD4 increase was 247 cells/ml and 34% experienced VF. AIDS and mortality rates at 5 years were 2% and 0.3%, respectively. In a MV model adjusted for known risk factors associated with treatment response, being on active duty (versus retired) at HAART initiation was associated with a decreased risk of AIDS (HR = 0.6, 95% CI 0.4-1.0) and mortality (0.6, 0.3-0.9), an increased probability of CD4 increase ≥ 50% (1.2, 1.0-1.4), but was not significant for VF. CONCLUSIONS: In this observational cohort, VS rates approach those described in clinical trials. Initiating HAART on active duty was associated with even better outcomes. These findings support the notion that free access to healthcare likely improves the response to HAART thereby reducing HIV-related morbidity and mortality.

A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate for the treatment of cutaneous Leishmania major infection.

BACKGROUND: Cutaneous Leishmania major has affected many travelers including military personnel in Iraq and Afghanistan. Optimal treatment for this localized infection has not been defined, but interestingly the parasite is thermosensitive. METHODOLOGY/PRINCIPAL FINDINGS: Participants with parasitologically confirmed L. major infection were randomized to receive intravenous sodium stibogluconate (SSG) 20mg/kg/day for ten doses or localized ThermoMed (TM) device heat treatment (applied at 50 degrees C for 30 seconds) in one session. Those with facial lesions, infection with other species of Leishmania, or more than 20 lesions were excluded. Primary outcome was complete re-epithelialization or visual healing at two months without relapse over 12 months. Fifty-four/56 enrolled participants received intervention, 27 SSG and 27 TM. In an intent to treat analysis the per subject efficacy at two months with 12 months follow-up was 54% SSG and 48% TM (p = 0.78), and the per lesion efficacy was 59% SSG and 73% TM (p = 0.053). Reversible abdominal pain/pancreatitis, arthralgias, myalgias, headache, fatigue, mild cytopenias, and elevated transaminases were more commonly present in the SSG treated participants, whereas blistering, oozing, and erythema were more common in the TM arm. CONCLUSIONS/SIGNIFICANCE: Skin lesions due to L. major treated with heat delivered by the ThermoMed device healed at a similar rate and with less associated systemic toxicity than lesions treated with intravenous SSG. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT 00884377.