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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Prevention and management 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 less than 5%, if an infection develops there is a very high associated morbidity and mortality. This review focuses on the management and prevention of infections related to injuries to the brain or the spinal cord. Management strategies emphasize the importance of expert evaluation and management by a neurosurgeon. This review provides evidence-based recommendations from military and civilian data to the management of combat-related CNS injuries. Areas of focus include bacteria cultures, antimicrobial therapy, irrigation and debridement, timing of surgical care, and wound coverage. Given these recommendations are not supported by randomized control trials or adequate cohorts studies in a military population, further efforts are needed to answer best treatment strategies.

Guidelines for the prevention of infection after combat-related injuries.

Management of combat-related trauma is derived from skills and data collected in past conflicts and civilian trauma, and from information and experience obtained during ongoing conflicts. The best methods to prevent infections associated with injuries observed in military combat are not fully established. Current methods to prevent infections in these types of injuries are derived primarily from controlled trials of elective surgery and civilian trauma as well as retrospective studies of civilian and military trauma interventions. The following guidelines integrate available evidence and expert opinion, from within and outside of the US military medical community, to provide guidance to US military health care providers (deployed and in permanent medical treatment facilities) in the diagnosis, treatment, and prevention of infections in those individuals wounded in combat. These guidelines may be applicable to noncombat traumatic injuries under certain circumstances. Early wound cleansing and surgical debridement, antibiotics, bony stabilization, and maintenance of infection control measures are the essential components to diminish or prevent these infections. Future research should be directed at ideal treatment strategies for prevention of combat-related injury infections, including investigation of unique infection control techniques, more rapid diagnostic strategies for infection, and better defining the role of antimicrobial agents, including the appropriate spectrum of activity and duration.

Operation Enduring Freedom: the 48th Combat Support Hospital in Afghanistan.

OBJECTIVE: To examine the experience of the 48th Combat Support Hospital (CSH) while deployed to Afghanistan, with an emphasis on trauma care. MATERIALS AND METHODS: Before redeployment, a retrospective review was performed on the medical records of all patients treated at the 48th CSH from December 6, 2002 through June 7, 2003. RESULTS: During the 6-month period, 10,679 patients were evaluated and/or treated. There were 477 hospital admissions (adults, 387; children, 90; trauma, 204) and 634 operating room procedures. The most common mechanisms of injury were land mines/unexploded ordinance (74 = 36%) and gunshot wounds (41 = 20%). Extremities were the most common site. A total of 358 cases was performed on 168 trauma patients (mean, 2 cases per patient; range, 1-12). There were 63 complications in 40 trauma patients and 11 patients died. CONCLUSIONS: The 48th CSH supported military and humanitarian operations with an ongoing process of re-evaluation, adaptation, and medical education that resulted in low morbidity and mortality rates.

Endoscopy in a deployed combat support hospital: maintaining military end-strength.

OBJECTIVE: The objective was to examine the safety and efficacy of the 48th Combat Support Hospital's use of diagnostic endoscopy in Afghanistan. METHODS: A retrospective review was performed on the medical records of all endoscopy patients treated at the 48th Combat Support Hospital in Bagram, Afghanistan, from December 6, 2002 through June 7, 2003. RESULTS: Twenty-four patients (male, 21; female, 3; mean age, 35 years) underwent 28 endoscopic procedures as follows: colonoscopy, 14; esophagogastroduodenoscopy (EGD), 13; and flexible sigmoidoscopy, 1. Four patients underwent both EGD and colonoscopy. There were no complications. Of the 18 U.S. military patients, 3 (15%) were evacuated for further evaluation and/or treatment and 1 (5%) patient underwent an elective screening colonoscopy. For 14 of 17 U.S. military personnel (82%), the endoscopic procedures obviated evacuation from Afghanistan. CONCLUSIONS: Diagnostic colonoscopy and EGD were valuable and safe adjuncts that precluded evacuations out of theater for 82% of military patients. Endoscopy should be used when U.S. military operations necessitate the deployment of large numbers of forces for protracted periods.

A case of Enterococcus faecalis prosthetic joint infection: a rare and difficult infection to treat.

Enterococcus faecalis septic arthritis in native and prosthetic joints is a very rare infection. A case of an African American man with Enterococcus faecalis prosthetic joint infection is presented as well as a brief review of the literature.

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.