IDCRP Trauma-Related Infection Research

The longest period of war for the USA was accompanied by unprecedented advances in combat casualty care. Few outside of the Military Health System fully appreciate how approaches to caring for combat casualties swiftly adapted and evolved with each lesson learned. In a recently published book detailing the transformation of combat casualty care during these wars,¹ Dr. Arthur Kellermann and CAPT (ret) Eric Elster (respective prior and current Deans of the School of Medicine, Uniformed Services University of the Health Sciences, USU) explain:

Typically, medical advances are made incrementally, through painstaking research. This was not feasible in Iraq and Afghanistan or in the skies between these distant lands and the United States. Moreover, few of the innovations were the product of top-down decision making. In every phase of the continuum of care – from the point of injury on the battlefield to rehabilitation and reintegration of wounded warriors into their communities – military innovators challenged existing dogma and pushed the envelope by rapidly devising, implementing, refining, and spreading new techniques and technologies throughout the force. They were able to succeed because the Military Health System was willing to learn from its failures and build on its successes. Through a mix of keen observation and the systematic collection and analysis of data (most notably, creation of the Joint Trauma System), military medicine continually improved.

Through these wide-ranging advancements in combat casualty care, including the development of the Joint Trauma System (JTS), the survivability of battlefield wounds increased, which resulted in a greater incidence of trauma-related infections, creating new challenges for clinicians caring for the wounded.^2,3 The prevention and management of these highly morbid infectious complications became a top priority for the Military Health System. Thus, the standardized collection of infection-related data from combat casualties was identified as an essential need and led to the establishment of the multicenter DoD—Veterans Affairs (VA) Trauma Infectious Disease Outcomes Study (TIDOS) through the USU Infectious Disease Clinical Research Program (IDCRP) and the development of the Infectious Disease Module designed to augment and supplement the JTS DoD Trauma Registry (DoDTR). This supplement highlights the development of this effort, contributions to the care of wounded personnel, and lessons to inform DoD’s response to future conflicts.

In the first article, myself and colleagues⁴ discuss the development and impact of the Infectious Disease Module of the JTS DoDTR with the goal of supporting process improvements and clinical research to mitigate overall deployment trauma, and specifically battlefield injury, infectious complications. The Infectious Disease Module, through the overall TIDOS project, evolved over the years to respond to emergent threats, such as invasive fungal wound infections (IFIs) among military service members sustaining improvised explosive device (IED) blast injuries while on foot patrol in Southern Afghanistan. In addition, the Infectious Disease Module served as a foundation to rapidly develop the DoD COVID-19 Case Registry during the pandemic.

Since inception, data collected through the TIDOS project have resulted in important research findings (Table I). In particular, TIDOS data have supported the development and refinement of JTS Clinical Practice Guidelines (CPGs) for combat trauma-related infection prevention and the management of IFIs, as discussed in this supplement.⁴ Benefits gained from use of evidence-based CPGs include less practice variation, improved antibiotic stewardship, and improved clinical outcomes. The threat of multidrug-resistant organisms associated with battlefield wound colonization and infections required the refinement of infection control practices and post-trauma antibiotic prophylaxis recommendations. Adherence to these recommendations was assessed through multiple TIDOS analyses with findings provided back to the JTS.

TABLE I.

IDCRP Trauma-Related Infection Research Findings and Accomplishments

Focal area	Select key findings and accomplishments
Extremity wound infections (EWIs)	Comprehensive 6-year studies of osteomyelitis risk factors with open fractures of tibia, femur, and upper extremities; high risk with fracture severity and amputations, substantial muscle damage, and extensive degloving7–9 Personnel with amputations as their most severe extremity injury had highest proportion of EWIs10 Assessment of antibiotic practice patterns in period surrounding EWI diagnosis date identified substantial variation with frequent receipt of multiple antibiotics11 Use of expanded Gram-negative coverage with open fractures did not have benefit with reducing osteomyelitis compared to use of cefazolin, supporting JTS CPG recommendations12
Invasive fungal wound infections (IFIs)	DoD IFI Outbreak Investigation (TIDOS led) provided recommendations for early diagnosis and surgical/medical management13 Findings from IFI Outbreak Investigation and subsequent TIDOS IFI analyses supported development and refinement of JTS CPG for the management of IFIs in war wounds14 Adverse impact of IFIs on wound healing confirmed (longer time to wound closure)15; pathogenicity of fungi of order Mucorales also confirmed (longer time to wound closure vs non-Mucorales fungi)16 Proposed trauma-related IFI definitions, which provide a framework to support clinical decision-making and reduce practice variation A panfungal polymerase chain reaction-based assay was 99% specific at identifying filamentious fungi in surgical pathology specimens, but not as sensitive (63%); sensitivity improved in specimens from sites with angioinvasion17
Combat wound microbiology	>8,300 isolates collected from surveillance swabs and clinical infection work-ups in TIDOS Microbiology Repository Collaborative network with DoD laboratories established to assess microbiology with a focus on MDR and virulent organisms18 Cefazolin use prior to isolate collection associated with risk of MDR Gram-negative colonization among trauma patients19 Doxycycline use as antimalarial prophylaxis not associated with increase in Staphylococcus aureus tetracycline resistance20 27% of patients with ≥1 infection had an infection with a MDR Gram-negative bacilli; 58% of these patients were colonized with a MDR Gram-negative bacilli prior to infection21 Enterococcus infections largely polymicrobial with ESKAPE pathogens being co-cultured from the majority of infections22 Gram-negative bacteria predominant among EWIs: 57% of monomicrobial EWIs and 86% of polymicrobial EWIs23
Long-term outcomes	Successful research collaboration between the DoD and the VA St. Louis Health Care System 38% of veterans in the TIDOS-VA cohort developed a trauma-related infection during follow-up24 28% of patients with tibia osteomyelitis during their hospitalization had a recurrence during follow-up25 21% of TIDOS-VA enrollees with genitourinary trauma developed an UTI (75% of UTI events diagnosed during follow-up)26
Miscellaneous	TIDOS analyses supported refinement of JTS CPG for the prevention of combat trauma-related infections27 Examination of patients who received blood products with/without TXA found no significant association with infections on mulitvariable analysis; high proportion of infections among TXA recipients likely attributed to greater injury severity28 Infections not restricted to combat trauma; 15% of personnel with deployment-related non-combat injuries had ≥1 infection29 Adherence to JTS CPG post-trauma prophylactic recommendations showed increased over 5-year period, particularly with reduction in use of expanded Gram-negative coverage with open fractures30 14% of personnel who underwent combat-related exploratory laparotomy developed an abdominal surgical site infection31 13% of patients who received vancomycin plus piperacillin-tazobactam developed acute kidney injury; however, severity was low and duration was short32

Abbreviations: CPG—clinical practice guideline; DoD—Department of Defense; JTS—Joint Trauma System; MDR—multidrug-resistant; TIDOS—Trauma Infectious Disease Outcomes Study; TXA—tranexamic acid; UTI—urinary tract infection; VA—Veterans Affairs; ESKAPE—Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.

Extremity and orthopedic injuries most commonly occurred among combat casualties and are associated with frequent infections incurring substantial morbidity. Petfield and colleagues⁵ discuss the findings of TIDOS and the IDCRP Trauma-Associated Osteomyelitis study related to battlefield extremity wound infections. Risk factors for developing infections among combat casualties with severe injuries (e.g., amputations and open fractures) were assessed, along with long-term outcomes and antibiotic practice patterns.

Following the surge of U.S. personnel into Southern Afghanistan, an outbreak of IFIs was reported among casualties injured by IED blast while on foot patrol. Rodriguez and colleagues⁶ discuss the TIDOS IFI outbreak investigation with the findings being utilized by the JTS to develop their first CPG on managing IFIs. Due to the high morbidity and mortality associated with IFIs, the disease has been the focus of several TIDOS analyses over the years, leading to greater understanding of epidemiology, risk factors, clinically relevant IFI classification, diagnostic approach, clinical mycology, and short- and long-term outcomes affecting the patient.

The multidrug-resistant organism threat assessment, coupled with approaches to clinical management, has been a major focus area for the TIDOS project. As a component of the TIDOS project, a real-time capture of microbiological isolates, both from infection control surveillance and from clinical infection workups, has secured a unique repository of wartime isolates. Mende and colleagues¹⁸ discuss the TIDOS Multidrug-Resistant and Virulent Organism Initiative and the many important takeaways on wound microbiology and clinical outcomes. The IDCRP TIDOS team partnered with a collaborative network of DoD laboratories (i.e., Brooke Army Medical Center Infectious Disease Laboratory, Walter Reed Army Institute of Research, Naval Medical Research Center, and U.S. Army Institute of Surgical Research) to further assess microbiology-related research questions and provide an ongoing resource for DoD product developers to mitigate future threats.

Infectious and non-infectious complications of severe combat trauma may occur long after the initial hospitalization, spanning both the periods of active duty service and into the veteran phase for the individual. To truly evaluate the continuum of care and long-term outcomes, an effective collaboration between DoD and VA is needed. Dr. McDonald and colleagues³³ discuss the collaborative approach that has been taken to achieve these goals both for TIDOS and for the IDCRP Trauma-Associated Osteomyelitis study.

As IDCRP research into battlefield-related infections continues to evolve, analyses will further refine aspects of preventive and treatment approaches with the goal of continued support of evidence-based recommendations for JTS CPGs on the treatment of combat-related infections (Table II). Future conflicts have added challenges beyond the experiences of Iraq and Afghanistan due to potential for peer–peer scenarios by potentially leading to a prolonged field care requirement. The examination of combat-related infection data can inform clinical decision making in future conflicts and support the mitigation of these high-consequence infections. Future directions for IDCRP combat trauma-related research include further evaluation of long-term consequences, re-assessment of the risk of infections and outcomes following surgical/medical care, examination of the relative impact of specific surgical and antimicrobial therapy on outcomes, assessment of the impact of prolonged field care on early-onset infections, and the development of clinical decision support tools for infection risk stratification (Table II). During a peacetime period, it is important to assess utilization, ease of use, timeliness, and specific critical data elements in the DoDTR and the Infectious Disease Module to assure future readiness to optimize and support a learning healthcare system responsive to changing contingencies. The functionality and capacity to rapidly impact clinical practice of the trauma registry would benefit from a more direct connection and upload from Military Health System electronic medical records to include blood bank data, as well as greater incorporation of outcome metrics related to post-trauma complications and therapeutic response. During wars, it is extraordinarily challenging from both a human subjects protection standpoint and logistics to conduct critically needed randomized controlled trials to provide best evidence for practice guidance. The development of “on-the-shelf” contingency protocol(s) that could be activated with future conflicts to conduct interventional trials is an approach that should be considered. In addition, a wartime serum/tissue repository, with appropriate regulatory approval and rules for use, would provide invaluable clinical material to support biomarker analysis for prognostic, diagnostic, and therapeutic monitoring. Lastly, collaborative approach to wartime wound infection surveillance with country partners can provide greater standardization and cross-platform application during future conflicts (Table II). The TIDOS project, now over 10 years and ongoing, has provided a means for greater understanding of the common and highly impactful consequences of infections complicating battlefield injuries during modern warfare plus evidence that informs approaches to the prevention and management of adverse outcomes of our military service members who are placed in harm’s way.

TABLE II.

Future Directions and Considerations in Combat Trauma-Related Infection Research

Future directions
	Evaluation of long-term consequences: incident diagnoses (not limited to infections), healthcare utilization, and costs Re-assessment of infection risk and outcomes following surgical/medical care, applying improved injury/wound and microbiologic classifications Relative impact of specific surgical and antimicrobial therapy on outcomes Prolonged field care and the impact on early onset infections, particularly high-consequence infections, such as IFIs and sepsis Clinical decision support tools for triage and diagnostic support downrange to risk stratify casualties based on likelihood of developing high-consequence infections to aid in prioritization of medevac, resuscitative care, and en-route care
Future considerations
	Next-generation DoDTR and ID module Direct connection to existing Military Health System electronic data to lessen abstraction requirement and increase critical data availability and timeliness Refine ID module to support near real-time infection/wound microbiology surveillance, combat-related infection syndrome surveillance, and priority outcome metrics to support accelerated generation of evidence to inform practice change and respond to emerging threats
	Contingency planning Best evidence to support wound infection prevention and treatment requires well-designed randomized controlled trials. Optimal to initiate during periods between wars in best comparable civilian trauma settings “On-the-shelf” contingency protocol(s) for future conflicts that could be used to conduct interventional trials during wartime with prioritized research questions addressing gaps Wartime serum/tissue repository framework with accompanying regulatory guidance to support development and deployment of biomarkers for prognostic, diagnostic, and therapeutic monitoring purposes Interoperable approaches to wartime wound infection surveillance developed through collaboration with ally country partners

Abbreviations: DoDTR—Department of Defense Trauma Registry; ID—infectious disease; IFI—invasive fungal wound infection.

CONFLICT OF INTEREST

None declared.

FUNDING

This work was conducted by the Infectious Disease Clinical Research Program, a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences, Department of Preventive Medicine and Biostatistics through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded by the National Institute of Allergy and Infectious Diseases, National Institute of Health [Inter-Agency Agreement Y1-AI-5072], the Defense Health Program, U.S. DoD, under award HU0001190002, the Department of the Navy under the Wounded, Ill, and Injured Program, and the Defense Medical Research and Development Program.