Invasive Fungal Infection in War Wounds

Summary of Changes

1. Updates to IFI wound epidemiology to include surgical and wound healing outcomes
2. Addition of pan-fungal PCR as a potential rapid molecular diagnostic modality
3. Updates on the use of IV voriconazole in those with impaired renal function
4. Updates on posaconazole administration
5. Addition of isavuconazole as a mold active triazole
6. Addition of tissue sample handling considerations to increase culture yield of fungi (i.e. Mucor)
7. Updated Jul 2021 with the Dakin’s half-strength solution

BACKGROUND

Clinically significant infections, including invasive fungal wound infections (IFIs), have occurred in the DoD’s wounded warrior patient population since the beginning of the current conflicts in Iraq and Afghanistan. During 2009-2010, a substantial increase in the incidence of IFIs was observed among military personnel with wounds sustained in Afghanistan, corresponding to a greater frequency of improvised explosive device blast injuries sustained while on foot patrol in Helmand and Kandahar provinces.1-3 Mold contamination of the wounds was associated with regions in southern Afghanistan characterized by lower elevation, warmer temperatures,4 and followed waterways. Of particular clinical concern was an apparent association between patient outcome and the presence of angioinvasive filamentous fungi (e.g., order Mucorales, Aspergillus species, and Fusarium species) often called “molds.”5,6 In general, IFIs are devastating infections associated with increased mortality, morbidity, limb loss, and prolonged hospitalization for survivors.2,7-10 In civilian literature, mortality rates have been reported as high as 38%.5 Among the military population, the crude mortality rate was as high as 8% during the first two years of increased prevalence.11 Dismounted blast injuries were highly contaminated with debris (e.g., soil, plant matter, and shrapnel) and coinfection with bacteria and other fungi was common.12-14

Following recognition of the high number of IFI cases, the Joint Trauma System, in collaboration with the Uniformed Services University of the Health Sciences Infectious Disease Clinical Research Program (IDCRP) Trauma Infectious Disease Outcomes Study (TIDOS), launched an outbreak investigation. Review of the findings demonstrated that the most common mechanistic and clinical factors associated with IFI included dismounted blast injury, above-knee traumatic amputations, extensive perineal/pelvic injury (observed trend, but not statistically significant), and massive packed red blood cell transfusion (≥20 units in the first 24 hours).1,2 Importantly, all IFI patients had a suspicious wound (i.e. unhealthy appearance), defined as recurrent tissue necrosis following at least two surgical debridements. Additional work on IFI classification emphasizes the temporal relationship between surgical findings and laboratory evidence of IFI. (See Appendix A: Examples of Suspicious Wounds.)15

The morbidity associated with IFI in war wounds, which may include significant tissue loss, necessitates early surgical and antifungal treatment of patients identified as high risk. Early and aggressive debridement of devitalized tissue and removal of debris are universally accepted as the most important interventions. Patients frequently require surgical amputations and/or amputation revisions, which include extending to more proximal levels (e.g., transtibial to transfemoral or transfemoral to proximal transfemoral, hip disarticulation, or hemipelvectomy).16 IFI wounds with order Mucorales and Gram-negative bacterial co-infections were observed to have longer time to wound closure, highlighting the need for antifungal and antibacterial therapy.14

The 3 main principles of IFI treatment:

1. Surgical debridement of infected tissue;
2. Minimization of immunosuppression (e.g., avoidance of malnutrition or excessive blood product transfusion); and
3. Utilization of empiric dual antifungal medications (e.g., amphotericin B and a broad-spectrum triazole agent) when there is a strong suspicion of an IFI.9

Wounds with IFI require a significantly higher number of surgical (not bedside) debridements compared to other wound infections. There are also more changes in amputation level (e.g., revision of a transfemoral amputation to either a hemipelvectomy or hip disarticulation); longer duration following injury to wound closure; and an increased frequency of return to the operating room after wound closure due to infectious complications or drainage.12 The role of topical antifungal therapy in the prevention of IFI is not clear, but topical therapies have not been demonstrated to have adverse local or systemic effects.

#### Debridement

Early and aggressive debridement of devitalized tissue and removal of debris are universally accepted as the most important interventions.