The Burden of High-Energy Musculoskeletal Trauma in High-Income Countries.

INTRODUCTION TO THE PROBLEM: Though declining in the recent decades, high-energy musculoskeletal trauma remains a major contributor to the burden of disease in high-income countries (HICs). However, due to limitations in the available body of the literature, evaluation of this burden is challenging. The purpose of this review is to assess: (1) the current epidemiologic data on the surgical burden of high-energy musculoskeletal trauma in HICs; (2) the current data on the economic impact of high-energy musculoskeletal trauma; and (3) potential strategies for addressing gaps in musculoskeletal trauma care for the future. REVIEW OF LITERATURE: In 2016, mortality from road traffic injuries (RTIs) between the ages of 15-49 was reported to be 9.5% (9.0-9.9) in high-income countries, accounting for approximately 255 million DALYs. While RTIs do not fully capture the extent of high-energy musculoskeletal trauma, as the most common mechanism, they serve as a useful indicator of the impact on the surgical and economic burden. In 2009, the global losses related to RTIs were estimated to be 518 billion USD, costing governments between 1 and 3% of their gross domestic product (GDP). In the last decade, both the total direct per-person healthcare cost and the incremental direct per-person costs for those with a musculoskeletal injury in the USA rose 75 and 58%, respectively. FUTURE DIRECTIONS: ADDRESSING THE GAPS: While its impact is large, research on musculoskeletal conditions, including high-energy trauma, is underfunded compared to other fields of medicine. An increased awareness among policy makers and healthcare professionals of the importance of care for the high-energy musculoskeletal trauma patient is critical. Full implementation of trauma systems is imperative, and metrics such as the ICD-DALY have the potential to allow for real-time evaluation of prevention and treatment programs aimed to reduce injury-related morbidity and mortality. The dearth in knowledge in optimal and cost-effective post-acute care for high-energy musculoskeletal trauma is a reason for concern, especially since almost half of the costs are attributed to this phase of care. Multidisciplinary rehabilitation teams as part of a musculoskeletal trauma system may be of interest to decrease further the long-term negative effects and the economic burden of high-energy musculoskeletal trauma.

Tissue engineering and regenerative approaches to improving the healing of large bone defects.

Despite the high innate regenerative capacity of bone, large osseous defects fail to heal and remain a clinical challenge. Healing such defects requires the formation of large amounts of bone in an environment often rendered hostile to osteogenesis by damage to the surrounding soft tissues and vasculature. In recent years, there have been intensive research efforts directed towards tissue engineering and regenerative approaches designed to overcome this multifaceted challenge. In this paper, we describe and critically evaluate the state-of-the-art approaches to address the various components of this intricate problem. The discussion includes (i) the properties of synthetic and natural scaffolds, their use in conjunction with cell and growth factor delivery, (ii) their vascularisation, (iii) the potential of gene therapies and (iv) the role of the mechanical environment. In particular, we present a critical analysis of where the field stands, and how it can move forward in a coordinated fashion.

Cell therapy for bone repair: narrowing the gap between vision and practice.

This position paper summarises a vision of how cell-based therapies can be applied clinically to regenerate bone, as well as the steps needed to narrow the gap between that vision and clinical reality. It is a result of the presentations and discussion of the "Cell Therapy for Bone Repair" breakout session at the AO Foundation Symposium "Where Science Meets Clinics" in Davos, Switzerland from September 5-7, 2013. Participants included leaders from science, medicine, and industry from around the world. The session included clinical and scientific presentations, as well as an extended discussion among participants. Bone tissue has an innate regenerative capacity that in most cases allows functional healing at damage sites. However, there are a number of serious conditions in which bone does not fully heal and the result is significant morbidity. The clinical need for new therapies is clear, and the breakout session participants were enthusiastic about the potential impact on cell-based therapies for bone repair in the clinic. However, they also recognised the significant challenges that face the development of commercially viable cell therapy products. This paper outlines a vision in which patient selection is based on expected therapeutic outcome to create a consistently successful, cost-effective, cell-based therapy for bone repair. The need for a more complete understanding of bone repair, a better infrastructure for preclinical studies, and the need for collaboration among stakeholders is discussed.

Barriers and strategies for the clinical translation of advanced orthopaedic tissue engineering protocols.

Research in orthopaedic tissue engineering has intensified over the last decade and new protocols continue to emerge. The clinical translation of these new applications, however, remains associated with a number of obstacles. This report highlights the major issues that impede the clinical translation of advanced tissue engineering concepts, discusses strategies to overcome these barriers, and examines the need to increase incentives for translational strategies. The statements are based on presentations and discussions held at the AO Foundation-sponsored symposium "Where Science meets Clinics 2013" held at the Congress Center in Davos, Switzerland, in September, 2013. The event organisers convened a diverse group of over one hundred stakeholders involved in clinical translation of orthopaedic tissue engineering, including scientists, clinicians, healthcare industry professionals and regulatory agency representatives. A major point that emerged from the discussions was that there continues to be a critical need for early trans-disciplinary communication and collaboration in the development and execution of research approaches. Equally importantly was the need to address the shortage of sustained funding programs for multidisciplinary teams conducting translational research. Such detailed discussions between experts contribute towards the development of a roadmap to more successfully advance the clinical translation of novel tissue engineering concepts and ultimately improve patient care in orthopaedic and trauma surgery.

A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair.

While formation and regeneration of the skeleton have been studied for a long period of time, significant scientific advances in this field continue to emerge based on an unmet clinical need to improve options to promote bone repair. In this review, we discuss the relationship between mechanisms of bone formation and bone regeneration. Data clearly show that regeneration is not simply a reinduction of the molecular and cellular programs that were used for development. Instead, the mechanical environment exerts a strong influence on the mode of repair, while during development, cell-intrinsic processes drive the mode of skeletal formation. A major advance in the field has shown that cell fate is flexible, rather than terminal, and that chondrocytes are able to differentiate into osteoblasts and other cell types during development and regeneration. This is discussed in a larger context of regeneration in vertebrates as well as the clinical implication that this shift in understanding presents.

The Contribution of Macrophages in Old Mice to Periodontal Disease.

The prevalence of periodontal disease increases with age. Systemic inflammatory dysregulation also increases with age and has been reported to contribute to the myriad of diseases and conditions that become more prevalent with advanced age. As periodontal disease involves a dysregulated host inflammatory response, the age-related inflammatory dysregulation may contribute to the pathogenesis of periodontal disease in aging populations. However, our understanding of what drives the age-related inflammatory dysregulation is limited. Here, we investigate the macrophage and its contribution to periodontal disease in old and young mice using a ligature-induced periodontal disease model. We demonstrate that control old mice present with an aged periodontal phenotype, characterized by increased alveolar bone loss and increased local inflammatory cytokine expression compared to young mice. Macrophages were demonstrated to be present in the periodontium of old and young mice in equal numbers in controls, during disease induction, and during disease recovery. However, it appears age may have a detrimental effect on macrophage activity during disease recovery. Depletion of macrophages during disease recovery in old mice resulted in decreased inflammatory cytokines within the gingiva and decreased bone loss as measured by micro-computed tomography. In young mice, macrophage depletion during disease recovery had no beneficial or detrimental effect. Macrophage depletion during disease induction resulted in decreased disease severity similarly in young and old mice. Findings from this work support the diverse roles of macrophages in disease induction as well as the active roles of disease recovery, including the resolution of inflammation. Here, we conclude that age-related changes to the macrophage appear to be detrimental to the recovery from disease and may explain, in part, the age-related increase in prevalence of periodontal disease. Future studies examining the specific intrinsic age-related changes to the macrophage will help identify therapeutic targets.

Fracture repair in the elderly: Clinical and experimental considerations.

Fractures in the elderly represent a significant and rising socioeconomic problem. Although aging has been associated with delays in healing, there is little direct clinical data isolating the effects of aging on bone healing from the associated comorbidities that are frequently present in elderly populations. Basic research has demonstrated that all of the components of fracture repair-cells, extracellular matrix, blood supply, and molecules and their receptors-are negatively impacted by the aging process, which likely explains poorer clinical outcomes. Improved understanding of age-related fracture healing should aid in the development of novel treatment strategies, technologies, and therapies to improve bone repair in elderly patients.

Does adult fracture repair recapitulate embryonic skeletal formation?

Bone formation is a continuous process that begins during fetal development and persists throughout life as a remodeling process. In the event of injury, bones heal by generating new bone rather than scar tissue; thus, it can accurately be described as a regenerative process. To elucidate the extent to which fetal skeletal development and skeletal regeneration are similar, we performed a series of detailed expression analyses using a number of genes that regulate key stages of endochondral ossification. They included genes in the indian hedgehog (ihh) and core binding factor 1 (cbfa1) pathways, and genes associated with extracellular matrix remodeling and vascular invasion including vascular endothelial growth factor (VEGF) and matrix metalloproteinase 13 (mmp13). Our analyses suggested that even at the earliest stages of mesenchymal cell condensation, chondrocyte (ihh, cbfa1 and collagen type II-positive) and perichondrial (gli1 and osteocalcin-positive) cell populations were already specified. As chondrocytes matured, they continued to express cbfa1 and ihh whereas cbfa1, osteocalcin and gli1 persisted in presumptive periosteal cells. Later, VEGF and mmp13 transcripts were abundant in chondrocytes as they underwent hypertrophy and terminal differentiation. Based on these expression patterns and available genetic data, we propose a model where Ihh and Cbfa1, together with Gli1 and Osteocalcin participate in establishing reciprocal signal site of injury. The persistence of cbfa1 and ihh, and their targets osteocalcin and gli1, in the callus suggests comparable processes of chondrocyte maturation and specification of a neo-perichondrium occur following injury. VEGF and mmp13 are expressed during the later stages of healing, coincident with the onset of vascularization of the callus and subsequent ossification. Taken together, these data suggest the genetic mechanisms regulating fetal skeletogenesis also regulate adult skeletal regeneration, and point to important regulators of angiogenesis and ossification in bone regeneration.

Common molecular pathways in skeletal morphogenesis and repair.

The formation of bone is a continual process in vertebrate development, initiated during fetal development and persisting in adulthood in the form of remodeling and repair. The remarkable capacity of skeletal tissues to regenerate has led to the hypothesis that the molecular signaling pathways regulating skeletogenesis are shared during fetal development and adult wound healing. A number of key regulatory pathways that are required for endochondral ossification during fetal development are described, and their reintroduction in fracture repair demonstrated. Secreted proteins such as Sonic and Indian hedgehog exert their effect on pattern formation and chondrogenesis in the appendicular skeleton, partly through regulation of molecules such as bone morphogenic proteins (Bmps) and parathyroid hormone-related peptide (PTHrP). Once chondrocytes have matured and hypertrophied, they undergo apoptosis and are replaced by bone; the transcription factor Cbfal plays a critical role in this process of chondrocyte differentiation and ossification. Analyses of the expression patterns of these genes during fracture healing strongly suggest that they play equivalent roles in adult wound repair. Knowledge acquired through the study of fetal skeletogenesis will undoubtedly contribute to an understanding of fracture repair, and subsequently guide the development of biologically based therapeutic interventions.

In vitro pharmacokinetics of antibiotic release from locally implantable materials.

Local deposition of antibiotics has became increasingly popular in the management of open fractures or osteomyelitis, and several substances have been employed as the vehicle for delivery. Although the elution characteristics of some substances have been documented, a comparative study of the characteristics of the commonly used substances could establish the clinical indications for particular vehicles. Cylindrical pellets of uniform size (6 x 4 mm) were prepared from bone graft (BG), demineralized bone matrix (DBM), plaster of Paris (POP), or polymethylmethacrylate (PMMA), with 25 mg of tobramycin/g of substance in each pellet. The pellets were suspended in phosphate buffered saline, and the antibiotic concentration in the buffer was determined at various time intervals by an enzyme immunoassay. BG and DBM eluted 70 and 45% of their antibiotic load by 24 h, and negligible amounts were detected at 1 week; POP released 17% of its load by 24 h, with trace amounts detected at 3 weeks; and PMMA eluted 7% at 24 h, with trace amounts detected for as long as 14 days. These findings suggest that the optimal vehicle for local deposition of antibiotic depends on the clinical setting. BG and DBM may be best employed when brief antibiotic coverage is required (as for acute contaminated open fractures), whereas POP and PMMA may be better suited for long-term coverage (such as for established osteomyelitis).

Cellular and molecular characterization of a murine non-union model.

PURPOSE: We have developed a method to study the molecular and cellular events underlying delayed skeletal repair in a model that utilizes distraction osteogenesis. METHODS: The clinical states of delayed union and non-union were reproduced in this murine model by altering distraction parameters such as the inclusion and exclusion of a latency phase and variations in the rate and rhythm of distraction. Radiographic, cellular, and molecular analyses were performed on the distraction tissues. RESULTS: Eliminating the latency period delayed bony union, but did not appreciably alter the extent of platelet endothelial cell adhesion marker (PECAM) immunostaining. Following elimination of a latency phase and a threefold increase in the rate of distraction, there was a further delay in bone regeneration and a higher rate of non-union (60%). Instead of bone, the distraction gap was comprised of adipose or fibrous tissue. Once again, despite the rigorous distraction protocol, we detected equivalent PECAM staining within the distraction gap. In a minority of cases, cartilage and osseous tissues occupied the distraction gap likely by a prolonged process of endochondral ossification. CONCLUSIONS: Here, we have altered the mechanical environment in such a way to reproducibly create delays in skeletal regeneration. These delays in skeletal tissue regeneration appear to develop even in the presence of endothelial cells, which suggests that mechanisms other than a disruption to the vascular network can account for some cases of non-union.

Molecular aspects of healing in stabilized and non-stabilized fractures.

Bone formation is a continuous process that is initiated during fetal development and persists in adults in the form of bone regeneration and remodeling. These latter two aspects of bone formation are clearly influenced by the mechanical environment. In this study we tested the hypothesis that alterations in the mechanical environment regulate the program of mesenchymal cell differentiation, and thus the formation of a cartilage or bony callus, at the site of injury. As a first step in testing this hypothesis we produced stabilized and non-stabilized tibial fractures in a mouse model, then used molecular and cellular methods to examine the stage of healing. Using the "molecular map" of the fracture callus, we divided our analyzes into three phases of fracture healing: the inflammatory or initial phase of healing, the soft callus or intermediate stage, and the hard callus stage. Our results show that indian hedgehog(ihh), which regulates aspects of chondrocyte maturation during fetal and early postnatal skeletogenesis, was expressed earlier in an non-stabilized fracture callus as compared to a stabilized callus. ihh persisted in the non-stabilized fracture whereas its expression was down-regulated in the stabilized bone. IHH exerts its effects on chondrocyte maturation through a feedback loop that may involve bone morphogenetic protein 6 [bmp6; (S. Pathi, J.B. Rutenberg, R.L. Johnson, A. Vortkamp, Developmental Biology 209 (1999) 239-253)] and the transcription factor gli3. bmp6 and gli3 were re-induced in domain adjacent to the ihh-positive cells during the soft and hard callus stages of healing. Thus, stabilizing the fracture, which circumvents or decreases the cartilaginous phase of bone repair, correlates with a decrease in ihh signaling in the fracture callus. Collectively, our results illustrate that the ihh signaling pathway participates in fracture repair, and that the mechanical environment affects the temporal induction of ihh, bmp6 and gli3. These data support the hypothesis that mechanical influences affect mesenchymal cell differentiation to bone.

Deformation of femoral nails with intramedullary insertion.

Current methods of distal interlocking of intramedullary femoral nails are dependent on image intensification. However, radiation exposure to the patient, the operating room staff, and the surgeon remains a concern. Proximally mounted, radiation-free aiming systems for distal interlocking of femoral nails have reportedly failed because of nail deformation with insertion. To better understand this deformation, a three-dimensional magnetic motion tracking system was used to determine the position of the distal interlocking hole following nail insertion. The amount and direction of deformation of commercially available small-diameter implants (unslotted 9-mm nails inserted without reaming) and large-diameter implants (slotted 13-mm nails inserted with reaming) from a single manufacturer were analyzed. Measurements of deformation (three translations and three angles), based on the center of the distal transverse locking hole, were performed on 10 paired intact human cadaveric femora before and after insertion. The technique produced the following results for the small and large-diameter nails, respectively: lateral translations of 18.1+/-10.0 mm (mean+/-SD, range: 47.8 mm) and 21.5+/-7.9 mm (range: 26.4 mm), dorsal translations of -3.1+/-4.3 mm (range: 15.2 mm) and 0.4+/-9.8 mm (range: 30.1 mm), and rotation about the longitudinal axes of -0.1+/-0.2 degrees (range: 0.7 degrees) and 10.0+/-3.1 degrees (range: 7.8 degrees). This technique is useful for measuring insertion-related femoral nail deformation. The data for the nails tested suggest that a simple aiming arm, mounted on the proximal end of the femoral nail alone, will not sufficiently provide accurate distal aiming.

Effect of ciprofloxacin on the proliferation of osteoblast-like MG-63 human osteosarcoma cells in vitro.

Locally applied antibiotic therapy is gaining popularity for the treatment of infections associated with open fractures and posttraumatic osteomyelitis. With use of local techniques, ciprofloxacin levels as high as 1,300 microg/ml, or over 200 times the bone levels achieved with intravenous administration, have been reported. To study the possible effects of ciprofloxacin on bone, osteoblast-like cells from the MG-63 human osteosarcoma cell line were studied. The cells were grown in antibiotic-free media and exposed to concentrations of ciprofloxacin at 0, 10, 100, 200, and 1,000 microg/ml to establish an initial dose-response curve. Media containing the appropriate dose of ciprofloxacin were changed every 24 hours. Cell number and [3H]thymidine incorporation per cell were determined at 0, 24, and 72 hours. A second dose-response curve was performed at concentrations of 0, 10, 20, 40, and 80 microg/ml. Three experiments, each with four observations, were performed. The results of this study demonstrated that ciprofloxacin caused significant decreases (p < 0.05) in cell number at 40 microg/ml at 24 hours and 20 microg/ml at 72 hours. [3H]thymidine incorporation per cell decreased significantly at levels of 80 microg/ml at 24 hours and 20 microg/ml at 72 hours. The authors conclude that reported local levels of ciprofloxacin seen in vivo inhibit the proliferation of human osteoblast-like cells in vitro.

The deformation of small diameter solid tibial nails with unreamed intramedullary insertion.

'Radiation-independent' aiming systems for the placement of interlocking screws in intramedullary tibial nails have failed because of insertional related nail deformation. Prior to the development of these distal aiming systems, the variable position of the nails' interlocking holes after insertion must be known. In this study, the amount and direction of implant deformation of solid stainless-steel tibial nails (diameters of 8 and 9 mm, n = 20) were analyzed. Measurement of implant deflection (three translations, three angles) in the center of distal transverse locking hole was performed with a three-dimensional-magnetic motion tracker system after nail insertion in paired human cadaver tibiae. The results showed combined mean lateral translation of the 8 and 9 mm nails (n = 20) of -4.5 +/- 3.5 mm (range: 14.3 mm) and dorsal translation -7.8 +/- 5.8 mm (range: 19.2 mm). The combined mean rotational deformation about the longitudinal axis of the nail was 0.3 +/- 0.7 degree (range: 2.4 degrees). The authors conclude that a simple aiming arm, mounted on the proximal nail end alone, is not sufficient to provide accurate distal aiming.

Imaging assessment of sacroiliac screw placement relative to the neuroforamen.

STUDY DESIGN: Twenty-four cannulated sacroiliac screws were placed bilaterally into 12 cadaveric pelvi (12 titanium screws and 12 stainless-steel screws) and were imaged using conventional and multiplanar reconstructed computed tomography. OBJECTIVES: To determine whether sacroiliac screw position assessment relative to the neuroforamen is enhanced by: 1) computed tomography using multiplanar reconstructions and 2) the use of titanium screws rather than stainless-steel screws. SUMMARY OF BACKGROUND DATA: To the authors' knowledge, there have been no prior studies demonstrating the accuracy of multiplanar computed tomography compared with that of conventional (axial) tomography in determining the position of sacroiliac screws relative to the neuroforamen. Although titanium screws have been shown to have less scatter than stainless-steel screws, the effect of alloy composition on the radiographic accuracy of interpreting the screw position relative to the sacral neuroforamen is unknown. METHODS: Screws were deliberately placed into: position A, in which the screw did not violate the neuroforamen; position B, in which the threads of the screw came within 3 mm of the neuroforamen; and position C, in which the screw clearly was nearly centered in the neuroforamen. The degrees of accuracy in assessing screw position relative to the neuroforamen using conventional (axial) images and using multiplanar reconstructed images were compared. RESULTS: The axial images were accurate in determining screw position relative to the neuroforamen in 50% of cases in which titanium screws were used and in 42% of cases in which stainless-steel screws were used. The corresponding values for multiplanar reconstructions were 92% for cases in which titanium screws were used and 67% for cases in which stainless-steel screws were used. The accuracy of multiplanar reconstructions was statistically better than that of axial images (P < 0.05). Metallic scatter was increased in stainless-steel screws. CONCLUSIONS: The results of this study suggest that the use of computed tomography with multiplanar reconstruction improves accuracy in determining sacroiliac screw position relative to the neuroforamen. The assessment of screw position may be facilitated using titanium screws.

Accuracy of intramedullary templates in femoral and tibial radiographs.

The accuracy of templates used for the preoperative planning of the fixation of intramedullary fractures depends on radiological magnification. To study the accuracy of these templates, we randomly selected 100 femoral and 100 tibial radiographs taken after stabilisation by an intramedullary nail using a standard technique. We then compared the known nail length with the corresponding measurements on the radiographs. The mean magnification factor for the femur was 9% and for the tibia 7%; these differ considerably from the range of magnification of the manufacturers' templates (femur, 15% to 17%; tibia 10% to 15%). We conclude that templates are unreliable for the selection of implant length and that this should be done by intraoperative measurements.

Recurrent rotational deformity of the femur after static locking of intramedullary nails: case reports.

Rotational deformity following intramedullary nailing may cause symptoms and require surgical correction by osteotomy. Reamed, locked intramedullary nailing may be performed, but concern about cortical blood supply and potential pulmonary dysfunction from reaming have led many surgeons to limit this and use smaller diameter nails. Slotted nails are commonly used but are less stiff in torsion than the newer unslotted nails, particularly at the lower diameters. We report two cases of recurrent femoral rotational deformity after using statically interlocked slotted intramedullary nails to correct existing femoral rotational deformities. These patients show that small diameter statically interlocked femoral nails with diminished bone-nail contact must be stiff enough in rotation to avoid potential recurrence.

The use of Poller screws as blocking screws in stabilising tibial fractures treated with small diameter intramedullary nails.

Intramedullary nailing of metaphyseal fractures may be associated with deformity as a result of instability after fixation. Our aim was to evaluate the clinical use of Poller screws (blocking screws) as a supplement to stability after fixation with statically locked intramedullary nails of small diameter. We studied, prospectively, 21 tibial fractures, 10 in the proximal third and 11 in the distal third in 20 patients after the insertion of Poller screws over a mean period of 18.5 months (12 to 29). All fractures had united. Healing was evident radiologically at a mean of 5.4+/-2.1 months (3 to 12) with a mean varus-valgus alignment of -1.0 degree (-5 to 3) and mean antecurvatum-recurvatum alignment of 1.6 degrees (-6 to 11). The mean loss of reduction between placement of the initial Poller screw and follow-up was 0.5 degrees in the frontal plane and 0.4 degrees in the sagittal plane. There were no complications related to the Poller screw. The clinical outcome, according to the Karström-Olerud score, was not influenced by previous or concomitant injuries in 18 patients and was judged as excellent in three (17%), good in seven (39%), satisfactory in six (33%), fair in one (6%), and poor in one (6%).

Necrotizing soft-tissue infections.

Necrotizing fasciitis is a rare and often fatal soft-tissue infection involving the superficial fascial layers of the extremities, abdomen, or perineum. Necrotizing fasciitis typically begins with trauma; however, the inciting event may be as seemingly innocuous as a simple contusion, minor burn, or insect bite. Differentiating necrotizing infections from common soft-tissue infections, such as cellulitis and impetigo, is both challenging and critically important. A high degree of suspicion may be the most important aid in early diagnosis. Prompt diagnosis is imperative because necrotizing infections typically spread rapidly and can result in multiple-organ failure, adult respiratory distress syndrome, and death. Although group A Streptococcus is the most common bacterial isolate, a polymicrobial infection with a variety of Gram-positive, Gram-negative, aerobic, and anaerobic bacteria is more common. Orthopaedic surgeons are often the first physicians to evaluate patients with such infections and therefore need to be familiar with this potentially devastating disease and its management. Prompt diagnosis, immediate administration of broad-spectrum antibiotic coverage, and emergent aggressive surgical debridement of all compromised tissues are critical to reduce the morbidity and mortality of these rapidly progressing infections.