Metformin and the risks of cellulitis, foot infections, and amputation in patients with type 2 diabetes.

BACKGROUND: Patients with diabetes tend to have cellulitis, foot infections, and amputation. We conducted this research to compare the risks of cellulitis, foot infections, and amputation between metformin no-use and use in persons with type 2 diabetes. METHODS: Using propensity score matching, we identified 23 234 pairs of metformin nonusers and users from the National Health Insurance Research Database of Taiwan, since January 1, 2000, to December 31, 2017. Cox proportional hazards models were adopted to examine the risks of incident cellulitis, recurrent cellulitis, foot infections, and amputation between metformin use and no-use. RESULTS: The mean follow-up period of metformin use and no-use was 6.31 (3.93) and 5.54 (3.97) years, respectively. Compared with metformin no-use, the adjusted hazard ratio and 95% confidence interval for metformin use in cellulitis development, recurrent cellulitis, foot infections, and amputation were 1.08 (1.04-1.12), 1.33 (1.14-1.55), 1.91 (1.75-2.09), and 1.88 (1.35-2.62), respectively. The longer cumulative duration of metformin usage had association with higher risks of these outcomes than metformin no-use. CONCLUSION: This population-based cohort study revealed that metformin use had association with significantly higher risks of incident cellulitis, recurrent cellulitis, foot infections, and amputation than metformin no-use in patients with type 2 diabetes.

Early Complications in Prepectoral Tissue Expander-Based Breast Reconstruction.

BACKGROUND: Prepectoral implant placement for postmastectomy breast reconstruction has increased in recent years. Benefits of prepectoral reconstruction may include lack of animation deformities and reduced postoperative pain, but its complication profile is currently unclear. This study aimed to examine the complication profile of prepectoral tissue expanders (TEs) to determine factors associated with TE loss. METHODS: A retrospective review was performed to identify all patients who underwent immediate prepectoral TE reconstruction from January 2018 to June 2021. The decision to use the prepectoral technique was based on mastectomy skin quality and patient comorbidities. Patient demographics, comorbidities, and operative details were evaluated. Outcomes of interest included TE loss, seroma, hematoma, infection/cellulitis, mastectomy skin flap necrosis requiring revision, and TE exposure. Logistic regression analysis was performed to identify factors associated with TE loss. RESULTS: The study identified 1225 TEs. The most frequent complications were seroma (8.7%, n = 106), infection/cellulitis (8.2%, n = 101), and TE loss (4.2%, n = 51). Factors associated with TE loss in the univariate analysis included ethnicity, history of smoking, body mass index, mastectomy weight, and neoadjuvant chemotherapy. In the multivariate regression analysis, only mastectomy weight had a positive association with TE loss (odds ratio, 1.001; p = 0.016). CONCLUSION: Prepectoral two-stage breast reconstruction can be performed safely with an acceptable early complication profile. The study data suggest that increasing mastectomy weight is the most significant factor associated with TE loss. Further research examining the quality of the soft tissue envelope and assessing patient-reported outcomes would prove beneficial.

Factors associated with cellulitis in lymphoedema of the arm - an international cross-sectional study (LIMPRINT).

BACKGROUND: Lymphoedema is a globally neglected health care problem and a common complication following breast cancer treatment. Lymphoedema is a well-known predisposing factor for cellulitis, but few have investigated the risk factors for cellulitis in this patient cohort on an international level. The aim of this study was to identify the frequency of cellulitis in patients with lymphoedema of the arm, including potential risk factors for cellulitis. METHODS: An international, multi-centre, cross-sectional study including patients with clinically assessed arm lymphoedema. The primary outcome was the incidence of cellulitis located to the arm with lymphoedema within the last 12 months, and its potential associated risk factors. The secondary outcome was life-time prevalence of cellulitis. Adults with clinically-assessed arm lymphoedema/chronic oedema (all causes) and able to give informed consent were included. End-of-life-patients or those judged as not in the patient's best interest were excluded. Both univariable and multivariable analysis were performed. RESULTS: A total of 2160 patients were included from Australia, Denmark, France, Ireland, Italy, Japan, Turkey and United Kingdom. Secondary lymphoedema was present in 98% of the patients; 95% of these were judged as related to cancer or its treatment. The lifetime prevalence of cellulitis was 22% and 1-year incidence 11%. Following multivariable analysis, factors associated with recent cellulitis were longer swelling duration and having poorly controlled lymphoedema. Compared to having lymphoedema less than 1 year, the risk increased with duration: 1-2 years (OR 2.15), 2-5 years (OR 2.86), 5-10 years (OR 3.15). Patients with well-controlled lymphoedema had a 46% lower risk of cellulitis (OR 0.54, 95% CI 0.39-0.73, p < 0.001). More advanced stages of lymphoedema were associated with cellulitis even after adjustment for swelling duration and control of swelling by logistic regression (stage II OR 5.44, stage III OR 9.13, p = 0.002), demonstrated in a subgroup analysis. CONCLUSION: Patients with advanced arm lymphoedema are at particular risk of developing cellulitis. Prevention of lymphoedema progression is crucial. The results lend towards a positive effect of having well-treated lymphoedema on the frequency of cellulitis.

Tattoo-induced allergic contact dermatitis presents diagnostic challenge as a cellulitis mimic.

Allergic contact dermatitis (ACD) is a prevalent condition associated with numerous potential allergen exposures. Tattoo ink is variable and may contain allergens that can be overlooked in patient education and diagnosis. We present a 27-year-old female with ACD following a new tattoo. The patient was repeatedly misdiagnosed with cellulitis by three different clinicians and treated with multiple antibiotics without improvement. The correct diagnosis was eventually made in the emergency department (ED). Although the patient was aware of her allergies to nickel and cobalt from patch testing, she was not aware of the potential for tattoo ink to contain these allergens because prior tattoos had not provoked an allergic reaction. Consequently, the appropriate care was delayed by a month, resulting in significant morbidity. This case demonstrates the potential for ACD to present similarly to cellulitis in an ED setting and the need for clinical vigilance in diagnosis of ACD. It also highlights the importance of detailed patient education on potential allergen sources particularly in the context of tattooing, which is performed with unregulated and variable ink products.

Lymphatic venous anastomosis and complex decongestive therapy for lymphoedema: randomized clinical trial.

BACKGROUND: Lymphatic venous anastomosis is associated with a low incidence of lower extremity lymphoedema-associated cellulitis; however, the exact relationship is unknown. This multicentre RCT evaluated the effect of lymphatic venous anastomosis on prevention of cellulitis. METHODS: Patients with secondary lower extremity lymphoedema who underwent at least 3 months of non-operative decongestive therapy were assigned randomly to lymphatic venous anastomosis or conservative therapy. The primary and secondary outcomes were cellulitis frequency, and assessments of circumference, hardness, and pain respectively. RESULTS: Overall, 336 patients were divided into two groups: 225 in the full-analysis set (primary outcome 225; secondary outcomes 170) and 156 in the per-protocol set (primary outcome 156; secondary outcomes 110). In both analyses, lymphatic venous anastomosis with non-operative decongestive therapy was more effective in preventing cellulitis than non-operative decongestive therapy alone; the difference between groups in reducing cellulitis frequency over 6 months was -0.35 (95 per cent c.i. -0.62 to -0.09; P = 0.010) in the full-analysis set (FAS) and -0.60 (-0.94 to -0.27; P = 0.001) in the per-protocol set (PPS) Limb circumference and pain were not significantly different, but lymphatic venous anastomosis reduced thigh area hardness (proximal medial and distal and lateral proximal). Four patients experienced contact dermatitis with non-operative decongestive therapy alone. CONCLUSION: Lymphatic venous anastomosis in combination with non-operative decongestive therapy prevents cellulitis. REGISTRATION NUMBER: UMIN00025137, UMIN00031462.

The critical role of phlebolymphedema in cellulitis associated with lymphedema: Its incidence and economic impact in a large real-world population.

OBJECTIVE: The aims of this study were: to define the incidence of cellulitis in patients with lymphedema (LED) overall and relate this to the etiology of LED; to determine how this rate might be affected by recurrence of cellulitis; and to quantify the contemporary economic burden of treatment. Understanding these factors is essential in developing targeted cellulitis prevention strategies and reducing health care costs. METHODS: The IBM MarketScan Research Database was examined from April 2013 to March 2019 for patients with a new diagnosis of LED (n = 85,601). Based on International Classification of Diseases (ICD)-9/ICD-10 diagnosis codes, the incidence and cost of cellulitis were ascertained during the 3-year follow-up period. Incidence rates (per 100 patient-years [PYs]) and cost (per patient per year) of cellulitis were evaluated among all patients with LED and within subgroups of LED etiologies. RESULTS: Among the three most common morbidities associated with LED (breast cancer-related lymphedema [BCRL], n = 17,954 [20.97%]; gynecological cancer-related LED [GCRL], n = 1256 [1.47%]; and phlebolymphedema [PLED], n = 8406 [9.82%]), rates of cellulitis were markedly lower for BCRL (8.9; 95% confidence interval [CI], 8.7-9.2) and GCRL (14.8; 95% CI, 13.4-16.4) vs PLED (47.7; 95% CI, 46.7-48.8). Patients with a history of cellulitis had markedly higher cellulitis rates during follow-up than those without-overall, 74.0% vs 16.4%; BCRL, 42.9%; 95% CI, 39.7%-46.3% vs 7.6%; 95% CI, 7.3%-7.9%; GCRL, 67.5%; 95% CI, 56.4%-80.8% vs 11.0%; 95% CI, 9.8%-12.4%; and PLED, 81.7%; 95% CI, 79.4%-84.1% vs 30.4%; 95% CI, 29.4%-31.4%, respectively. The mean $/patient/year of cellulitis-related costs for a patient with PLED ($2836; 95% CI, $2395-$3471) was significantly greater than that for BCRL ($503; 95% CI, $212-$1387) and GCRL ($609; 95% CI, $244-$1314). CONCLUSIONS: The incidence of cellulitis associated with LED varies by the etiology of LED. PLED has the highest rates of both an initial cellulitis episode and recurrent cellulitis events. Additionally, PLED has one of the largest cellulitis-related total costs per patient per year. Prevention, as well as early identification and treatment of PLED-associated cellulitis, could significantly decrease health care costs and improve patient quality of life.

Clinical outcomes in patients with complicated appendicitis.

BACKGROUND: Complicated appendicitis (appendicitis with abscess, perforation, or generalized peritonitis) poses a significant burden on healthcare systems, with incidence up to 28-29%. Current management options include antibiotic therapy and up-front surgery, antibiotic therapy and percutaneous drainage, or antibiotic therapy alone. There is no consensus on treatment guidelines in current literature. This study aims to better define treatment algorithms for patients presenting with acute complicated appendicitis by evaluating clinical outcomes in those treated with or without surgery. METHODS: We performed a single-institution, retrospective review of 220 adult patients (≥ 18 years old) treated for acute complicated appendicitis from January 2017 to June 2022. Demographic and clinicopathologic variables were collected and analyzed. We compared patients who were managed non-operatively versus operatively. Regression modeling was used to determine factors associated with non-operative management (NOM) and those predictive of failure of NOM. RESULTS: Our analysis showed 26.3% patients with acute complicated appendicitis underwent NOM (n = 58), versus 73.6% underwent operative management at index admission (n = 162). Within the NOM group, 55.1% patients were treated with antibiotics alone (n = 32) versus 44.8% with percutaneous drainage (n = 26). Within the operative cohort, 88.7% of patients underwent appendectomy (n = 142). Age, body mass index, comorbidities, vital signs and laboratory values on admission were similar between both groups. Clinical factors predictive of initial NOM were perforation (OR 7.9, 95% CI 3.7-16.5) and phlegmon (OR 6.3, 95% CI 2.8-14.1) at presentation. Clinical factors predictive of failure of NOM requiring surgery on index admission or within 30 days was larger abscess and/or phlegmon size (OR 1.76, 95% CI 1.0-3.0). CONCLUSION: There may be a role in identifying clinical factors in patients with complicated appendicitis that favor non operative versus operative management. Larger abscess and/or phlegmon size could be a predictor of failure of NOM.

Atopic Dermatitis and the Risk of Infection in End-Stage Renal Disease.

Background and Objectives: Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin condition affecting 16.5 million adults in the United States. AD is characterized by an impaired epidermal barrier that can predispose individuals to infection. End-stage renal disease (ESRD) is also commonly complicated by infections due to chronic vascular access and immune-system dysfunction, possibly related to uremia. Multiple studies have reported that renal disease is a common comorbidity in adults with atopic dermatitis. The aim of this study was to determine whether AD is a risk factor for certain infections in patients with ESRD. Materials and Methods: Using the United States Renal Data System, a retrospective cohort analysis was conducted on adult ESRD patients initiating dialysis between 2004 and 2019 to investigate associations between infections and AD in this population. Results: Of 1,526,266 patients, 2290 were identified with AD (0.2%). Infectious outcomes of interest were bacteremia, septicemia, cellulitis, herpes zoster, and conjunctivitis. In all infectious outcomes except for conjunctivitis, patients with the infectious outcomes were more likely to carry a diagnosis of AD. After controlling for demographic and clinical covariates, AD was associated with an increased risk of cellulitis (adjusted relative risk (aRR) = 1.39, 95% confidence interval (CI) = 1.31-1.47) and herpes zoster (aRR = 1.67, CI = 1.44-1.94), but not with bacteremia (aRR = 0.96, CI = 0.89-1.05), septicemia (aRR = 1.02, CI = 0.98-1.08), or conjunctivitis (aRR = 0.97, CI = 0.740-1.34). Conclusions: Overall, after controlling for demographic and clinical covariates and adjusting for person-years-at-risk, AD was associated with an increased risk for some, but not all, infections within the population of patients with ESRD.

Foam sclerotherapy for patients with Klipple-Trenaunary syndrome complicated by frequent cellulitis of lower extremity: A case report.

RATIONALE: Klipple-Trenaunary Syndrome (KTS) complicated by frequent cellulitis of lower extremity seriously affects a patient quality of life. The hemodynamic characteristics of the disease are still unclear. Direct skin incision or puncture to remove malformed veins at the lesion site carries the risk of non-healing of the surgical incision. Our aim is to explore initial management strategies based on the hemodynamic characteristics of this disease. PATIENT CONCERNS: A 29-year-old Manchu man was affected by KTS from childhood, characterized by an increase of the circumference and superficial varicose veins of the lower extremity. In the past 5 years, he suffered from frequent cellulitis in the left leg every 15 days or so. DIAGNOSES: KTS complicated by frequent cellulitis of lower extremity. INTERVENTIONS: The clinical and hemodynamic characteristics of KTS were evaluated by Doppler ultrasonography (DUS) combined with CT venography (CTV), and foam sclerotherapy and postoperative elastic bandage compression were performed accordingly. OUTCOMES: Based on evaluations, the reason for frequent cellulitis was the continuous increase of venous hypertension in the calf caused by the malformed superficial vein and its penetrating vein. After 3 operations, the patient had no recurrence of cellulitis of the leg. Follow-up for 1 year showed no recurrence of left leg cellulitis. LESSONS: This report emphasizes that foam sclerotherapy can significantly improve the clinical symptoms of KTS, such as cellulitis, and provide a safe skin environment for the implementation of other surgical methods, based on the evaluation of the pathological characteristics of KTS by DUS combined with CTV.

Erysipelothrix rhusiopathiae cellulitis with associated bacteraemia following seafood preparation.

Erysipelothrix rhusiopathiae is a pleomorphic Gram-positive bacillus, zoonotic pathogen of mammals, birds and fish. Human disease caused by this organism most commonly occurs following occupational or recreational exposure to infected animals and typically presents as a localised cutaneous disease. Invasive infection resulting in bacteraemia, endocarditis or other distant sequelae is infrequently seen. Most commonly, invasive infection is seen in patients with predisposing risk factors including diabetes, immunocompromising conditions, alcohol use disorder or chronic kidney disease. The organism is highly susceptible to penicillin-class drugs which serve as first-line antimicrobial therapy with prolonged courses typically prescribed for invasive disease, given the predilection of this organism to cause endocarditis. In this report, we present an interesting case of a polymicrobial finger abscess with E. rhusiopathiae bacteraemia following laceration with a fish spine in an immunocompetent patient in Southern US state. This bacteraemic episode was successfully treated with a fluoroquinolone course owing to patient's penicillin allergy.

Hidradenitis suppurativa and follicular occlusion syndrome: Where is the pathogenetic link?

The follicular occlusion tetrad complex encompasses several entities (hidradenitis suppurativa, acne conglobata, dissecting cellulitis of the scalp, and pilonidal cyst) that share common clinical features, risk factors, and pathophysiology. Follicular occlusion is a crucial triggering mechanism in the etiology in each of these disorders, leading to development of distinctive skin lesions such as deep-seated nodules, abscesses, comedones, and draining sinuses, often with accompanying scarring. Despite the fact that the follicular occlusion tetrad components manifest multiple similarities, they also exhibit many differences among themselves and require individual approaches and treatment.

Salmonella typhimurium necrotizing fasciitis: a case report.

BACKGROUND: Necrotizing fasciitis is an aggressive disease that causes necrosis in the muscular fascia and subcutaneous tissues. The infection spreads rapidly along the fascia and perifascial planes, followed by extension of the infection to nearby soft tissues and muscles. Necrotizing fasciitis can be attributed to different pathogens, namely Staphylococcus aureus, group A streptococci, and Clostridium perfringes. Only a few cases of skin and soft tissue infections from Salmonella species have been reported to date. Herein we report a case of Salmonella non-typhi necrotizing fasciitis, an exceedingly rare entity. This case report may serve as a potential management plan in similar cases in light of the scarcity of evidence. CASE PRESENTATION: A 20-year-old Caucasian male patient with congenital cardiac anomaly presented with diarrhea and unilateral lower extremity cellulitis causing septic shock. Cultures from blood and the bullae associated with the lower extremity cellulitis grew Salmonella typhimurium. Surgical debridement was performed. Intraoperative tissue cultures were positive for Salmonella typhimurium, and surgical pathology confirmed the diagnosis of necrotizing fasciitis. After a total of 6 weeks of appropriate antimicrobial therapy, another surgical debridement was executed for poor wound healing. New intraoperative cultures grew Fusarium species, and the patient received voriconazole with an adequate response. Immunologic studies showed humoral and cellular immunodeficiency. CONCLUSION: It is important to maintain a high index of suspicion for rare entities that can cause skin and soft tissue infections, such as Salmonella non-typhi, in particular in immunosuppressed patients where a delay in diagnosis and management may have significant morbidity and mortality.

Periorbital Necrotizing Sweet's Syndrome: A Case Report.

Sweet's syndrome (acute febrile neutrophilic dermatosis) is an uncommon inflammatory condition most often associated with painful skin lesions of the head, neck, and upper extremities. To the authors' knowledge, this case report is the only published record of the necrotizing clinical variant of Sweet's syndrome in the periorbital space. This case follows a 91-year-old female who presented with generalized cutaneous eruptions of tender erythematous plaques, including a necrotic plaque of the left upper eyelid, and pancytopenia. A biopsy of an inner thigh lesion was consistent with Sweet's syndrome. Initially diagnosed with preseptal cellulitis, the patient experienced marked clinical improvement with corticosteroids. This, coupled with the histopathologic findings of her thigh biopsy and the absence of eyelid margins, led to the diagnosis of periorbital necrotizing Sweet's syndrome. Although cases of Sweet's syndrome in the periorbital region are rare, these diagnoses should not be overlooked and may be critical to patient care.

Concurrent Pansinusitis and Orbital Cellulitis Complicated by Extensive Head and Neck Venous Thrombosis in an Unvaccinated Adolescent Patient with COVID-19: A Case Report.

BACKGROUND: Orbital cellulitis is an infrequent but serious infectious complication of rhinosinusitis, most commonly seen in the pediatric population. Extension into the cavernous sinus, leading to further infection and thrombosis, is a rare but life-threatening complication. Although COVID-19 has been linked to an increased risk of venous thromboembolism, most cases involve extremity deep venous thrombosis or pulmonary embolism; reports of intracranial or jugular system thrombosis are rare. CASE REPORT: We describe a case of a 17-year-old female patient with no significant medical history or thrombotic risk factors found to have orbital cellulitis and severe pansinusitis, complicated by multiple venous thromboses in the head and neck requiring emergent surgical intervention and pediatric intensive care admission. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Extensive head and neck venous thrombosis and intracranial abscesses are rare complications of pansinusitis and orbital cellulitis, and the thrombotic complications of COVID-19 are well documented. A delay in diagnosis and treatment can lead to potentially devastating consequences.

Skin and Soft Tissue Infections in Young Infants.

INTRODUCTION: The management of young infants with skin and soft tissue infection is not well-defined. METHODS: We performed a survey study of pediatric hospital medicine, emergency medicine, urgent care, and primary care physicians to assess the management of young infants with skin and soft tissue infection. The survey included 4 unique scenarios of a well-appearing infant with uncomplicated cellulitis of the calf with the combination of age ≤ 28 days vs 29-60 days and the presence vs absence of fever. RESULTS: Of 229 surveys distributed, 91 were completed (40%). Hospital admission was chosen more often for younger infants (≤ 28 days) versus older infants regardless of fever status (45% vs 10% afebrile, 97% vs 38% febrile, both P < 0.001). Younger infants were more likely to get blood, urine, and cerebrospinal fluid studies (P < 0.01). Clindamycin was chosen in 23% of admitted younger infants compared to 41% of older infants (P < 0.05). CONCLUSIONS: Frontline pediatricians appear relatively comfortable with outpatient management of cellulitis in young infants and rarely pursued meningitis evaluation in any afebrile infants or older febrile infants.

Evaluation of the Risk Factors for Cellulitis among Patients with Peripheral Artery Disease.

Background and objectives: The objective of this study is to elucidate peripheral occlusion artery disease (PAOD) as a risk factor for cellulitis. Materials and Methods: This is a retrospective population-based cohort study. The database is the Longitudinal Health Insurance Database, which covers two million beneficiaries from the entire population of the 2010 registry for beneficiaries in Taiwan. The PAOD group is composed of patients who were newly diagnosed with PAOD from 2001 to 2014. The non-PAOD group is composed of patients who were never diagnosed with PAOD from 2001 to 2015. All patients were followed until the onset of cellulitis, death, or until the end of 2015. Results: Finally, 29,830 patients who were newly diagnosed with PAOD were included in the PAOD group, and 29,830 patients who were never diagnosed with PAOD were included in the non-PAOD group. The incidence densities (ID) of cellulitis were 26.05 (95% CI = 25.31-26.80) patients per 1000 person-years in the PAOD group and 49.10 (95% CI = 48.04-50.19) in the non-PAOD group. The PAOD group had an increased risk of cellulitis (adjusted HR = 1.94, 95% CI = 1.87-2.01) compared to the non-PAOD group. Conclusions: Patients with PAOD were associated with a higher risk of subsequent cellulitis compared to patients without PAOD.

Preseptal cellulitis with Streptococcus pyogenes complicated by streptococcal toxic shock syndrome: A case report and review of literature.

Preseptal cellulitis, an infection of the eyelid and skin around the eye, can be distinguished from orbital cellulitis. It is common in children and is rarely complicated. Streptococcus pyogenes is one of the major pathogens causing preseptal cellulitis. Here, we report a case of a 46-year-old man with carcinoma of unknown primary presenting preseptal cellulitis of S. pyogenes complicated by streptococcal toxic shock syndrome and multiple metastatic abscesses involving right eyelid, subcutaneous tissue in the scalp, mediastinum, bilateral pleural spaces, pericardial space, and the left knee. Although he required a prolonged hospitalization, antibiotic therapy and multiple courses of debridement led to full recovery. A literature review revealed that there were only four cases of preseptal cellulitis with S. pyogenes in adults and two cases were complicated by streptococcal toxic shock syndrome. The cases had either trauma or immunocompromising factors similar to our patient. All patients survived with antibiotic therapy and debridement, and the functional outcome was favorable. In summary, preseptal cellulitis caused by S. pyogenes can be severe in adult cases where immunocompromising factors and type of strain may play a role in the severity of the disease. Awareness of the risk of severe complications, treatment with appropriate antibiotic therapy, and timely debridement are crucial for favorable prognoses.

Calcific uraemic arteriolopathy presenting as cellulitis of the dorsal foot.

Calcific uraemic arteriolopathy (CUA) is a rare and poorly understood entity that typically presents with painful lesions affecting adipose-rich areas of the lower extremities. We report an unusual case of CUA presenting as presumed cellulitis of the dorsal surface of the distal lower extremity with acute development of a bullous lesion. As CUA incidence is predicted to increase due to its relationship with end-stage renal disease, recognising the full clinical spectrum of this disease is essential to promote further understanding of this disorder and exploration of additional therapeutics to limit disease morbidity and mortality.