The economic case for scaling up health research and development: Lessons from the COVID-19 pandemic.

In response to the COVID-19 pandemic, governments directly funded vaccine research and development (R&D), quickly leading to multiple effective vaccines and resulting in enormous health and economic benefits to society. We develop a simple economic model showing this feat could potentially be repeated for other health challenges. Based on inputs from the economic and medical literatures, the model yields estimates of optimal R&D spending on treatments and vaccines for known diseases. Taking a global and societal perspective, we estimate the social benefits of such spending and a corresponding rate of return. Applications to Streptococcus A vaccines and Alzheimer's disease treatments demonstrate the potential of enhanced research and development funding to unlock massive global health and health-related benefits. We estimate that these benefits range from 2 to 60 trillion (2020 US$) and that the corresponding rates of return on R&D spending range from 12% to 23% per year for 30 y. We discuss the current shortfall in R&D spending and public policies that can move current funding closer to the optimal level.

Necrotizing Fasciitis Associated With Toxic Shock Syndrome.

Necrotizing fasciitis is a rapidly progressing bacterial infection that affects the deep fascia and subcutaneous tissues, often resulting in tissue necrosis and systemic toxicity. This case involves a male in his late forties who initially sought emergency care for a minor rash on his right lower extremity and symptoms of a viral illness. Despite an initial diagnosis of hematoma, his symptoms rapidly escalated within 24 hours, prompting his return to the emergency room. During this subsequent visit, signs of septic shock emerged, accompanied by a worsening rash and blister formation. Admitted to the intensive care unit, our patient received urgent treatment, including broad-spectrum antibiotics and surgical debridement based on the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score for assessing necrotizing fasciitis severity. Further debridement and a fasciotomy were performed, leading to improved clinical conditions, stabilized vitals, and normalized laboratory results. This case underscores the critical importance of early clinical suspicion, prompt diagnosis, and a collaborative, team-based approach in successfully managing necrotizing fasciitis.

A Case of Klippel-Trenaunay Syndrome Complicated by Group A Streptococcemia and Multiple Organ Failure.

Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder defined as a triad of capillary malformation, venous malformation, and hypertrophy of soft tissue and bones, with or without lymphatic malformation. We report a case of a KTS patient with a hospital course complicated by Group A Streptococcus bacteremia and multiple organ failure. The 39-year-old female with KTS presented to the emergency department with a fever, tachycardia, hypotension, and profuse diarrhea for one week. Blood cultures grew Group A Streptococcus necessitating a multi-antibiotic regimen and intravenous immunoglobulins (IVIG). Secondary to septic shock, the patient's renal function continuously declined requiring eight rounds of hemodialysis. She was electively intubated due to worsening acute hypoxic respiratory failure. Chest X-rays demonstrated consolidation, pneumonitis, pleural embolism, and effusions. The patient also required eight units of packed RBC throughout her hospitalization. An underlying autoimmune etiology was suspected due to multiorgan involvement and abnormal blood smears, which was confirmed by an autoimmune panel. The patient ultimately was stabilized and was optimized for discharge. This case demonstrates the importance of a multidisciplinary approach in managing patients with KTS due to their associated lymphatic abnormalities that predispose them to severe infections.

Time to negative throat culture following initiation of antibiotics for pharyngeal group A Streptococcus: a systematic review and meta-analysis up to October 2021 to inform public health control measures.

BackgroundPublic health guidance recommending isolation of individuals with group A streptococcal (GAS) infection or carriage for 12-24 h from antibiotic initiation to prevent onward transmission requires a strong evidence base.AimTo estimate the pooled proportion of individuals who remain GAS culture-positive at set intervals after initiation of antibiotics through a systematic literature review (PROSPERO CRD42021290364) and meta-analysis.MethodsWe searched Ovid MEDLINE (1946-), EMBASE (1974-) and Cochrane library. We included interventional or observational studies with ≥ 10 participants reporting rates of GAS throat culture positivity during antibiotic treatment for culture-confirmed GAS pharyngitis, scarlet fever and asymptomatic pharyngeal GAS carriage. We did not apply age, language or geographical restrictions.ResultsOf 5,058 unique records, 43 were included (37 randomised controlled studies, three non-randomised controlled trials and three before-and-after studies). The proportion of individuals remaining culture-positive on day 1, day 2 and days 3-9 were 6.9% (95% CI: 2.7-16.8%), 5.4% (95% CI: 2.1-13.3%) and 2.6% (95% CI: 1.6-4.2%). For penicillins and cephalosporins, day 1 positivity was 6.5% (95% CI: 2.5-16.1%) and 1.6% (95% CI: 0.04-42.9%), respectively. Overall, for 9.1% (95% CI: 7.3-11.3), throat swabs collected after completion of therapy were GAS culture-positive. Only six studies had low risk of bias.ConclusionsOur review provides evidence that antibiotics for pharyngeal GAS achieve a high rate of culture conversion within 24 h but highlights the need for further research given methodological limitations of published studies and imprecision of pooled estimates. Further evidence is needed for non-beta-lactam antibiotics and asymptomatic individuals.

Impact analysis of expanding narrow-spectrum antibiotic use for children with ear, sinus and throat infections.

Aim: Estimate the impacts treating acute respiratory tract infections (ARTIs) in children aged 6 months through 12 years with narrow-spectrum antibiotics. Materials & methods: Decision-tree model to estimate children's health, healthcare utilization and costs, and caregiver's time and costs for using narrow-spectrum antibiotics in eligible children with an ARTI, compared with current use of narrow- and broad-spectrum antibiotics. Results: Reduced adverse drug reactions by 35,750 (14%) cases) and 4750 (12%) fewer emergency department visits, 300 (12%) fewer hospitalizations, and 50,500 (10%) avoided outpatient visits. Annual healthcare costs fell by US$120 million (22%). Total societal costs declined by US$131 million (20%). Conclusion: National implementation of narrow-spectrum antibiotics to treat ARTIs in children improves patient outcomes and reduces caregiver burden and annual healthcare costs.

A Review of Streptococcus pyogenes: Public Health Risk Factors, Prevention and Control.

Streptococcus pyogenes, (colloquially named "group A streptococcus" (GAS)), is a pathogen of public health significance, infecting 18.1 million people worldwide and resulting in 500,000 deaths each year. This review identified published articles on the risk factors and public health prevention and control strategies for mitigating GAS diseases. The pathogen causing GAS diseases is commonly transmitted via respiratory droplets, touching skin sores caused by GAS or through contact with contaminated material or equipment. Foodborne transmission is also possible, although there is need for further research to quantify this route of infection. It was found that GAS diseases are highly prevalent in developing countries, and among indigenous populations and low socioeconomic areas in developed countries. Children, the immunocompromised and the elderly are at the greatest risk of S. pyogenes infections and the associated sequelae, with transmission rates being higher in schools, kindergartens, hospitals and residential care homes. This was attributed to overcrowding and the higher level of social contact in these settings. Prevention and control measures should target the improvement of living conditions, and personal and hand hygiene. Adherence to infection prevention and control practices should be emphasized in high-risk settings. Resource distribution by governments, especially in developed countries, should also be considered.

Diagnostic Methods, Clinical Guidelines, and Antibiotic Treatment for Group A Streptococcal Pharyngitis: A Narrative Review.

The most common bacterial cause of pharyngitis is infection by Group A ß-hemolytic streptococcus (GABHS), commonly known as strep throat. 5-15% of adults and 15-35% of children in the United States with pharyngitis have a GABHS infection. The symptoms of GABHS overlap with non-GABHS and viral causes of acute pharyngitis, complicating the problem of diagnosis. A careful physical examination and patient history is the starting point for diagnosing GABHS. After a physical examination and patient history is completed, five types of diagnostic methods can be used to ascertain the presence of a GABHS infection: clinical scoring systems, rapid antigen detection tests, throat culture, nucleic acid amplification tests, and machine learning and artificial intelligence. Clinical guidelines developed by professional associations can help medical professionals choose among available techniques to diagnose strep throat. However, guidelines for diagnosing GABHS created by the American and European professional associations vary significantly, and there is substantial evidence that most physicians do not follow any published guidelines. Treatment for GABHS using analgesics, antipyretics, and antibiotics seeks to provide symptom relief, shorten the duration of illness, prevent nonsuppurative and suppurative complications, and decrease the risk of contagion, while minimizing the unnecessary use of antibiotics. There is broad agreement that antibiotics with narrow spectrums of activity are appropriate for treating strep throat. But whether and when patients should be treated with antibiotics for GABHS remains a controversial question. There is no clearly superior management strategy for strep throat, as significant controversy exists regarding the best methods to diagnose GABHS and under what conditions antibiotics should be prescribed.

Spontaneous Streptococcus pyogenes pelvic inflammatory disease; Case report and review of the literature.

Streptococcus pyogenes gynecological infections generally occur in association with childbirth, intra-uterine devices, and other invasive gynecologic procedures, but rarely cause spontaneous pelvic inflammatory disease. We describe a case of a healthy young woman with spontaneous S. pyogenes pelvic inflammatory disease, bacteremia, and shock, and summarize an additional 13 cases found in the literature. The majority were bacteremic and a significant number were also hypotensive. The same proportion had presenting gastrointestinal symptoms as had genitourinary symptoms, masking the diagnosis in many. Many prior case reports postulate a connection with S. pyogenes pharyngitis in a close contact, and an oro-genital route of transmission has been proposed given the exceedingly low rates of genital colonization with S. pyogenes. A high index of suspicion is needed for an accurate and timely diagnosis of this rare but potentially fatal condition.

Group A Streptococcal Infection During Pregnancy and the Postpartum Period.

Group A Streptococcus, the causative organism for "childbed fever," continues to pose a threat to women during pregnancy and the postpartum period, despite advances in hygiene and the development of antibiotic therapy. This resilient bacterium has resurfaced with intensified virulence, and, for reasons not entirely clear, causes severe disease in some women. Sepsis and toxic shock syndrome caused by Group A Streptococcus contribute to the alarming rates of maternal morbidity and mortality in the United States. Early recognition of the subtle signs and symptoms of sepsis is critical to decrease the risk for mortality; however, early signs can be elusive during the perinatal period because of the physiologic changes of pregnancy. Care management requires a coordinated, collaborative, multidisciplinary team approach. Sepsis is a clinical emergency, and health care providers need to respond as a well-prepared team.

Postpartum Invasive Group A Streptococcus Infection: Case Report and Mini-review.

The overall incidence of postpartum invasive group A streptococcal (GAS) disease is low in the United States. However, postpartum women are much more likely to develop GAS disease than nonpregnant women. Additionally, postpartum GAS has the potential to develop into a severe disease and a delay in diagnosis can have deadly consequences. This case describes a patient with invasive postpartum endometritis in the setting of diastases of the pubic symphysis. Sepsis secondary to the endometritis develops along with bilateral pneumonia. This case characterizes some of the typical and atypical symptoms a patient with invasive postpartum GAS can present with. Further, it outlines the timely identification of the disease and its appropriate treatment to prevent a potentially disastrous outcome.

The Shock of Strep: Rapid Deaths Due to Group a Streptococcus.

Streptococcus pyogenes, also known as group A beta-hemolytic strep, is a Gram positive coccus responsible for several million infections every year. The types of infections vary widely from pharyngitis to myositis, but all can advance to severe life threatening invasive disease. Of those infected, approximately 1100 to 1600 people die each year due to invasive disease. Why certain individuals contract severe infections is not known, but many strains of Streptococcus pyogenes are known to produce toxins and superantigens. Invasive Streptococcus pyogenes infections have been shown to cause significant morbidity and rapid mortality. In many cases, patients expire before full antemortem testing can be performed, causing physicians and families to look to forensic pathologists for answers. Understanding the pathogenesis of invasive group A strep infections, relevant gross and microscopic findings, and proper culturing techniques is critical for forensic pathologists to diagnosis this condition and assist in the education and protection of the communities they serve.

Utilization of influenza and streptococcal pharyngitis point-of-care testing in the community pharmacy practice setting.

BACKGROUND: One way to reduce the complications and costs of influenza like illness and pharyngitis is to improve access to testing and treatment in early stages of infection. Pharmacy-based screening and treatment of group A streptococcus (GAS) infection and influenza has the potential to improve patient care and population health. OBJECTIVE: To improve patient care and population health, the objective of this retrospective study was to assess if a previously validated service model could be implemented by pharmacy chains without mandated standardization. METHODS: Researchers utilized a certificate program to provide initial training to pharmacists and shared templates from previous validated models. Pharmacy companies were responsible for navigation of all implementation within their company. Researchers analyzed the de-identified data from patients seeking point-of-care testing from the participating pharmacies. RESULTS: Participating pharmacies reported 661 visits for adult (age 18 and over) patients tested for influenza for GAS pharyngitis. For the GAS patients, 91 (16.9%) tested positive. For the Influenza patients, 22.9% tested positive and 64 (77.1%) testing negative. Access to care was improved as patients presented to the visit outside normal clinic hours for 38% of the pharmacy visits, and 53.7% did not have a primary care provider. CONCLUSION: A collaborative care model for managing patients with symptoms consistent with influenza or group A streptococcus can be successfully implemented, and improve access to care outside of normal clinic hours and for those without a regular primary care provider.

Ensuring the Quality of Point-of-Care Testing in a Large and Decentralized Ambulatory Care Setting.

OBJECTIVES: In this project, we assessed the breadth, quality, trends, and outcomes of point-of-care (POC) testing and regulatory compliance in 200 University of California, Los Angeles (UCLA) Health system outpatient clinics. METHODS: We retrospectively extracted clinic POC test orders, results, and e-prescription data from the UCLA electronic health record over a 1-year period. RESULTS: Over 100,000 total tests were performed, encompassing 10 POC tests. Initially, 40% of clinics did not have complete licensure, but after implementation of the POC team, this metric improved to 100% licensure within 6 months. Most clinics used two or fewer POC tests, resulted fewer than 200 tests per year, and performed little to no external quality control measures. Our data analytics approach showed that peak POC testing occurred in January 2015, driven by influenza and urinalysis testing, and that both the testing and resulting clinical decision making do not routinely follow society guidelines. CONCLUSIONS: This decentralization of laboratory testing presents challenges to ensuring quality POC testing. Optimization and analysis of informatics data allow for the identification of POC test utilization trends, areas of improvement for clinical workflows, and increased education on national guidelines.

Incidence and Characteristics of Scarlet Fever, South Korea, 2008-2015.

The incidence rate for scarlet fever in South Korea is rising. During 2008-2015, we collected group A Streptococcus isolates and performed emm and exotoxin genotyping and disk-diffusion antimicrobial tests. Scarlet fever in South Korea was most closely associated with emm types emm4, emm28, emm1, and emm3. In 2015, tetracycline resistance started increasing.

Development of a recombinant fusion protein vaccine formulation to protect against Streptococcus pyogenes.

Diseases resulting from infection by group A streptococcus (GAS) are an increasing burden on global health. A novel vaccine was developed targeting infection by Streptococcus pyogenes. The vaccine incorporates a recombinant fusion protein antigen (SpeAB) which was engineered by combining inactive mutant forms of streptococcal pyrogenic exotoxin A (SpeA) and streptococcal pyrogenic exotoxin B (SpeB) from S. pyogenes. A rational, scientific approach to vaccine development was utilized to determine optimal formulation conditions with aluminum adjuvants. Investigations of the pH stability profile of SpeAB concluded the antigen was most stable near pH 8. Incorporation of the stabilizers sucrose and mannitol significantly enhanced the stability of the antigen. Vaccines were formulated in which most of the SpeAB was adsorbed to the adjuvant or remained in solution. A SpeAB vaccine formulation, stabilized with sucrose, in which the antigen remains adsorbed to the aluminum adjuvant retained the greatest potency as determined by evaluation of neutralizing antibody responses in mice. This vaccine has great potential to provide a safe and effective method for prevention of GAS disease.