Cost-Effective Solutions to Prevent Orthopedic Infections

The unprecedented rising cost of health­ care in the United States has been at the forefront of national debate for the past decade and represents a seri­ous threat to the infrastructure of our society. Health care costs are currently following an unsustainable growth rate and are projected to constitute 34% of the US gross domestic prod­uct by 2040. Commercial and government payers have become increasingly interested in improved resource utilization through regulation, price fixing, and assigning value levels to physician care as a means of cutting costs and improving quality of care. A key component of transitioning from a volume-driven to a value-driven model is individual surgeon accountability to make use of effective, inexpensive solutions supported by cost-effectiveness data. Groups such as the Social and Economic Value of Orthopaedic Surgery Project Team, lead by current AAOS president Dr. John R. Tongue, represent a modern, proactive approach by surgeons to take personal responsibility for reducing health care spending. However, while we often think of technological innovation as the primary means to provide improved health care solutions, these answers are often expensive and impracti­cal when applied large-scale. Recent findings in the field of perioperative infec­tions show us that we cannot forget to look at past discoveries in other medical disciplines that may offer cost-effective adaptations in orthopedic surgery.^1-3

Perioperative infections after orthopedic procedures can be devastating complications for patients, families, and physicians alike, with an enor­mous cost to the health care system. The morbidity from surgical site infec­tions includes pain, loss of function, increased hospitalization, prolonged rehabilitation, and higher rates of reoperation.⁴ Research has shown that certain orthopedic operations have a significantly greater risk of infection such as revision total knee arthroplasty, ankle fusion, and subtalar fusion.⁵ Specialty areas, such as foot and ankle surgery in particular, have been shown to have higher infection rates, compared with other procedures.⁶ The resource allocation and financial costs of treating perioperative infec­tions in orthopedic surgery can often rise 3-13 times more than the cost of the index procedure, thus mak­ing perioperative infections an ideal target for cost-effective solutions in a value-driven health care model.^7,8 There is a tremendous need for effec­tive, low-cost, safe, and easy to use methods of preventing perioperative infections after orthopedic proce­dures, and dilute Betadine lavage is an example of such a solution.

Povidone-iodine is a stable chemi­cal complex of polyvinylpyrrolidone and elemental iodine (9-12%) that was first sold in 1955 and is now one of the most widely used antiseptics for skin, mucous membranes, and wounds. Betadine is a brand name for a range of povidone-iodine topi­cal antiseptics and has been shown to have bactericidal activity against multiple pathogens, including meth­icillin-resistant Staphlococcus aure­us.⁹ It is cheap ($1), safe, fast, widely used, and easy to alter into various concentrations. The earliest study by Sindelar and Mason¹⁰ investigating the potential decreases in periopera­tive infection rates with dilute povi­done-iodine irrigation in general and urologic surgery date back as early as 1977. Since then, there have been 14 studies conducted in multiple coun­tries, involving the fields of general, cardiovascular, and urologic surgery. Many of these studies showed similar decreases in infection rates before the idea of using a dilute Betadine lavage was implemented in orthopedic sur­gery 3 decades later.¹¹

In 2005, Cheng and colleagues¹² prospectively studied the effect of a dilute 3.5% Betadine 3-minute lavage on the incidence of postoperative spine infections. They found a significant decrease in infection rate, compared with saline lavage alone, without adverse effects on clinical outcomes. Recently, a research group led by Dr. Craig Della Valle¹³ demonstrated that a 0.35% Betadine lavage for 3 minutes significantly lowered the rate of acute postoperative infection after total hip and knee arthroplasty from 0.97% to 0.15% in a group of 2550 patients.

Using inexpensive tools that cur­rently exist and applying them in new and innovative ways, represents an area of orthopedic research that should be further pursued and that may pro­vide the cost-effective solutions that the current healthcare environment demands. Parvizi² recently showed that levels of synovial C-reactive pro­tein (CRP) could help differentiate between infected and uninfected revi­sion total knee arthroplasties with a sensitivity of 70% and specificity of 100%. CRP is a relatively inexpen­sive ($15), widely used laboratory test that has been known to rise in response to acute inflammation since its discovery in 1930 by Tillett and Francis.¹⁴ The use of serum CRP has changed the management of ortho­pedic perioperative infections, and specifically, the diagnosis algorithm for periprosthetic joint infections.13 CRP represents another example of how using old tools in new ways can address both orthopedic and resource management needs. The use of intra­wound vancomycin powder ($12) to decrease postsurgical wound infec­tion in instrumented thoracolumbar fusions may also represent a cost-effective method of infection pre­vention that is applicable to other orthopedic specialties and should be explored further.³

The price of innovation does not need to be high and with the current economic environment and rising costs of health care, it is doubtful that expen­sive solutions to common orthopedic problems will be feasible or sustain­able when increased in scale. We need to focus more attention on how to improve our resourcefulness and col­laboration with other medical disci­plines to foster creative and innovative low-cost solutions to challenging prob­lems. The examples discussed here of dilute Betadine lavage, CRP assays, and vancomycin powder are recent and relevant examples in the orthopedic literature that show that these solutions can and do exist. Furthermore, these existing technologies warrant further research across additional orthopedic specialties to improve the quality of patient care without the additional cost. Translational research has become a cornerstone of modern medicine and is often described as the synthesis of basic and applied research in order to take basic science advancements and turn them into clinical treatments in a “bench-to-bedside” model. What we should not forget is that translation can take many forms and that discovering new applications to existing technolo­gies may represent a form of transla­tional research in orthopedics that can improve our field within the framework of healthcare reform. Future solutions may exist by looking at the past, but only if we keep our eyes open for them.

Author's Disclosure Statement. The author reports no actual or poten­tial conflict of interest in relation to this article.

REFERENCES
1. Brown NM, Cipriano CA, Moric M, Sporer SM, Della Valle CJ. Dilute betadine lavage before closure for the prevention of acute postop­erative deep periprosthetic joint infection. J Arthroplasty. 2012;27:27-30.
2. Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry Award: synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin Orthop Relat Res. 2012;470:54-60.
3. Sweet FA, Roh M, Sliva C. Intrawound applica­tion of vancomycin for prophylaxis in instru­mented thoracolumbar fusions: efficacy, drug levels, and patient outcomes. Spine (PhilaPa 1976). 2011;36:2084-2088.
4. Garvin KL, Konigsberg BS. Infection following total knee arthroplasty: prevention and management. J Bone Joint Surg Am. 2011;93:1167-1175.
5. Taylor GJ, Bannister GC, Calder S. Perioperative wound infection in elective orthopaedic surgery. J Hosp Infect. 1990;16:241-247.
6. Miller WA. Postoperative wound infection in foot and ankle surgery. Foot Ankle. 1983;4:102-104.
7. Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty. 2008;23:984-991.
8. Calderone RR, GarlandDE, Capen DA, Oster H. Cost of medical care for postoperative spinal infec­tions. Orthop Clin North Am. 1996;27:171-182.
9. McLure AR, Gordon J. In-vitro evaluation of povidone-iodine and chlorhexidine against methicillin-resistant Staphylococcus aureus. J Hosp Infect. 1992;21:291-229.
10. Sindelar WF, Mason GR. Efficacy of povidone-iodine irrigation in prevention of surgical wound infections. Surg Forum. 1977;28:48-51.
11. Chundamala J, Wright JG. The efficacy and risks of using povidone-iodine irrigation to pre­vent surgical site infection: an evidence-based review. Can J Surg. 2007;50:473-481.
12. Cheng MT, Chang MC, Wang ST, Yu WK, Liu CL, Chen TH. Efficacy of dilute betadine solu­tion irrigation in the prevention of postopera­tive infection of spinal surgery. Spine (PhilaPa 1976). 2005;30:1689-1693.
13. Della Valle C, Parvizi J, Bauer TW, et al. AmericanAcademy of Orthopaedic Surgeons clinical prac­tice guideline on: the diagnosis of periprosthetic joint infections of the hip and knee. J Bone Joint Surg Am. 2011;93:1355-1357.
14. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med.1930;52:561-571.

The unprecedented rising cost of health­ care in the United States has been at the forefront of national debate for the past decade and represents a seri­ous threat to the infrastructure of our society. Health care costs are currently following an unsustainable growth rate and are projected to constitute 34% of the US gross domestic prod­uct by 2040. Commercial and government payers have become increasingly interested in improved resource utilization through regulation, price fixing, and assigning value levels to physician care as a means of cutting costs and improving quality of care. A key component of transitioning from a volume-driven to a value-driven model is individual surgeon accountability to make use of effective, inexpensive solutions supported by cost-effectiveness data. Groups such as the Social and Economic Value of Orthopaedic Surgery Project Team, lead by current AAOS president Dr. John R. Tongue, represent a modern, proactive approach by surgeons to take personal responsibility for reducing health care spending. However, while we often think of technological innovation as the primary means to provide improved health care solutions, these answers are often expensive and impracti­cal when applied large-scale. Recent findings in the field of perioperative infec­tions show us that we cannot forget to look at past discoveries in other medical disciplines that may offer cost-effective adaptations in orthopedic surgery.^1-3

Perioperative infections after orthopedic procedures can be devastating complications for patients, families, and physicians alike, with an enor­mous cost to the health care system. The morbidity from surgical site infec­tions includes pain, loss of function, increased hospitalization, prolonged rehabilitation, and higher rates of reoperation.⁴ Research has shown that certain orthopedic operations have a significantly greater risk of infection such as revision total knee arthroplasty, ankle fusion, and subtalar fusion.⁵ Specialty areas, such as foot and ankle surgery in particular, have been shown to have higher infection rates, compared with other procedures.⁶ The resource allocation and financial costs of treating perioperative infec­tions in orthopedic surgery can often rise 3-13 times more than the cost of the index procedure, thus mak­ing perioperative infections an ideal target for cost-effective solutions in a value-driven health care model.^7,8 There is a tremendous need for effec­tive, low-cost, safe, and easy to use methods of preventing perioperative infections after orthopedic proce­dures, and dilute Betadine lavage is an example of such a solution.

Povidone-iodine is a stable chemi­cal complex of polyvinylpyrrolidone and elemental iodine (9-12%) that was first sold in 1955 and is now one of the most widely used antiseptics for skin, mucous membranes, and wounds. Betadine is a brand name for a range of povidone-iodine topi­cal antiseptics and has been shown to have bactericidal activity against multiple pathogens, including meth­icillin-resistant Staphlococcus aure­us.⁹ It is cheap ($1), safe, fast, widely used, and easy to alter into various concentrations. The earliest study by Sindelar and Mason¹⁰ investigating the potential decreases in periopera­tive infection rates with dilute povi­done-iodine irrigation in general and urologic surgery date back as early as 1977. Since then, there have been 14 studies conducted in multiple coun­tries, involving the fields of general, cardiovascular, and urologic surgery. Many of these studies showed similar decreases in infection rates before the idea of using a dilute Betadine lavage was implemented in orthopedic sur­gery 3 decades later.¹¹

In 2005, Cheng and colleagues¹² prospectively studied the effect of a dilute 3.5% Betadine 3-minute lavage on the incidence of postoperative spine infections. They found a significant decrease in infection rate, compared with saline lavage alone, without adverse effects on clinical outcomes. Recently, a research group led by Dr. Craig Della Valle¹³ demonstrated that a 0.35% Betadine lavage for 3 minutes significantly lowered the rate of acute postoperative infection after total hip and knee arthroplasty from 0.97% to 0.15% in a group of 2550 patients.

Using inexpensive tools that cur­rently exist and applying them in new and innovative ways, represents an area of orthopedic research that should be further pursued and that may pro­vide the cost-effective solutions that the current healthcare environment demands. Parvizi² recently showed that levels of synovial C-reactive pro­tein (CRP) could help differentiate between infected and uninfected revi­sion total knee arthroplasties with a sensitivity of 70% and specificity of 100%. CRP is a relatively inexpen­sive ($15), widely used laboratory test that has been known to rise in response to acute inflammation since its discovery in 1930 by Tillett and Francis.¹⁴ The use of serum CRP has changed the management of ortho­pedic perioperative infections, and specifically, the diagnosis algorithm for periprosthetic joint infections.13 CRP represents another example of how using old tools in new ways can address both orthopedic and resource management needs. The use of intra­wound vancomycin powder ($12) to decrease postsurgical wound infec­tion in instrumented thoracolumbar fusions may also represent a cost-effective method of infection pre­vention that is applicable to other orthopedic specialties and should be explored further.³

The price of innovation does not need to be high and with the current economic environment and rising costs of health care, it is doubtful that expen­sive solutions to common orthopedic problems will be feasible or sustain­able when increased in scale. We need to focus more attention on how to improve our resourcefulness and col­laboration with other medical disci­plines to foster creative and innovative low-cost solutions to challenging prob­lems. The examples discussed here of dilute Betadine lavage, CRP assays, and vancomycin powder are recent and relevant examples in the orthopedic literature that show that these solutions can and do exist. Furthermore, these existing technologies warrant further research across additional orthopedic specialties to improve the quality of patient care without the additional cost. Translational research has become a cornerstone of modern medicine and is often described as the synthesis of basic and applied research in order to take basic science advancements and turn them into clinical treatments in a “bench-to-bedside” model. What we should not forget is that translation can take many forms and that discovering new applications to existing technolo­gies may represent a form of transla­tional research in orthopedics that can improve our field within the framework of healthcare reform. Future solutions may exist by looking at the past, but only if we keep our eyes open for them.

Author's Disclosure Statement. The author reports no actual or poten­tial conflict of interest in relation to this article.

REFERENCES
1. Brown NM, Cipriano CA, Moric M, Sporer SM, Della Valle CJ. Dilute betadine lavage before closure for the prevention of acute postop­erative deep periprosthetic joint infection. J Arthroplasty. 2012;27:27-30.
2. Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry Award: synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin Orthop Relat Res. 2012;470:54-60.
3. Sweet FA, Roh M, Sliva C. Intrawound applica­tion of vancomycin for prophylaxis in instru­mented thoracolumbar fusions: efficacy, drug levels, and patient outcomes. Spine (PhilaPa 1976). 2011;36:2084-2088.
4. Garvin KL, Konigsberg BS. Infection following total knee arthroplasty: prevention and management. J Bone Joint Surg Am. 2011;93:1167-1175.
5. Taylor GJ, Bannister GC, Calder S. Perioperative wound infection in elective orthopaedic surgery. J Hosp Infect. 1990;16:241-247.
6. Miller WA. Postoperative wound infection in foot and ankle surgery. Foot Ankle. 1983;4:102-104.
7. Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty. 2008;23:984-991.
8. Calderone RR, GarlandDE, Capen DA, Oster H. Cost of medical care for postoperative spinal infec­tions. Orthop Clin North Am. 1996;27:171-182.
9. McLure AR, Gordon J. In-vitro evaluation of povidone-iodine and chlorhexidine against methicillin-resistant Staphylococcus aureus. J Hosp Infect. 1992;21:291-229.
10. Sindelar WF, Mason GR. Efficacy of povidone-iodine irrigation in prevention of surgical wound infections. Surg Forum. 1977;28:48-51.
11. Chundamala J, Wright JG. The efficacy and risks of using povidone-iodine irrigation to pre­vent surgical site infection: an evidence-based review. Can J Surg. 2007;50:473-481.
12. Cheng MT, Chang MC, Wang ST, Yu WK, Liu CL, Chen TH. Efficacy of dilute betadine solu­tion irrigation in the prevention of postopera­tive infection of spinal surgery. Spine (PhilaPa 1976). 2005;30:1689-1693.
13. Della Valle C, Parvizi J, Bauer TW, et al. AmericanAcademy of Orthopaedic Surgeons clinical prac­tice guideline on: the diagnosis of periprosthetic joint infections of the hip and knee. J Bone Joint Surg Am. 2011;93:1355-1357.
14. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med.1930;52:561-571.

The unprecedented rising cost of health­ care in the United States has been at the forefront of national debate for the past decade and represents a seri­ous threat to the infrastructure of our society. Health care costs are currently following an unsustainable growth rate and are projected to constitute 34% of the US gross domestic prod­uct by 2040. Commercial and government payers have become increasingly interested in improved resource utilization through regulation, price fixing, and assigning value levels to physician care as a means of cutting costs and improving quality of care. A key component of transitioning from a volume-driven to a value-driven model is individual surgeon accountability to make use of effective, inexpensive solutions supported by cost-effectiveness data. Groups such as the Social and Economic Value of Orthopaedic Surgery Project Team, lead by current AAOS president Dr. John R. Tongue, represent a modern, proactive approach by surgeons to take personal responsibility for reducing health care spending. However, while we often think of technological innovation as the primary means to provide improved health care solutions, these answers are often expensive and impracti­cal when applied large-scale. Recent findings in the field of perioperative infec­tions show us that we cannot forget to look at past discoveries in other medical disciplines that may offer cost-effective adaptations in orthopedic surgery.^1-3

Perioperative infections after orthopedic procedures can be devastating complications for patients, families, and physicians alike, with an enor­mous cost to the health care system. The morbidity from surgical site infec­tions includes pain, loss of function, increased hospitalization, prolonged rehabilitation, and higher rates of reoperation.⁴ Research has shown that certain orthopedic operations have a significantly greater risk of infection such as revision total knee arthroplasty, ankle fusion, and subtalar fusion.⁵ Specialty areas, such as foot and ankle surgery in particular, have been shown to have higher infection rates, compared with other procedures.⁶ The resource allocation and financial costs of treating perioperative infec­tions in orthopedic surgery can often rise 3-13 times more than the cost of the index procedure, thus mak­ing perioperative infections an ideal target for cost-effective solutions in a value-driven health care model.^7,8 There is a tremendous need for effec­tive, low-cost, safe, and easy to use methods of preventing perioperative infections after orthopedic proce­dures, and dilute Betadine lavage is an example of such a solution.

Povidone-iodine is a stable chemi­cal complex of polyvinylpyrrolidone and elemental iodine (9-12%) that was first sold in 1955 and is now one of the most widely used antiseptics for skin, mucous membranes, and wounds. Betadine is a brand name for a range of povidone-iodine topi­cal antiseptics and has been shown to have bactericidal activity against multiple pathogens, including meth­icillin-resistant Staphlococcus aure­us.⁹ It is cheap ($1), safe, fast, widely used, and easy to alter into various concentrations. The earliest study by Sindelar and Mason¹⁰ investigating the potential decreases in periopera­tive infection rates with dilute povi­done-iodine irrigation in general and urologic surgery date back as early as 1977. Since then, there have been 14 studies conducted in multiple coun­tries, involving the fields of general, cardiovascular, and urologic surgery. Many of these studies showed similar decreases in infection rates before the idea of using a dilute Betadine lavage was implemented in orthopedic sur­gery 3 decades later.¹¹

In 2005, Cheng and colleagues¹² prospectively studied the effect of a dilute 3.5% Betadine 3-minute lavage on the incidence of postoperative spine infections. They found a significant decrease in infection rate, compared with saline lavage alone, without adverse effects on clinical outcomes. Recently, a research group led by Dr. Craig Della Valle¹³ demonstrated that a 0.35% Betadine lavage for 3 minutes significantly lowered the rate of acute postoperative infection after total hip and knee arthroplasty from 0.97% to 0.15% in a group of 2550 patients.

Using inexpensive tools that cur­rently exist and applying them in new and innovative ways, represents an area of orthopedic research that should be further pursued and that may pro­vide the cost-effective solutions that the current healthcare environment demands. Parvizi² recently showed that levels of synovial C-reactive pro­tein (CRP) could help differentiate between infected and uninfected revi­sion total knee arthroplasties with a sensitivity of 70% and specificity of 100%. CRP is a relatively inexpen­sive ($15), widely used laboratory test that has been known to rise in response to acute inflammation since its discovery in 1930 by Tillett and Francis.¹⁴ The use of serum CRP has changed the management of ortho­pedic perioperative infections, and specifically, the diagnosis algorithm for periprosthetic joint infections.13 CRP represents another example of how using old tools in new ways can address both orthopedic and resource management needs. The use of intra­wound vancomycin powder ($12) to decrease postsurgical wound infec­tion in instrumented thoracolumbar fusions may also represent a cost-effective method of infection pre­vention that is applicable to other orthopedic specialties and should be explored further.³

The price of innovation does not need to be high and with the current economic environment and rising costs of health care, it is doubtful that expen­sive solutions to common orthopedic problems will be feasible or sustain­able when increased in scale. We need to focus more attention on how to improve our resourcefulness and col­laboration with other medical disci­plines to foster creative and innovative low-cost solutions to challenging prob­lems. The examples discussed here of dilute Betadine lavage, CRP assays, and vancomycin powder are recent and relevant examples in the orthopedic literature that show that these solutions can and do exist. Furthermore, these existing technologies warrant further research across additional orthopedic specialties to improve the quality of patient care without the additional cost. Translational research has become a cornerstone of modern medicine and is often described as the synthesis of basic and applied research in order to take basic science advancements and turn them into clinical treatments in a “bench-to-bedside” model. What we should not forget is that translation can take many forms and that discovering new applications to existing technolo­gies may represent a form of transla­tional research in orthopedics that can improve our field within the framework of healthcare reform. Future solutions may exist by looking at the past, but only if we keep our eyes open for them.

Author's Disclosure Statement. The author reports no actual or poten­tial conflict of interest in relation to this article.

REFERENCES
1. Brown NM, Cipriano CA, Moric M, Sporer SM, Della Valle CJ. Dilute betadine lavage before closure for the prevention of acute postop­erative deep periprosthetic joint infection. J Arthroplasty. 2012;27:27-30.
2. Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry Award: synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin Orthop Relat Res. 2012;470:54-60.
3. Sweet FA, Roh M, Sliva C. Intrawound applica­tion of vancomycin for prophylaxis in instru­mented thoracolumbar fusions: efficacy, drug levels, and patient outcomes. Spine (PhilaPa 1976). 2011;36:2084-2088.
4. Garvin KL, Konigsberg BS. Infection following total knee arthroplasty: prevention and management. J Bone Joint Surg Am. 2011;93:1167-1175.
5. Taylor GJ, Bannister GC, Calder S. Perioperative wound infection in elective orthopaedic surgery. J Hosp Infect. 1990;16:241-247.
6. Miller WA. Postoperative wound infection in foot and ankle surgery. Foot Ankle. 1983;4:102-104.
7. Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty. 2008;23:984-991.
8. Calderone RR, GarlandDE, Capen DA, Oster H. Cost of medical care for postoperative spinal infec­tions. Orthop Clin North Am. 1996;27:171-182.
9. McLure AR, Gordon J. In-vitro evaluation of povidone-iodine and chlorhexidine against methicillin-resistant Staphylococcus aureus. J Hosp Infect. 1992;21:291-229.
10. Sindelar WF, Mason GR. Efficacy of povidone-iodine irrigation in prevention of surgical wound infections. Surg Forum. 1977;28:48-51.
11. Chundamala J, Wright JG. The efficacy and risks of using povidone-iodine irrigation to pre­vent surgical site infection: an evidence-based review. Can J Surg. 2007;50:473-481.
12. Cheng MT, Chang MC, Wang ST, Yu WK, Liu CL, Chen TH. Efficacy of dilute betadine solu­tion irrigation in the prevention of postopera­tive infection of spinal surgery. Spine (PhilaPa 1976). 2005;30:1689-1693.
13. Della Valle C, Parvizi J, Bauer TW, et al. AmericanAcademy of Orthopaedic Surgeons clinical prac­tice guideline on: the diagnosis of periprosthetic joint infections of the hip and knee. J Bone Joint Surg Am. 2011;93:1355-1357.
14. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med.1930;52:561-571.