HCA of Nashville, Tenn., had more discharges in 2016 than any other health system in the United States, according to the Agency for Healthcare Research and Quality.

HCA’s 192 hospitals recorded over 1.7 million discharges last year, more than twice as many as Ascension Health in St. Louis, which discharged almost 860,000 patients from its 136 hospitals. Tennessee is also the home of the nation’s third-largest health system, Community Health Systems of Franklin, which totaled just over 805,000 discharges in 2016. Tenet Healthcare Corporation in Dallas was fourth with 752,000 discharges, and Trinity Health in Livonia, Mich., was fifth with 737,000 discharges, the AHRQ said in its Compendium of U.S. Health Systems, 2016.

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HCA of Nashville, Tenn., had more discharges in 2016 than any other health system in the United States, according to the Agency for Healthcare Research and Quality.

HCA’s 192 hospitals recorded over 1.7 million discharges last year, more than twice as many as Ascension Health in St. Louis, which discharged almost 860,000 patients from its 136 hospitals. Tennessee is also the home of the nation’s third-largest health system, Community Health Systems of Franklin, which totaled just over 805,000 discharges in 2016. Tenet Healthcare Corporation in Dallas was fourth with 752,000 discharges, and Trinity Health in Livonia, Mich., was fifth with 737,000 discharges, the AHRQ said in its Compendium of U.S. Health Systems, 2016.

[email protected]

HCA of Nashville, Tenn., had more discharges in 2016 than any other health system in the United States, according to the Agency for Healthcare Research and Quality.

HCA’s 192 hospitals recorded over 1.7 million discharges last year, more than twice as many as Ascension Health in St. Louis, which discharged almost 860,000 patients from its 136 hospitals. Tennessee is also the home of the nation’s third-largest health system, Community Health Systems of Franklin, which totaled just over 805,000 discharges in 2016. Tenet Healthcare Corporation in Dallas was fourth with 752,000 discharges, and Trinity Health in Livonia, Mich., was fifth with 737,000 discharges, the AHRQ said in its Compendium of U.S. Health Systems, 2016.

[email protected]

Q1: Answer: A

Campylobacter species are a major cause of diarrheal illness in the world. The organism inhabits the intestinal tracts of a wide range of animal hosts, notably poultry; contamination from these sources can lead to foodborne disease. Given the self-limited nature of most Campylobacter infections and the limited efficacy of routine antimicrobial therapy, treatment is warranted only for patients with features of severe disease or risk for severe disease.

Patients with severe disease include individuals with bloody stools, high fever, extra-intestinal infection, worsening or relapsing symptoms, or symptoms lasting longer than 1 week. Those at risk for severe disease include patients who are elderly, pregnant, or immunocompromised. First-line agents for treatment of Campylobacter infection include fluoroquinolones (if sensitive) or azithromycin. Campylobacter is inherently resistant to trimethoprim and beta-lactam antibiotics, including penicillin and most cephalosporins.

In the United States, the rate of resistance to fluoroquinolones is also increasing. The rate of ciprofloxacin resistance among Campylobacter isolated in the United States increased from 0% to 19% between 1989 and 2001. Inappropriate and overprescription of fluoroquinolones in humans combined with increased fluoroquinolone use in the poultry industry in particular have contributed to the increased prevalence of fluoroquinolone resistance.

The rate of macrolide-resistance among Campylobacter has remained stable at less than 5% in most parts of the world.

References

1. Dasti J.I., Tareen A.M., Lugert R., et al. Campylobacter jejuni: A brief overview on pathogenicity-associated factors and disease-mediating mechanisms. Int J Med Microbiol. 2010;300:205–11.

2. Gupta A., Nelson J.M., Barrett T.J., et al. Antimicrobial resistance among Campylobacter strains, United States, 1997-2001. Emerging infectious diseases. Jun 2004;10(6):1102-9.

Q1: Answer: A

Campylobacter species are a major cause of diarrheal illness in the world. The organism inhabits the intestinal tracts of a wide range of animal hosts, notably poultry; contamination from these sources can lead to foodborne disease. Given the self-limited nature of most Campylobacter infections and the limited efficacy of routine antimicrobial therapy, treatment is warranted only for patients with features of severe disease or risk for severe disease.

Patients with severe disease include individuals with bloody stools, high fever, extra-intestinal infection, worsening or relapsing symptoms, or symptoms lasting longer than 1 week. Those at risk for severe disease include patients who are elderly, pregnant, or immunocompromised. First-line agents for treatment of Campylobacter infection include fluoroquinolones (if sensitive) or azithromycin. Campylobacter is inherently resistant to trimethoprim and beta-lactam antibiotics, including penicillin and most cephalosporins.

In the United States, the rate of resistance to fluoroquinolones is also increasing. The rate of ciprofloxacin resistance among Campylobacter isolated in the United States increased from 0% to 19% between 1989 and 2001. Inappropriate and overprescription of fluoroquinolones in humans combined with increased fluoroquinolone use in the poultry industry in particular have contributed to the increased prevalence of fluoroquinolone resistance.

The rate of macrolide-resistance among Campylobacter has remained stable at less than 5% in most parts of the world.

References

1. Dasti J.I., Tareen A.M., Lugert R., et al. Campylobacter jejuni: A brief overview on pathogenicity-associated factors and disease-mediating mechanisms. Int J Med Microbiol. 2010;300:205–11.

2. Gupta A., Nelson J.M., Barrett T.J., et al. Antimicrobial resistance among Campylobacter strains, United States, 1997-2001. Emerging infectious diseases. Jun 2004;10(6):1102-9.

Q1: Answer: A

Campylobacter species are a major cause of diarrheal illness in the world. The organism inhabits the intestinal tracts of a wide range of animal hosts, notably poultry; contamination from these sources can lead to foodborne disease. Given the self-limited nature of most Campylobacter infections and the limited efficacy of routine antimicrobial therapy, treatment is warranted only for patients with features of severe disease or risk for severe disease.

Patients with severe disease include individuals with bloody stools, high fever, extra-intestinal infection, worsening or relapsing symptoms, or symptoms lasting longer than 1 week. Those at risk for severe disease include patients who are elderly, pregnant, or immunocompromised. First-line agents for treatment of Campylobacter infection include fluoroquinolones (if sensitive) or azithromycin. Campylobacter is inherently resistant to trimethoprim and beta-lactam antibiotics, including penicillin and most cephalosporins.

In the United States, the rate of resistance to fluoroquinolones is also increasing. The rate of ciprofloxacin resistance among Campylobacter isolated in the United States increased from 0% to 19% between 1989 and 2001. Inappropriate and overprescription of fluoroquinolones in humans combined with increased fluoroquinolone use in the poultry industry in particular have contributed to the increased prevalence of fluoroquinolone resistance.

The rate of macrolide-resistance among Campylobacter has remained stable at less than 5% in most parts of the world.

References

1. Dasti J.I., Tareen A.M., Lugert R., et al. Campylobacter jejuni: A brief overview on pathogenicity-associated factors and disease-mediating mechanisms. Int J Med Microbiol. 2010;300:205–11.

2. Gupta A., Nelson J.M., Barrett T.J., et al. Antimicrobial resistance among Campylobacter strains, United States, 1997-2001. Emerging infectious diseases. Jun 2004;10(6):1102-9.

The diagnosis

Answer: Necrolytic acral erythema

The patient’s clinicopathologic picture is consistent with necrolytic acral erythema (NAE). Notably, her serum zinc level was 121 mcg/dL (normal is greater than 55 mcg/dL). The patient was started on oral zinc supplementation. Several days after initiation of zinc therapy, her pain and pruritus dramatically improved.

NAE is a rare condition, first described in a cohort study of seven Egyptian patients with active HCV infection in 1996, and is considered a distinctive cutaneous presentation of HCV infection.¹ Clinical presentation typically involves severe pruritus on acral surfaces accompanied by pain and a burning sensation. The skin findings include well-circumscribed, dusky, erythematous to hyperpigmented plaques with variable scaling and erosion that extend from dorsal feet to the legs. The pathogenesis of NAE remains unknown. However, it has been proposed that zinc deficiency and dysregulation secondary to hepatocellular dysfunction in HCV infection, is associated with NAE.²

Zinc supplementation has shown favorable outcomes in NAE patients with zinc deficiency.³ However, the appropriate threshold of serum zinc level in patients with NAE is unclear. Herein, we have reported a patient with NAE who responded to zinc supplementation despite a normal zinc level. A plausible explanation is that clinical zinc deficiency may occur in the skin before the development of decreased serum zinc levels.

Skin pruritus is a common presentation in patients with chronic HCV infection. Increased awareness of the distinct features of NAE may result in early diagnosis and initiation of effective therapy. Zinc supplementation may be beneficial in NAE patients with and without decreased serum zinc level.

References

1. el Darouti, M., Abu el Ela, M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol. 1996;35:252-6.

2. Hadziyannis, S.J. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol. 1998;10:12-21.

3. Abdallah, M.A., Hull, C., Horn, T.D. Necrolytic acral erythema: A patient from the United States successfully treated with oral zinc. Arch Dermatol. 2005;141:85-7.

The diagnosis

Answer: Necrolytic acral erythema

The patient’s clinicopathologic picture is consistent with necrolytic acral erythema (NAE). Notably, her serum zinc level was 121 mcg/dL (normal is greater than 55 mcg/dL). The patient was started on oral zinc supplementation. Several days after initiation of zinc therapy, her pain and pruritus dramatically improved.

NAE is a rare condition, first described in a cohort study of seven Egyptian patients with active HCV infection in 1996, and is considered a distinctive cutaneous presentation of HCV infection.¹ Clinical presentation typically involves severe pruritus on acral surfaces accompanied by pain and a burning sensation. The skin findings include well-circumscribed, dusky, erythematous to hyperpigmented plaques with variable scaling and erosion that extend from dorsal feet to the legs. The pathogenesis of NAE remains unknown. However, it has been proposed that zinc deficiency and dysregulation secondary to hepatocellular dysfunction in HCV infection, is associated with NAE.²

Zinc supplementation has shown favorable outcomes in NAE patients with zinc deficiency.³ However, the appropriate threshold of serum zinc level in patients with NAE is unclear. Herein, we have reported a patient with NAE who responded to zinc supplementation despite a normal zinc level. A plausible explanation is that clinical zinc deficiency may occur in the skin before the development of decreased serum zinc levels.

Skin pruritus is a common presentation in patients with chronic HCV infection. Increased awareness of the distinct features of NAE may result in early diagnosis and initiation of effective therapy. Zinc supplementation may be beneficial in NAE patients with and without decreased serum zinc level.

References

1. el Darouti, M., Abu el Ela, M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol. 1996;35:252-6.

2. Hadziyannis, S.J. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol. 1998;10:12-21.

3. Abdallah, M.A., Hull, C., Horn, T.D. Necrolytic acral erythema: A patient from the United States successfully treated with oral zinc. Arch Dermatol. 2005;141:85-7.

The diagnosis

Answer: Necrolytic acral erythema

The patient’s clinicopathologic picture is consistent with necrolytic acral erythema (NAE). Notably, her serum zinc level was 121 mcg/dL (normal is greater than 55 mcg/dL). The patient was started on oral zinc supplementation. Several days after initiation of zinc therapy, her pain and pruritus dramatically improved.

NAE is a rare condition, first described in a cohort study of seven Egyptian patients with active HCV infection in 1996, and is considered a distinctive cutaneous presentation of HCV infection.¹ Clinical presentation typically involves severe pruritus on acral surfaces accompanied by pain and a burning sensation. The skin findings include well-circumscribed, dusky, erythematous to hyperpigmented plaques with variable scaling and erosion that extend from dorsal feet to the legs. The pathogenesis of NAE remains unknown. However, it has been proposed that zinc deficiency and dysregulation secondary to hepatocellular dysfunction in HCV infection, is associated with NAE.²

Zinc supplementation has shown favorable outcomes in NAE patients with zinc deficiency.³ However, the appropriate threshold of serum zinc level in patients with NAE is unclear. Herein, we have reported a patient with NAE who responded to zinc supplementation despite a normal zinc level. A plausible explanation is that clinical zinc deficiency may occur in the skin before the development of decreased serum zinc levels.

Skin pruritus is a common presentation in patients with chronic HCV infection. Increased awareness of the distinct features of NAE may result in early diagnosis and initiation of effective therapy. Zinc supplementation may be beneficial in NAE patients with and without decreased serum zinc level.

References

1. el Darouti, M., Abu el Ela, M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol. 1996;35:252-6.

2. Hadziyannis, S.J. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol. 1998;10:12-21.

3. Abdallah, M.A., Hull, C., Horn, T.D. Necrolytic acral erythema: A patient from the United States successfully treated with oral zinc. Arch Dermatol. 2005;141:85-7.

DALLAS – Older patients with carpal tunnel syndrome that requires release surgery appear to have a relatively high prevalence of amyloidosis that, in some, involves their heart, suggesting that routine screening for amyloidosis is warranted in elderly patients undergoing the surgery.

Routine Congo red staining of a tenosynovial biopsy taken at the time of carpal tunnel release surgery in a single-center experience with 96 patients showed that 10 (10%) were positive for amyloidosis, Mazen Hanna, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

DALLAS – Older patients with carpal tunnel syndrome that requires release surgery appear to have a relatively high prevalence of amyloidosis that, in some, involves their heart, suggesting that routine screening for amyloidosis is warranted in elderly patients undergoing the surgery.

Routine Congo red staining of a tenosynovial biopsy taken at the time of carpal tunnel release surgery in a single-center experience with 96 patients showed that 10 (10%) were positive for amyloidosis, Mazen Hanna, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

DALLAS – Older patients with carpal tunnel syndrome that requires release surgery appear to have a relatively high prevalence of amyloidosis that, in some, involves their heart, suggesting that routine screening for amyloidosis is warranted in elderly patients undergoing the surgery.

Routine Congo red staining of a tenosynovial biopsy taken at the time of carpal tunnel release surgery in a single-center experience with 96 patients showed that 10 (10%) were positive for amyloidosis, Mazen Hanna, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Learn about the “State of the Art” in HIV care from three of the biggest names in the business on Thursday, Oct. 5, at IDWeek 2017 in San Diego.

Joseph Eron Jr., MD, director of the UNC Center for AIDS Research Medicine at the University of North Carolina at Chapel Hill, in his talk “What to Start and When to Switch,” will help clinicians identify the most appropriate antiretroviral therapy regimens for initial HIV treatment in adults, as well as subsequent therapies for management of infection. Much of Dr. Eron’s research has focused on HIV resistance to antiretroviral therapy and the use of resistance testing and pharmacokinetic assessment to construct successful therapy.

Speaking about cost considerations in HIV treatment is Rochelle Walensky, MD, MPH, of the division of infectious diseases, Massachusetts General Hospital. Dr. Walensky will help attendees better understand and evaluate drug costs and their potential impact on HIV treatment. Dr. Walensky has published work on the impact of routine HIV screening, on the clinical and cost-effectiveness of HIV vaccines of varying efficacies, and on the value of primary genotypic resistance testing.

[email protected]

On Twitter @richpizzi

Learn about the “State of the Art” in HIV care from three of the biggest names in the business on Thursday, Oct. 5, at IDWeek 2017 in San Diego.

Joseph Eron Jr., MD, director of the UNC Center for AIDS Research Medicine at the University of North Carolina at Chapel Hill, in his talk “What to Start and When to Switch,” will help clinicians identify the most appropriate antiretroviral therapy regimens for initial HIV treatment in adults, as well as subsequent therapies for management of infection. Much of Dr. Eron’s research has focused on HIV resistance to antiretroviral therapy and the use of resistance testing and pharmacokinetic assessment to construct successful therapy.

Speaking about cost considerations in HIV treatment is Rochelle Walensky, MD, MPH, of the division of infectious diseases, Massachusetts General Hospital. Dr. Walensky will help attendees better understand and evaluate drug costs and their potential impact on HIV treatment. Dr. Walensky has published work on the impact of routine HIV screening, on the clinical and cost-effectiveness of HIV vaccines of varying efficacies, and on the value of primary genotypic resistance testing.

[email protected]

On Twitter @richpizzi

Learn about the “State of the Art” in HIV care from three of the biggest names in the business on Thursday, Oct. 5, at IDWeek 2017 in San Diego.

Joseph Eron Jr., MD, director of the UNC Center for AIDS Research Medicine at the University of North Carolina at Chapel Hill, in his talk “What to Start and When to Switch,” will help clinicians identify the most appropriate antiretroviral therapy regimens for initial HIV treatment in adults, as well as subsequent therapies for management of infection. Much of Dr. Eron’s research has focused on HIV resistance to antiretroviral therapy and the use of resistance testing and pharmacokinetic assessment to construct successful therapy.

Speaking about cost considerations in HIV treatment is Rochelle Walensky, MD, MPH, of the division of infectious diseases, Massachusetts General Hospital. Dr. Walensky will help attendees better understand and evaluate drug costs and their potential impact on HIV treatment. Dr. Walensky has published work on the impact of routine HIV screening, on the clinical and cost-effectiveness of HIV vaccines of varying efficacies, and on the value of primary genotypic resistance testing.

[email protected]

On Twitter @richpizzi

DALLAS – The percentage of left ventricular assist devices placed in U.S. heart failure patients at least 75 years of age jumped sharply during 2003-2014, and concurrently the short-term survival of these patients improved dramatically, according to data collected by the National Inpatient Sample.

During the 12-year period examined, the percentage of left-ventricular assist devices (LVADs) placed in U.S. heart failure patients aged 75 years and older rose from 3% of all LVADs in 2003 to 11% in 2014, Aniket S. Rali, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

DALLAS – The percentage of left ventricular assist devices placed in U.S. heart failure patients at least 75 years of age jumped sharply during 2003-2014, and concurrently the short-term survival of these patients improved dramatically, according to data collected by the National Inpatient Sample.

During the 12-year period examined, the percentage of left-ventricular assist devices (LVADs) placed in U.S. heart failure patients aged 75 years and older rose from 3% of all LVADs in 2003 to 11% in 2014, Aniket S. Rali, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

DALLAS – The percentage of left ventricular assist devices placed in U.S. heart failure patients at least 75 years of age jumped sharply during 2003-2014, and concurrently the short-term survival of these patients improved dramatically, according to data collected by the National Inpatient Sample.

During the 12-year period examined, the percentage of left-ventricular assist devices (LVADs) placed in U.S. heart failure patients aged 75 years and older rose from 3% of all LVADs in 2003 to 11% in 2014, Aniket S. Rali, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Compartment syndrome is a common complication after revascularization for acute lower extremity ischemia. Treatment with four compartment fasciotomy can result in significant morbidity, with wounds that are challenging to manage for both the patient and practitioner.

An alternative to wound VAC or simple wet-to-dry dressings, the “Roman sandal” technique makes bedside closure of these wounds possible, especially in patients with minimal postdecompression muscle edema.

Courtesy Dr. Richard Hershberger

Compartment syndrome is a common complication after revascularization for acute lower extremity ischemia. Treatment with four compartment fasciotomy can result in significant morbidity, with wounds that are challenging to manage for both the patient and practitioner.

An alternative to wound VAC or simple wet-to-dry dressings, the “Roman sandal” technique makes bedside closure of these wounds possible, especially in patients with minimal postdecompression muscle edema.

Courtesy Dr. Richard Hershberger

Compartment syndrome is a common complication after revascularization for acute lower extremity ischemia. Treatment with four compartment fasciotomy can result in significant morbidity, with wounds that are challenging to manage for both the patient and practitioner.

An alternative to wound VAC or simple wet-to-dry dressings, the “Roman sandal” technique makes bedside closure of these wounds possible, especially in patients with minimal postdecompression muscle edema.

Courtesy Dr. Richard Hershberger

Take-Home Points

• In cases of failed TJA, it is important to differentiate between septic and aseptic etiologies.
• Chronic and low-grade infections are challenging for orthopedic surgeons, as the symptoms often overlap with aseptic etiologies.
• Verification of infection eradication before beginning the second-stage reimplantation surgery is extremely important, but pre- and intraoperative findings can be unreliable. 
• Synovial fluid cytokines have been shown to accurately diagnose PJIs.
• Synovial fluid cytokines may help surgeons differentiate between septic and aseptic cases of failed TJA.

Total joint arthroplasty (TJA) is an effective procedure that has been extensively used to relieve pain and improve quality of life in patients with various forms of joint disease. Although advances in technology and surgical technique have improved the success of TJA, periprosthetic joint infection (PJI) remains a serious complication. In the United States, it is estimated that PJI is the most common reason for total knee arthroplasty failure and the third most common reason for total hip arthroplasty revision.¹ Although the incidence of PJI is 1% to 2%, the dramatic increase in TJA volume is expected to be accompanied by a similar rise in the number of infected TJAs; that number is expected to exceed 60,000 in the United States by 2020.² Moreover, management of PJI is expensive and imposes a heavy burden on the healthcare system, with costs expected to hit $20 billion by 2020 in the US.² Therefore, treating asepsis cases as infections imposes a heavy burden on the healthcare system and may result in excessive morbidity.³ At the same time, inadequate management of a PJI may result in recurrences that require infection treatment with morbid procedures, such as arthrodesis or amputation. Accurate diagnosis of PJI is of paramount importance in preventing potential implications of a misdiagnosed case. Unfortunately, the PJI diagnosis is extremely challenging, and the available diagnostic tests are often unreliable.⁴ Thus, research has recently focused on use of several synovial fluid cytokines in the detection of PJI.^5-7 In this article, we provide an overview of the synovial biomarkers being used to diagnose PJI.

Diagnosis of Periprosthetic Joint Infection

Differentiating between septic and aseptic failed TJA is important, as the treatment options differ considerably. PJI can be broadly classified as acute or early postoperative (<6 weeks), late chronic (indolent onset), and acute-on-chronic (acute onset in well-functioning prosthesis, secondary to hematogenous spread).⁸ The acute and acute-on-chronic presentations are often associated with obvious signs of infection.⁹ However, chronic and low-grade infections pose a challenge to modern orthopedic practice, as the symptoms often overlap with that of aseptic causes of TJA failure.¹⁰ As a result, the International Consensus Group on Periprosthetic Joint Infection developed complex criteria using the Musculoskeletal Infection Society definition of PJI and involving a battery of tests for PJI diagnosis.¹¹ According to these criteria, PJI is diagnosed when 1 of the 2 major criteria or 3 of the 5 minor criteria are met (Table 1).

Although these criteria constitute the most agreed on and widely used standard for PJI diagnosis, the definition is complex and often incomplete until surgical intervention. An ideal diagnostic test would aid in managing a PJI and provide results before a treatment decision is made. Many revision surgeries are being performed with insufficient information about the true diagnosis, and the diagnosis might change during or after surgery. About 10% of the revisions presumed to be aseptic may unexpectedly grow cultures during surgery and thereby satisfy the criteria for PJI after surgery.¹² Moreover, with the use of novel methods such as polymerase chain reaction, microorganisms were identified in more than three-fourths of the presumed aseptic revisions.¹³ The optimal management of such cases is controversial, and it is unclear whether positive cultures should be treated as possible contaminants or true infection.^12,14

A 2-stage revision procedure, widely accepted as the standard treatment for PJI, has success rates approaching 94%.¹⁵ In this procedure, it is important to verify infection eradication before beginning the second-stage reimplantation. Verification is crucial in avoiding reimplantation of an infected joint.¹⁶ After the first stage, patients are usually administered intravenous antibiotics for at least 6 weeks; these antibiotics are then withheld, and systemic inflammatory markers are evaluated for infection eradication. Although reliable criteria have been established for PJI diagnosis, guidelines for detecting eradication of infection are rudimentary. Most surgeons monitor the decrease in serologic markers, such as erythrocyte sedimentation rate and C-reactive protein (CRP) level, to assess the response to treatment. However, noninfectious etiologies may result in continued elevation of these markers.¹⁷ Even though aspirations are often performed to diagnose persistent infection before the second-stage procedure, their diagnostic utility may be limited.¹⁸ Use of cultures is also limited, as presence of antibiotic-loaded spacers can decrease the sensitivity of culture.¹⁹ Inadequate diagnosis often leads to unnecessary continuation of antimicrobial therapy or additional surgical débridement. Nuclear scans often remain positive because of aseptic inflammation related to surgery and are not useful in documenting sepsis arrest.²⁰ Given the limitations of available tests, novel strategies for identifying the presence of infection at the second stage are being tested.

Synovial Fluid Cytokines

PJI pathogenesis begins with colonization of the implant surfaces with microorganisms and subsequent formation of biofilms.²¹ The human immune system is activated by the microbial products, cell wall components, and various biofilm proteins. Immune cells are recruited to the site, where they secrete a myriad of inflammatory biomarkers, such as cytokines, which promote further recruitment of inflammatory cells and aid in the eradication of pathogens.⁹ These inflammatory cytokines and cells are involved in aseptic inflammatory joint conditions, such as rheumatoid arthritis^22,23; however, some are specifically involved in immune pathways combating pathogens.²⁴ This action is the basis for increasing interest in using various synovial fluid cytokines and other biomarkers in the diagnosis of PJI. Here we describe some of the commonly studied cytokines.

Interleukin 1β

Interleukin 1β (IL-1β) is a major proinflammatory cytokine that is synthesized by multiple cells, including macrophages and monocytes.²⁵ IL-1β is produced in response to microorganisms, other cytokines, antigen-presenting cells, and immune complexes; stimulates production of acute-phase proteins by the liver; and is an important pyrogen.²⁵ Deirmengian and colleagues⁵ found that synovial IL-1β increased 258-fold in patients with a PJI. Studies have found that synovial IL-1β has sensitivity ranging from 66.7% to 100% and specificity ranging from 87% to 100%, with 1 study reporting an accuracy of 100%.^5,6,26,27

Interleukin 6

Also produced by macrophages and monocytes, interleukin 6 (IL-6) is a potent stimulator of acute-phase proteins.^28,29 IL-6 has a role as a chemoattractant and helps with cell differentiation when changing from innate to acquired immunity.³⁰ It is also used as an aid in diagnosing PJI; it has sensitivity ranging from 62% to 100% and specificity ranging from 85% to 100%.^5,6,26,31,32 Synovial IL-6 measurements were more accurate than serum IL-6 measurements.²⁶ Furthermore, synovial IL-6 can be increased up to 27-fold in PJI cases.⁵ In one study, synovial IL-6 levels >2100 pg/mL had sensitivity of 62.5% and specificity of 85.7% in PJI diagnosis²⁶; in another study, an IL-6 threshold of 4270 pg/mL had sensitivity of 87.1%, specificity of 100%, and accuracy of 94.6%.³¹

C-Reactive Protein

CRP is an acute-phase reactant. Blood levels increase in response to aseptic inflammatory processes and systemic infection.³³ CRP plays an important role in host defense by activating complement and helping mediate phagocytosis.^33,34 Although serum CRP levels have been used in diagnosing PJIs,⁶ they can yield false-negative results.^35,36 Therefore, attention turned to synovial CRP levels, which were found to be increased 13-fold in PJI cases.⁵ It has been shown that synovial CRP levels are significantly higher in infected vs noninfected prosthetic joints³⁴ and had diagnostic accuracy better than that of serum CRP levels in diagnosing PJI.³⁷ One study found that CRP at a threshold of 3.7 mg/L had sensitivity of 84%, specificity of 97.1%, and accuracy of 91.5%,³⁷ whereas another study found that CRP at a threshold of 3.61 mg/L had sensitivity of 87.1%, specificity of 97.7%, and accuracy of 93.3%.³¹

α-Defensin, a natural peptide produced and secreted by neutrophils in response to pathogens, has antimicrobial and cytotoxic properties,^38-40 signals for the secretion of various cytokines, and acts as a chemoattractant for various immune cells.⁴¹ Deirmengian and colleagues6 found that α-defensin was consistently elevated in patients with PJI. α-Defensin is extremely accurate in diagnosing PJI; it has sensitivity ranging from 97% to 100% and specificity ranging from 96% to 100%.^6,27,42 Moreover, α-defensin was effective in diagnosing PJI caused by a wide spectrum of organisms, including various low-virulence bacteria and fungi.⁴³

Leukocyte Esterase

Leukocyte esterase is an enzyme produced and secreted by neutrophils at sites of active infection.^7,44 Testing for this enzyme is performed with a colorimetric strip and was originally performed for the diagnosis of urinary tract infections.^44,45 In a study conducted by Parvizi and colleagues,⁷ this strip was used to test for leukocyte esterase in synovial fluid samples; a ++ reading was found to have sensitivity of 80.6% and specificity of 100% in diagnosing knee PJI. Similarly, De Vecchi and colleagues⁴⁵ found sensitivity of 92.6% and specificity of 97%.

Other Synovial Markers

Research has identified numerous molecular biomarkers that may be associated with the pathogenesis of PJI. Although several (eg, cytokines) have demonstrated higher levels in synovial fluid in patients with PJI than in normal controls, only a few have had clinically relevant diagnostic utility.⁶ Deirmengian and colleagues⁶ screened 43 synovial fluid biomarkers that potentially could be used in the diagnosis of PJI. Besides the cytokine α-defensin, 4 other biomarkers—lactoferrin, neutrophil gelatinase-associated lipocalcin, neutrophil elastase 2, and bactericidal/permeability-increasing protein—had accuracy of 100%. In addition, 8 cytokines and biomarkers (IL-8, CRP, resistin, thrombospondin, IL-1β, IL-6, IL-10, IL-1α) had area under the curve values higher than 0.9. Studies have also evaluated the diagnostic utility of metabolic products such as lactate, lactate dehydrogenase, and glucose; their accuracy was comparable to that of serum CRP.³²

Serum Markers

In addition to the synovial fluid cytokines, several serum inflammatory cytokines have been studied as potential targets in diagnosing infection. Serum IL-6 has had excellent diagnostic accuracy⁴⁶ and, when combined with CRP, could increase sensitivity in diagnosing PJI; such a combination (vs either test alone) could be useful in screening patients.^47,48 Biomarkers such as tumor necrosis factor α and procalcitonin are considered very specific for PJI and may be useful in confirmatory testing.⁴⁸ Evidence also suggests that toll-like receptor 2 proteins are elevated in the serum of patients with PJI and therefore are a potential diagnostic tool.⁴⁹

Limitations of Synovial Cytokines

The literature suggests that some synovial fluid cytokines have promise.⁶ However, the best biomarker or combination of biomarkers is yet to be determined. Results have been consistent with α-defensin and other cytokines but mixed with IL-6 and still others^32,42,50 (Table 2).

Information on the utility of synovial biomarkers in detecting persistent infection is limited. Frangiamore and colleagues50 found that IL-1 and IL-6 levels decreased between the stages of 2-stage revision. Unfortunately, none of the synovial fluid cytokines investigated (IL-1, IL-2, IL-6, IL-8, Il-10, interferon γ, granulocyte macrophage-colony stimulating factor, tumor necrosis factor α, IL-12p70) satisfactorily detected resolution of infection in the setting of prior treatment for PJI. Although cytokines are expected to be elevated in the presence of infection, the internal milieu at the time of stage 2 of the revision makes diagnosis of infection difficult. In addition, presence of spacer particles and recent surgery may activate immune pathways and yield false-positive results. Furthermore, antibiotic cement spacers may suppress the microorganisms to very low levels and yield false-negative results even if these organisms remain virulent.¹⁹

Even though the synovial molecular markers can detect the presence of infection, they are unable to identify pathogens. As identifying the pathogen is important in the treatment of PJI, there has been interest in using polymerase chain reaction (PCR) techniques.⁵¹ These tests may also provide specific information about the pathogen, such as its antibiotic sensitivity. A recently developed technology, the Ibis T5000 Universal Biosensor (Ibis Biosciences), uses novel pan-domain primers in a series of PCRs. This biosensor is useful in diagnosing infections when cultures are negative and appears to be more accurate than conventional PCR.¹³ As reported by Jacovides and colleagues,¹³ this novel PCR technique identified an organism in about 88% of presumed cases of aseptic revision.

Conclusion

PJI poses an extreme challenge to the healthcare system. Given the morbidity associated with improper management of PJI, accurate diagnosis is of paramount importance. Given the limitations of current tests, synovial fluid cytokines hold promise in the diagnosis of PJIs. However, these cytokines are expensive, and their clinical utility in PJI management is not well established. More research is needed before guidelines for synovial fluid cytokines and biomarkers can replace or be incorporated into guidelines for the treatment of PJIs.

Take-Home Points

• In cases of failed TJA, it is important to differentiate between septic and aseptic etiologies.
• Chronic and low-grade infections are challenging for orthopedic surgeons, as the symptoms often overlap with aseptic etiologies.
• Verification of infection eradication before beginning the second-stage reimplantation surgery is extremely important, but pre- and intraoperative findings can be unreliable. 
• Synovial fluid cytokines have been shown to accurately diagnose PJIs.
• Synovial fluid cytokines may help surgeons differentiate between septic and aseptic cases of failed TJA.

Total joint arthroplasty (TJA) is an effective procedure that has been extensively used to relieve pain and improve quality of life in patients with various forms of joint disease. Although advances in technology and surgical technique have improved the success of TJA, periprosthetic joint infection (PJI) remains a serious complication. In the United States, it is estimated that PJI is the most common reason for total knee arthroplasty failure and the third most common reason for total hip arthroplasty revision.¹ Although the incidence of PJI is 1% to 2%, the dramatic increase in TJA volume is expected to be accompanied by a similar rise in the number of infected TJAs; that number is expected to exceed 60,000 in the United States by 2020.² Moreover, management of PJI is expensive and imposes a heavy burden on the healthcare system, with costs expected to hit $20 billion by 2020 in the US.² Therefore, treating asepsis cases as infections imposes a heavy burden on the healthcare system and may result in excessive morbidity.³ At the same time, inadequate management of a PJI may result in recurrences that require infection treatment with morbid procedures, such as arthrodesis or amputation. Accurate diagnosis of PJI is of paramount importance in preventing potential implications of a misdiagnosed case. Unfortunately, the PJI diagnosis is extremely challenging, and the available diagnostic tests are often unreliable.⁴ Thus, research has recently focused on use of several synovial fluid cytokines in the detection of PJI.^5-7 In this article, we provide an overview of the synovial biomarkers being used to diagnose PJI.

Diagnosis of Periprosthetic Joint Infection

Differentiating between septic and aseptic failed TJA is important, as the treatment options differ considerably. PJI can be broadly classified as acute or early postoperative (<6 weeks), late chronic (indolent onset), and acute-on-chronic (acute onset in well-functioning prosthesis, secondary to hematogenous spread).⁸ The acute and acute-on-chronic presentations are often associated with obvious signs of infection.⁹ However, chronic and low-grade infections pose a challenge to modern orthopedic practice, as the symptoms often overlap with that of aseptic causes of TJA failure.¹⁰ As a result, the International Consensus Group on Periprosthetic Joint Infection developed complex criteria using the Musculoskeletal Infection Society definition of PJI and involving a battery of tests for PJI diagnosis.¹¹ According to these criteria, PJI is diagnosed when 1 of the 2 major criteria or 3 of the 5 minor criteria are met (Table 1).

Although these criteria constitute the most agreed on and widely used standard for PJI diagnosis, the definition is complex and often incomplete until surgical intervention. An ideal diagnostic test would aid in managing a PJI and provide results before a treatment decision is made. Many revision surgeries are being performed with insufficient information about the true diagnosis, and the diagnosis might change during or after surgery. About 10% of the revisions presumed to be aseptic may unexpectedly grow cultures during surgery and thereby satisfy the criteria for PJI after surgery.¹² Moreover, with the use of novel methods such as polymerase chain reaction, microorganisms were identified in more than three-fourths of the presumed aseptic revisions.¹³ The optimal management of such cases is controversial, and it is unclear whether positive cultures should be treated as possible contaminants or true infection.^12,14

A 2-stage revision procedure, widely accepted as the standard treatment for PJI, has success rates approaching 94%.¹⁵ In this procedure, it is important to verify infection eradication before beginning the second-stage reimplantation. Verification is crucial in avoiding reimplantation of an infected joint.¹⁶ After the first stage, patients are usually administered intravenous antibiotics for at least 6 weeks; these antibiotics are then withheld, and systemic inflammatory markers are evaluated for infection eradication. Although reliable criteria have been established for PJI diagnosis, guidelines for detecting eradication of infection are rudimentary. Most surgeons monitor the decrease in serologic markers, such as erythrocyte sedimentation rate and C-reactive protein (CRP) level, to assess the response to treatment. However, noninfectious etiologies may result in continued elevation of these markers.¹⁷ Even though aspirations are often performed to diagnose persistent infection before the second-stage procedure, their diagnostic utility may be limited.¹⁸ Use of cultures is also limited, as presence of antibiotic-loaded spacers can decrease the sensitivity of culture.¹⁹ Inadequate diagnosis often leads to unnecessary continuation of antimicrobial therapy or additional surgical débridement. Nuclear scans often remain positive because of aseptic inflammation related to surgery and are not useful in documenting sepsis arrest.²⁰ Given the limitations of available tests, novel strategies for identifying the presence of infection at the second stage are being tested.

Synovial Fluid Cytokines

PJI pathogenesis begins with colonization of the implant surfaces with microorganisms and subsequent formation of biofilms.²¹ The human immune system is activated by the microbial products, cell wall components, and various biofilm proteins. Immune cells are recruited to the site, where they secrete a myriad of inflammatory biomarkers, such as cytokines, which promote further recruitment of inflammatory cells and aid in the eradication of pathogens.⁹ These inflammatory cytokines and cells are involved in aseptic inflammatory joint conditions, such as rheumatoid arthritis^22,23; however, some are specifically involved in immune pathways combating pathogens.²⁴ This action is the basis for increasing interest in using various synovial fluid cytokines and other biomarkers in the diagnosis of PJI. Here we describe some of the commonly studied cytokines.

Interleukin 1β

Interleukin 1β (IL-1β) is a major proinflammatory cytokine that is synthesized by multiple cells, including macrophages and monocytes.²⁵ IL-1β is produced in response to microorganisms, other cytokines, antigen-presenting cells, and immune complexes; stimulates production of acute-phase proteins by the liver; and is an important pyrogen.²⁵ Deirmengian and colleagues⁵ found that synovial IL-1β increased 258-fold in patients with a PJI. Studies have found that synovial IL-1β has sensitivity ranging from 66.7% to 100% and specificity ranging from 87% to 100%, with 1 study reporting an accuracy of 100%.^5,6,26,27

Interleukin 6

Also produced by macrophages and monocytes, interleukin 6 (IL-6) is a potent stimulator of acute-phase proteins.^28,29 IL-6 has a role as a chemoattractant and helps with cell differentiation when changing from innate to acquired immunity.³⁰ It is also used as an aid in diagnosing PJI; it has sensitivity ranging from 62% to 100% and specificity ranging from 85% to 100%.^5,6,26,31,32 Synovial IL-6 measurements were more accurate than serum IL-6 measurements.²⁶ Furthermore, synovial IL-6 can be increased up to 27-fold in PJI cases.⁵ In one study, synovial IL-6 levels >2100 pg/mL had sensitivity of 62.5% and specificity of 85.7% in PJI diagnosis²⁶; in another study, an IL-6 threshold of 4270 pg/mL had sensitivity of 87.1%, specificity of 100%, and accuracy of 94.6%.³¹

C-Reactive Protein

CRP is an acute-phase reactant. Blood levels increase in response to aseptic inflammatory processes and systemic infection.³³ CRP plays an important role in host defense by activating complement and helping mediate phagocytosis.^33,34 Although serum CRP levels have been used in diagnosing PJIs,⁶ they can yield false-negative results.^35,36 Therefore, attention turned to synovial CRP levels, which were found to be increased 13-fold in PJI cases.⁵ It has been shown that synovial CRP levels are significantly higher in infected vs noninfected prosthetic joints³⁴ and had diagnostic accuracy better than that of serum CRP levels in diagnosing PJI.³⁷ One study found that CRP at a threshold of 3.7 mg/L had sensitivity of 84%, specificity of 97.1%, and accuracy of 91.5%,³⁷ whereas another study found that CRP at a threshold of 3.61 mg/L had sensitivity of 87.1%, specificity of 97.7%, and accuracy of 93.3%.³¹

α-Defensin, a natural peptide produced and secreted by neutrophils in response to pathogens, has antimicrobial and cytotoxic properties,^38-40 signals for the secretion of various cytokines, and acts as a chemoattractant for various immune cells.⁴¹ Deirmengian and colleagues6 found that α-defensin was consistently elevated in patients with PJI. α-Defensin is extremely accurate in diagnosing PJI; it has sensitivity ranging from 97% to 100% and specificity ranging from 96% to 100%.^6,27,42 Moreover, α-defensin was effective in diagnosing PJI caused by a wide spectrum of organisms, including various low-virulence bacteria and fungi.⁴³

Leukocyte Esterase

Leukocyte esterase is an enzyme produced and secreted by neutrophils at sites of active infection.^7,44 Testing for this enzyme is performed with a colorimetric strip and was originally performed for the diagnosis of urinary tract infections.^44,45 In a study conducted by Parvizi and colleagues,⁷ this strip was used to test for leukocyte esterase in synovial fluid samples; a ++ reading was found to have sensitivity of 80.6% and specificity of 100% in diagnosing knee PJI. Similarly, De Vecchi and colleagues⁴⁵ found sensitivity of 92.6% and specificity of 97%.

Other Synovial Markers

Research has identified numerous molecular biomarkers that may be associated with the pathogenesis of PJI. Although several (eg, cytokines) have demonstrated higher levels in synovial fluid in patients with PJI than in normal controls, only a few have had clinically relevant diagnostic utility.⁶ Deirmengian and colleagues⁶ screened 43 synovial fluid biomarkers that potentially could be used in the diagnosis of PJI. Besides the cytokine α-defensin, 4 other biomarkers—lactoferrin, neutrophil gelatinase-associated lipocalcin, neutrophil elastase 2, and bactericidal/permeability-increasing protein—had accuracy of 100%. In addition, 8 cytokines and biomarkers (IL-8, CRP, resistin, thrombospondin, IL-1β, IL-6, IL-10, IL-1α) had area under the curve values higher than 0.9. Studies have also evaluated the diagnostic utility of metabolic products such as lactate, lactate dehydrogenase, and glucose; their accuracy was comparable to that of serum CRP.³²

Serum Markers

In addition to the synovial fluid cytokines, several serum inflammatory cytokines have been studied as potential targets in diagnosing infection. Serum IL-6 has had excellent diagnostic accuracy⁴⁶ and, when combined with CRP, could increase sensitivity in diagnosing PJI; such a combination (vs either test alone) could be useful in screening patients.^47,48 Biomarkers such as tumor necrosis factor α and procalcitonin are considered very specific for PJI and may be useful in confirmatory testing.⁴⁸ Evidence also suggests that toll-like receptor 2 proteins are elevated in the serum of patients with PJI and therefore are a potential diagnostic tool.⁴⁹

Limitations of Synovial Cytokines

The literature suggests that some synovial fluid cytokines have promise.⁶ However, the best biomarker or combination of biomarkers is yet to be determined. Results have been consistent with α-defensin and other cytokines but mixed with IL-6 and still others^32,42,50 (Table 2).

Information on the utility of synovial biomarkers in detecting persistent infection is limited. Frangiamore and colleagues50 found that IL-1 and IL-6 levels decreased between the stages of 2-stage revision. Unfortunately, none of the synovial fluid cytokines investigated (IL-1, IL-2, IL-6, IL-8, Il-10, interferon γ, granulocyte macrophage-colony stimulating factor, tumor necrosis factor α, IL-12p70) satisfactorily detected resolution of infection in the setting of prior treatment for PJI. Although cytokines are expected to be elevated in the presence of infection, the internal milieu at the time of stage 2 of the revision makes diagnosis of infection difficult. In addition, presence of spacer particles and recent surgery may activate immune pathways and yield false-positive results. Furthermore, antibiotic cement spacers may suppress the microorganisms to very low levels and yield false-negative results even if these organisms remain virulent.¹⁹

Even though the synovial molecular markers can detect the presence of infection, they are unable to identify pathogens. As identifying the pathogen is important in the treatment of PJI, there has been interest in using polymerase chain reaction (PCR) techniques.⁵¹ These tests may also provide specific information about the pathogen, such as its antibiotic sensitivity. A recently developed technology, the Ibis T5000 Universal Biosensor (Ibis Biosciences), uses novel pan-domain primers in a series of PCRs. This biosensor is useful in diagnosing infections when cultures are negative and appears to be more accurate than conventional PCR.¹³ As reported by Jacovides and colleagues,¹³ this novel PCR technique identified an organism in about 88% of presumed cases of aseptic revision.

Conclusion

PJI poses an extreme challenge to the healthcare system. Given the morbidity associated with improper management of PJI, accurate diagnosis is of paramount importance. Given the limitations of current tests, synovial fluid cytokines hold promise in the diagnosis of PJIs. However, these cytokines are expensive, and their clinical utility in PJI management is not well established. More research is needed before guidelines for synovial fluid cytokines and biomarkers can replace or be incorporated into guidelines for the treatment of PJIs.

Take-Home Points

• In cases of failed TJA, it is important to differentiate between septic and aseptic etiologies.
• Chronic and low-grade infections are challenging for orthopedic surgeons, as the symptoms often overlap with aseptic etiologies.
• Verification of infection eradication before beginning the second-stage reimplantation surgery is extremely important, but pre- and intraoperative findings can be unreliable. 
• Synovial fluid cytokines have been shown to accurately diagnose PJIs.
• Synovial fluid cytokines may help surgeons differentiate between septic and aseptic cases of failed TJA.

Total joint arthroplasty (TJA) is an effective procedure that has been extensively used to relieve pain and improve quality of life in patients with various forms of joint disease. Although advances in technology and surgical technique have improved the success of TJA, periprosthetic joint infection (PJI) remains a serious complication. In the United States, it is estimated that PJI is the most common reason for total knee arthroplasty failure and the third most common reason for total hip arthroplasty revision.¹ Although the incidence of PJI is 1% to 2%, the dramatic increase in TJA volume is expected to be accompanied by a similar rise in the number of infected TJAs; that number is expected to exceed 60,000 in the United States by 2020.² Moreover, management of PJI is expensive and imposes a heavy burden on the healthcare system, with costs expected to hit $20 billion by 2020 in the US.² Therefore, treating asepsis cases as infections imposes a heavy burden on the healthcare system and may result in excessive morbidity.³ At the same time, inadequate management of a PJI may result in recurrences that require infection treatment with morbid procedures, such as arthrodesis or amputation. Accurate diagnosis of PJI is of paramount importance in preventing potential implications of a misdiagnosed case. Unfortunately, the PJI diagnosis is extremely challenging, and the available diagnostic tests are often unreliable.⁴ Thus, research has recently focused on use of several synovial fluid cytokines in the detection of PJI.^5-7 In this article, we provide an overview of the synovial biomarkers being used to diagnose PJI.

Diagnosis of Periprosthetic Joint Infection

Differentiating between septic and aseptic failed TJA is important, as the treatment options differ considerably. PJI can be broadly classified as acute or early postoperative (<6 weeks), late chronic (indolent onset), and acute-on-chronic (acute onset in well-functioning prosthesis, secondary to hematogenous spread).⁸ The acute and acute-on-chronic presentations are often associated with obvious signs of infection.⁹ However, chronic and low-grade infections pose a challenge to modern orthopedic practice, as the symptoms often overlap with that of aseptic causes of TJA failure.¹⁰ As a result, the International Consensus Group on Periprosthetic Joint Infection developed complex criteria using the Musculoskeletal Infection Society definition of PJI and involving a battery of tests for PJI diagnosis.¹¹ According to these criteria, PJI is diagnosed when 1 of the 2 major criteria or 3 of the 5 minor criteria are met (Table 1).

Although these criteria constitute the most agreed on and widely used standard for PJI diagnosis, the definition is complex and often incomplete until surgical intervention. An ideal diagnostic test would aid in managing a PJI and provide results before a treatment decision is made. Many revision surgeries are being performed with insufficient information about the true diagnosis, and the diagnosis might change during or after surgery. About 10% of the revisions presumed to be aseptic may unexpectedly grow cultures during surgery and thereby satisfy the criteria for PJI after surgery.¹² Moreover, with the use of novel methods such as polymerase chain reaction, microorganisms were identified in more than three-fourths of the presumed aseptic revisions.¹³ The optimal management of such cases is controversial, and it is unclear whether positive cultures should be treated as possible contaminants or true infection.^12,14

A 2-stage revision procedure, widely accepted as the standard treatment for PJI, has success rates approaching 94%.¹⁵ In this procedure, it is important to verify infection eradication before beginning the second-stage reimplantation. Verification is crucial in avoiding reimplantation of an infected joint.¹⁶ After the first stage, patients are usually administered intravenous antibiotics for at least 6 weeks; these antibiotics are then withheld, and systemic inflammatory markers are evaluated for infection eradication. Although reliable criteria have been established for PJI diagnosis, guidelines for detecting eradication of infection are rudimentary. Most surgeons monitor the decrease in serologic markers, such as erythrocyte sedimentation rate and C-reactive protein (CRP) level, to assess the response to treatment. However, noninfectious etiologies may result in continued elevation of these markers.¹⁷ Even though aspirations are often performed to diagnose persistent infection before the second-stage procedure, their diagnostic utility may be limited.¹⁸ Use of cultures is also limited, as presence of antibiotic-loaded spacers can decrease the sensitivity of culture.¹⁹ Inadequate diagnosis often leads to unnecessary continuation of antimicrobial therapy or additional surgical débridement. Nuclear scans often remain positive because of aseptic inflammation related to surgery and are not useful in documenting sepsis arrest.²⁰ Given the limitations of available tests, novel strategies for identifying the presence of infection at the second stage are being tested.

Synovial Fluid Cytokines

PJI pathogenesis begins with colonization of the implant surfaces with microorganisms and subsequent formation of biofilms.²¹ The human immune system is activated by the microbial products, cell wall components, and various biofilm proteins. Immune cells are recruited to the site, where they secrete a myriad of inflammatory biomarkers, such as cytokines, which promote further recruitment of inflammatory cells and aid in the eradication of pathogens.⁹ These inflammatory cytokines and cells are involved in aseptic inflammatory joint conditions, such as rheumatoid arthritis^22,23; however, some are specifically involved in immune pathways combating pathogens.²⁴ This action is the basis for increasing interest in using various synovial fluid cytokines and other biomarkers in the diagnosis of PJI. Here we describe some of the commonly studied cytokines.

Interleukin 1β

Interleukin 1β (IL-1β) is a major proinflammatory cytokine that is synthesized by multiple cells, including macrophages and monocytes.²⁵ IL-1β is produced in response to microorganisms, other cytokines, antigen-presenting cells, and immune complexes; stimulates production of acute-phase proteins by the liver; and is an important pyrogen.²⁵ Deirmengian and colleagues⁵ found that synovial IL-1β increased 258-fold in patients with a PJI. Studies have found that synovial IL-1β has sensitivity ranging from 66.7% to 100% and specificity ranging from 87% to 100%, with 1 study reporting an accuracy of 100%.^5,6,26,27

Interleukin 6

Also produced by macrophages and monocytes, interleukin 6 (IL-6) is a potent stimulator of acute-phase proteins.^28,29 IL-6 has a role as a chemoattractant and helps with cell differentiation when changing from innate to acquired immunity.³⁰ It is also used as an aid in diagnosing PJI; it has sensitivity ranging from 62% to 100% and specificity ranging from 85% to 100%.^5,6,26,31,32 Synovial IL-6 measurements were more accurate than serum IL-6 measurements.²⁶ Furthermore, synovial IL-6 can be increased up to 27-fold in PJI cases.⁵ In one study, synovial IL-6 levels >2100 pg/mL had sensitivity of 62.5% and specificity of 85.7% in PJI diagnosis²⁶; in another study, an IL-6 threshold of 4270 pg/mL had sensitivity of 87.1%, specificity of 100%, and accuracy of 94.6%.³¹

C-Reactive Protein

CRP is an acute-phase reactant. Blood levels increase in response to aseptic inflammatory processes and systemic infection.³³ CRP plays an important role in host defense by activating complement and helping mediate phagocytosis.^33,34 Although serum CRP levels have been used in diagnosing PJIs,⁶ they can yield false-negative results.^35,36 Therefore, attention turned to synovial CRP levels, which were found to be increased 13-fold in PJI cases.⁵ It has been shown that synovial CRP levels are significantly higher in infected vs noninfected prosthetic joints³⁴ and had diagnostic accuracy better than that of serum CRP levels in diagnosing PJI.³⁷ One study found that CRP at a threshold of 3.7 mg/L had sensitivity of 84%, specificity of 97.1%, and accuracy of 91.5%,³⁷ whereas another study found that CRP at a threshold of 3.61 mg/L had sensitivity of 87.1%, specificity of 97.7%, and accuracy of 93.3%.³¹

α-Defensin, a natural peptide produced and secreted by neutrophils in response to pathogens, has antimicrobial and cytotoxic properties,^38-40 signals for the secretion of various cytokines, and acts as a chemoattractant for various immune cells.⁴¹ Deirmengian and colleagues6 found that α-defensin was consistently elevated in patients with PJI. α-Defensin is extremely accurate in diagnosing PJI; it has sensitivity ranging from 97% to 100% and specificity ranging from 96% to 100%.^6,27,42 Moreover, α-defensin was effective in diagnosing PJI caused by a wide spectrum of organisms, including various low-virulence bacteria and fungi.⁴³

Leukocyte Esterase

Leukocyte esterase is an enzyme produced and secreted by neutrophils at sites of active infection.^7,44 Testing for this enzyme is performed with a colorimetric strip and was originally performed for the diagnosis of urinary tract infections.^44,45 In a study conducted by Parvizi and colleagues,⁷ this strip was used to test for leukocyte esterase in synovial fluid samples; a ++ reading was found to have sensitivity of 80.6% and specificity of 100% in diagnosing knee PJI. Similarly, De Vecchi and colleagues⁴⁵ found sensitivity of 92.6% and specificity of 97%.

Other Synovial Markers

Research has identified numerous molecular biomarkers that may be associated with the pathogenesis of PJI. Although several (eg, cytokines) have demonstrated higher levels in synovial fluid in patients with PJI than in normal controls, only a few have had clinically relevant diagnostic utility.⁶ Deirmengian and colleagues⁶ screened 43 synovial fluid biomarkers that potentially could be used in the diagnosis of PJI. Besides the cytokine α-defensin, 4 other biomarkers—lactoferrin, neutrophil gelatinase-associated lipocalcin, neutrophil elastase 2, and bactericidal/permeability-increasing protein—had accuracy of 100%. In addition, 8 cytokines and biomarkers (IL-8, CRP, resistin, thrombospondin, IL-1β, IL-6, IL-10, IL-1α) had area under the curve values higher than 0.9. Studies have also evaluated the diagnostic utility of metabolic products such as lactate, lactate dehydrogenase, and glucose; their accuracy was comparable to that of serum CRP.³²

Serum Markers

In addition to the synovial fluid cytokines, several serum inflammatory cytokines have been studied as potential targets in diagnosing infection. Serum IL-6 has had excellent diagnostic accuracy⁴⁶ and, when combined with CRP, could increase sensitivity in diagnosing PJI; such a combination (vs either test alone) could be useful in screening patients.^47,48 Biomarkers such as tumor necrosis factor α and procalcitonin are considered very specific for PJI and may be useful in confirmatory testing.⁴⁸ Evidence also suggests that toll-like receptor 2 proteins are elevated in the serum of patients with PJI and therefore are a potential diagnostic tool.⁴⁹

Limitations of Synovial Cytokines

The literature suggests that some synovial fluid cytokines have promise.⁶ However, the best biomarker or combination of biomarkers is yet to be determined. Results have been consistent with α-defensin and other cytokines but mixed with IL-6 and still others^32,42,50 (Table 2).

Information on the utility of synovial biomarkers in detecting persistent infection is limited. Frangiamore and colleagues50 found that IL-1 and IL-6 levels decreased between the stages of 2-stage revision. Unfortunately, none of the synovial fluid cytokines investigated (IL-1, IL-2, IL-6, IL-8, Il-10, interferon γ, granulocyte macrophage-colony stimulating factor, tumor necrosis factor α, IL-12p70) satisfactorily detected resolution of infection in the setting of prior treatment for PJI. Although cytokines are expected to be elevated in the presence of infection, the internal milieu at the time of stage 2 of the revision makes diagnosis of infection difficult. In addition, presence of spacer particles and recent surgery may activate immune pathways and yield false-positive results. Furthermore, antibiotic cement spacers may suppress the microorganisms to very low levels and yield false-negative results even if these organisms remain virulent.¹⁹

Even though the synovial molecular markers can detect the presence of infection, they are unable to identify pathogens. As identifying the pathogen is important in the treatment of PJI, there has been interest in using polymerase chain reaction (PCR) techniques.⁵¹ These tests may also provide specific information about the pathogen, such as its antibiotic sensitivity. A recently developed technology, the Ibis T5000 Universal Biosensor (Ibis Biosciences), uses novel pan-domain primers in a series of PCRs. This biosensor is useful in diagnosing infections when cultures are negative and appears to be more accurate than conventional PCR.¹³ As reported by Jacovides and colleagues,¹³ this novel PCR technique identified an organism in about 88% of presumed cases of aseptic revision.

Conclusion

PJI poses an extreme challenge to the healthcare system. Given the morbidity associated with improper management of PJI, accurate diagnosis is of paramount importance. Given the limitations of current tests, synovial fluid cytokines hold promise in the diagnosis of PJIs. However, these cytokines are expensive, and their clinical utility in PJI management is not well established. More research is needed before guidelines for synovial fluid cytokines and biomarkers can replace or be incorporated into guidelines for the treatment of PJIs.

LONDON—Several experimental therapies targeting tau are currently under investigation in phase I and II clinical trials. Researchers at the 2017 Alzheimer’s Association International Conference described the design of, and early results from, studies of two monoclonal antibodies and an antisense oligonucleotide.

RO7105705 for Alzheimer’s Disease

Dr. Kerchner presented data from a phase I trial of RO7105705, a humanized anti-tau monoclonal antibody. RO7105705 binds specifically to tau and is intended to intercept tau in the extracellular space of the brain, blocking its cell-to-cell spread.

The primary objective of the study was to evaluate the safety of single and multiple doses of the drug, compared with placebo. The secondary objective was to look at the pharmacokinetic profile following IV and subcutaneous doses. Study participants included healthy volunteers ages 18 to 80 and patients with probable Alzheimer’s disease. Patients with Alzheimer’s disease were between ages 50 and 80 and had a Mini-Mental State Examination score of 16 to 28; a Clinical Dementia Rating global score of 0.5, 1.0, or 2.0; and 18F-florbetapir PET scan evidence of cerebral amyloid pathology.

In the single-dose escalation phase, six cohorts of eight healthy volunteers each received IV doses that ranged from 225 mg to 16,800 mg. Another cohort received 1,200 mg of the drug subcutaneously. In the multiple-dose phase, a cohort of healthy volunteers and a cohort of patients with mild-to-moderate Alzheimer’s disease received four weekly doses of 8.4 g.

“The drug was well tolerated, even at these high doses,” Dr. Kerchner said. “So far, there have been no dose-limiting adverse events, no serious adverse events, no deaths, and no one who stopped the drug due to adverse events.” In the single-dose cohorts, adverse events that occurred in more than one participant included headache, infusion/injection site reaction, upper respiratory tract infection, nausea, vomiting, and gastrointestinal viral infection. In the multiple-dose cohorts, adverse events that occurred in more than one participant included vessel puncture site complications and postural dizziness.

ABBV-8E12 for PSP and Alzheimer’s Disease

Kumar Budur, MD, of AbbVie, Chicago, presented the results of a phase I study of ABBV-8E12, a humanized anti-tau monoclonal antibody, in patients with progressive supranuclear palsy (PSP). He also gave an overview of two ongoing phase II studies of ABBV-8E12 for early Alzheimer’s disease and PSP.

“PSP is a chronic progressive neurodegenerative disorder that affects movement, control of gait and balance, speech, swallowing, vision, mood and behavior, and thinking,” Dr. Budur explained. “The time from the onset of symptoms to death is only seven years. There currently are no approved treatments for this condition.” PSP affects approximately 20,000 people in the United States, and symptoms typically begin after age 60.

The phase I trial in patients with PSP was a double-blind, placebo-controlled, single ascending dose study assessing the drug’s safety, tolerability, pharmacokinetics, and immunogenicity. Investigators randomized 30 participants to a single IV infusion of ABBV-8E12 (2.5, 7.5, 15, 25, or 50 mg/kg) or placebo in blocks of four subjects, with one subject in each block randomized to placebo and three to an active ABBV-8E12 dose. Researchers monitored safety and pharmacokinetics for 84 days post dosing.

Twenty-three patients received ABBV-8E12, and seven patients received placebo. At baseline, subjects’ mean age was 68.8; 16 (53%) were men. Patients had to be able to walk with minimal assistance to be included in the study. Twenty-seven subjects completed the 84-day follow-up and one subject (3.3%) withdrew from the study due to an adverse event.

Twenty-one subjects experienced an adverse event, including dermatitis (n = 5) and fall (n = 5). Three participants experienced serious adverse events. One patient had a subdural hematoma following two falls, one had agitation/anxiety/perseverative behavior, and one had hypertension. The serious adverse events occurred in the 15, 25, and 50 mg/kg cohorts, respectively. ABBV-8E12 exhibited an acceptable safety and tolerability profile to support repeat-dose testing in subjects with tauopathies, Dr. Budur said.

Dr. Budur and colleagues are recruiting subjects for a multinational phase II study evaluating ABBV-8E12 to delay the progression of Alzheimer’s disease. Eligible subjects (n = 400) will meet criteria for early Alzheimer’s disease and have a positive amyloid PET scan. “Subjects will be randomized to three doses of ABBV-8E12 versus placebo, 100 subjects per arm,” he said. In addition, investigators are recruiting patients with PSP for a phase II study evaluating the 52-week efficacy and safety of ABBV-8E12. The trial will assess whether the therapy can slow disease progression in 180 patients with PSP.

Antisense Oligonucleotide to Reduce Total Tau Expression in Mild Alzheimer’s Disease

Roger M. Lane, MD, MPH, of lonis Pharmaceuticals, Carlsbad, California, described a study that is designed to the test safety and pharmacokinetics of a tau-lowering antisense oligonucleotide (ASO) in patients with mild Alzheimer’s disease. The ASO, lonis-MAPT_RX, targets microtubule-associated protein tau (MAPT) messenger RNA to reduce the synthesis of tau in the CNS, Dr. Lane said. “In contrast, current investigational biologic or small molecule anti-tau drugs target the tau protein,” he said.

In a recent study, DeVos and colleagues identified ASOs that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After a reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and pre-existing tau pathology was reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In nonhuman primates, ASOs distributed throughout the brain and spinal cord, and reduced tau mRNA and protein in the brain and spinal cord, and tau protein in the CSF.

Based on these findings, researchers are studying lonis-MAPT_RX, a second generation 2’-O-methoxyethyl (2’-MOE) chimeric ASO identified as suitable for clinical trials. It is designed to bind and degrade the pre-mRNA transcribed from the MAPT gene and thereby reduce synthesis of tau protein.

“The first clinical trial is set up in 12 centers in Canada and five European countries,” Dr. Lane said. “Patients aged 50 to 75 with mild Alzheimer’s disease are being randomized to multiple ascending doses of lonis-MAPT_RX administered intrathecally.” The study drug will be given four times at monthly intervals, and there will be six months of follow-up. End points include CSF biomarkers, neuroimaging, and clinical outcomes. “We are expecting a 50–85% reduction in tau production in the cerebral cortex,” Dr. Lane said.

—Adriene Marshall

Suggested Reading

DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374).

LONDON—Several experimental therapies targeting tau are currently under investigation in phase I and II clinical trials. Researchers at the 2017 Alzheimer’s Association International Conference described the design of, and early results from, studies of two monoclonal antibodies and an antisense oligonucleotide.

RO7105705 for Alzheimer’s Disease

Dr. Kerchner presented data from a phase I trial of RO7105705, a humanized anti-tau monoclonal antibody. RO7105705 binds specifically to tau and is intended to intercept tau in the extracellular space of the brain, blocking its cell-to-cell spread.

The primary objective of the study was to evaluate the safety of single and multiple doses of the drug, compared with placebo. The secondary objective was to look at the pharmacokinetic profile following IV and subcutaneous doses. Study participants included healthy volunteers ages 18 to 80 and patients with probable Alzheimer’s disease. Patients with Alzheimer’s disease were between ages 50 and 80 and had a Mini-Mental State Examination score of 16 to 28; a Clinical Dementia Rating global score of 0.5, 1.0, or 2.0; and 18F-florbetapir PET scan evidence of cerebral amyloid pathology.

In the single-dose escalation phase, six cohorts of eight healthy volunteers each received IV doses that ranged from 225 mg to 16,800 mg. Another cohort received 1,200 mg of the drug subcutaneously. In the multiple-dose phase, a cohort of healthy volunteers and a cohort of patients with mild-to-moderate Alzheimer’s disease received four weekly doses of 8.4 g.

“The drug was well tolerated, even at these high doses,” Dr. Kerchner said. “So far, there have been no dose-limiting adverse events, no serious adverse events, no deaths, and no one who stopped the drug due to adverse events.” In the single-dose cohorts, adverse events that occurred in more than one participant included headache, infusion/injection site reaction, upper respiratory tract infection, nausea, vomiting, and gastrointestinal viral infection. In the multiple-dose cohorts, adverse events that occurred in more than one participant included vessel puncture site complications and postural dizziness.

ABBV-8E12 for PSP and Alzheimer’s Disease

Kumar Budur, MD, of AbbVie, Chicago, presented the results of a phase I study of ABBV-8E12, a humanized anti-tau monoclonal antibody, in patients with progressive supranuclear palsy (PSP). He also gave an overview of two ongoing phase II studies of ABBV-8E12 for early Alzheimer’s disease and PSP.

“PSP is a chronic progressive neurodegenerative disorder that affects movement, control of gait and balance, speech, swallowing, vision, mood and behavior, and thinking,” Dr. Budur explained. “The time from the onset of symptoms to death is only seven years. There currently are no approved treatments for this condition.” PSP affects approximately 20,000 people in the United States, and symptoms typically begin after age 60.

The phase I trial in patients with PSP was a double-blind, placebo-controlled, single ascending dose study assessing the drug’s safety, tolerability, pharmacokinetics, and immunogenicity. Investigators randomized 30 participants to a single IV infusion of ABBV-8E12 (2.5, 7.5, 15, 25, or 50 mg/kg) or placebo in blocks of four subjects, with one subject in each block randomized to placebo and three to an active ABBV-8E12 dose. Researchers monitored safety and pharmacokinetics for 84 days post dosing.

Twenty-three patients received ABBV-8E12, and seven patients received placebo. At baseline, subjects’ mean age was 68.8; 16 (53%) were men. Patients had to be able to walk with minimal assistance to be included in the study. Twenty-seven subjects completed the 84-day follow-up and one subject (3.3%) withdrew from the study due to an adverse event.

Twenty-one subjects experienced an adverse event, including dermatitis (n = 5) and fall (n = 5). Three participants experienced serious adverse events. One patient had a subdural hematoma following two falls, one had agitation/anxiety/perseverative behavior, and one had hypertension. The serious adverse events occurred in the 15, 25, and 50 mg/kg cohorts, respectively. ABBV-8E12 exhibited an acceptable safety and tolerability profile to support repeat-dose testing in subjects with tauopathies, Dr. Budur said.

Dr. Budur and colleagues are recruiting subjects for a multinational phase II study evaluating ABBV-8E12 to delay the progression of Alzheimer’s disease. Eligible subjects (n = 400) will meet criteria for early Alzheimer’s disease and have a positive amyloid PET scan. “Subjects will be randomized to three doses of ABBV-8E12 versus placebo, 100 subjects per arm,” he said. In addition, investigators are recruiting patients with PSP for a phase II study evaluating the 52-week efficacy and safety of ABBV-8E12. The trial will assess whether the therapy can slow disease progression in 180 patients with PSP.

Antisense Oligonucleotide to Reduce Total Tau Expression in Mild Alzheimer’s Disease

Roger M. Lane, MD, MPH, of lonis Pharmaceuticals, Carlsbad, California, described a study that is designed to the test safety and pharmacokinetics of a tau-lowering antisense oligonucleotide (ASO) in patients with mild Alzheimer’s disease. The ASO, lonis-MAPT_RX, targets microtubule-associated protein tau (MAPT) messenger RNA to reduce the synthesis of tau in the CNS, Dr. Lane said. “In contrast, current investigational biologic or small molecule anti-tau drugs target the tau protein,” he said.

In a recent study, DeVos and colleagues identified ASOs that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After a reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and pre-existing tau pathology was reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In nonhuman primates, ASOs distributed throughout the brain and spinal cord, and reduced tau mRNA and protein in the brain and spinal cord, and tau protein in the CSF.

Based on these findings, researchers are studying lonis-MAPT_RX, a second generation 2’-O-methoxyethyl (2’-MOE) chimeric ASO identified as suitable for clinical trials. It is designed to bind and degrade the pre-mRNA transcribed from the MAPT gene and thereby reduce synthesis of tau protein.

“The first clinical trial is set up in 12 centers in Canada and five European countries,” Dr. Lane said. “Patients aged 50 to 75 with mild Alzheimer’s disease are being randomized to multiple ascending doses of lonis-MAPT_RX administered intrathecally.” The study drug will be given four times at monthly intervals, and there will be six months of follow-up. End points include CSF biomarkers, neuroimaging, and clinical outcomes. “We are expecting a 50–85% reduction in tau production in the cerebral cortex,” Dr. Lane said.

—Adriene Marshall

Suggested Reading

DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374).

LONDON—Several experimental therapies targeting tau are currently under investigation in phase I and II clinical trials. Researchers at the 2017 Alzheimer’s Association International Conference described the design of, and early results from, studies of two monoclonal antibodies and an antisense oligonucleotide.

RO7105705 for Alzheimer’s Disease

Dr. Kerchner presented data from a phase I trial of RO7105705, a humanized anti-tau monoclonal antibody. RO7105705 binds specifically to tau and is intended to intercept tau in the extracellular space of the brain, blocking its cell-to-cell spread.

The primary objective of the study was to evaluate the safety of single and multiple doses of the drug, compared with placebo. The secondary objective was to look at the pharmacokinetic profile following IV and subcutaneous doses. Study participants included healthy volunteers ages 18 to 80 and patients with probable Alzheimer’s disease. Patients with Alzheimer’s disease were between ages 50 and 80 and had a Mini-Mental State Examination score of 16 to 28; a Clinical Dementia Rating global score of 0.5, 1.0, or 2.0; and 18F-florbetapir PET scan evidence of cerebral amyloid pathology.

In the single-dose escalation phase, six cohorts of eight healthy volunteers each received IV doses that ranged from 225 mg to 16,800 mg. Another cohort received 1,200 mg of the drug subcutaneously. In the multiple-dose phase, a cohort of healthy volunteers and a cohort of patients with mild-to-moderate Alzheimer’s disease received four weekly doses of 8.4 g.

“The drug was well tolerated, even at these high doses,” Dr. Kerchner said. “So far, there have been no dose-limiting adverse events, no serious adverse events, no deaths, and no one who stopped the drug due to adverse events.” In the single-dose cohorts, adverse events that occurred in more than one participant included headache, infusion/injection site reaction, upper respiratory tract infection, nausea, vomiting, and gastrointestinal viral infection. In the multiple-dose cohorts, adverse events that occurred in more than one participant included vessel puncture site complications and postural dizziness.

ABBV-8E12 for PSP and Alzheimer’s Disease

Kumar Budur, MD, of AbbVie, Chicago, presented the results of a phase I study of ABBV-8E12, a humanized anti-tau monoclonal antibody, in patients with progressive supranuclear palsy (PSP). He also gave an overview of two ongoing phase II studies of ABBV-8E12 for early Alzheimer’s disease and PSP.

“PSP is a chronic progressive neurodegenerative disorder that affects movement, control of gait and balance, speech, swallowing, vision, mood and behavior, and thinking,” Dr. Budur explained. “The time from the onset of symptoms to death is only seven years. There currently are no approved treatments for this condition.” PSP affects approximately 20,000 people in the United States, and symptoms typically begin after age 60.

The phase I trial in patients with PSP was a double-blind, placebo-controlled, single ascending dose study assessing the drug’s safety, tolerability, pharmacokinetics, and immunogenicity. Investigators randomized 30 participants to a single IV infusion of ABBV-8E12 (2.5, 7.5, 15, 25, or 50 mg/kg) or placebo in blocks of four subjects, with one subject in each block randomized to placebo and three to an active ABBV-8E12 dose. Researchers monitored safety and pharmacokinetics for 84 days post dosing.

Twenty-three patients received ABBV-8E12, and seven patients received placebo. At baseline, subjects’ mean age was 68.8; 16 (53%) were men. Patients had to be able to walk with minimal assistance to be included in the study. Twenty-seven subjects completed the 84-day follow-up and one subject (3.3%) withdrew from the study due to an adverse event.

Twenty-one subjects experienced an adverse event, including dermatitis (n = 5) and fall (n = 5). Three participants experienced serious adverse events. One patient had a subdural hematoma following two falls, one had agitation/anxiety/perseverative behavior, and one had hypertension. The serious adverse events occurred in the 15, 25, and 50 mg/kg cohorts, respectively. ABBV-8E12 exhibited an acceptable safety and tolerability profile to support repeat-dose testing in subjects with tauopathies, Dr. Budur said.

Dr. Budur and colleagues are recruiting subjects for a multinational phase II study evaluating ABBV-8E12 to delay the progression of Alzheimer’s disease. Eligible subjects (n = 400) will meet criteria for early Alzheimer’s disease and have a positive amyloid PET scan. “Subjects will be randomized to three doses of ABBV-8E12 versus placebo, 100 subjects per arm,” he said. In addition, investigators are recruiting patients with PSP for a phase II study evaluating the 52-week efficacy and safety of ABBV-8E12. The trial will assess whether the therapy can slow disease progression in 180 patients with PSP.

Antisense Oligonucleotide to Reduce Total Tau Expression in Mild Alzheimer’s Disease

Roger M. Lane, MD, MPH, of lonis Pharmaceuticals, Carlsbad, California, described a study that is designed to the test safety and pharmacokinetics of a tau-lowering antisense oligonucleotide (ASO) in patients with mild Alzheimer’s disease. The ASO, lonis-MAPT_RX, targets microtubule-associated protein tau (MAPT) messenger RNA to reduce the synthesis of tau in the CNS, Dr. Lane said. “In contrast, current investigational biologic or small molecule anti-tau drugs target the tau protein,” he said.

In a recent study, DeVos and colleagues identified ASOs that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After a reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and pre-existing tau pathology was reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In nonhuman primates, ASOs distributed throughout the brain and spinal cord, and reduced tau mRNA and protein in the brain and spinal cord, and tau protein in the CSF.

Based on these findings, researchers are studying lonis-MAPT_RX, a second generation 2’-O-methoxyethyl (2’-MOE) chimeric ASO identified as suitable for clinical trials. It is designed to bind and degrade the pre-mRNA transcribed from the MAPT gene and thereby reduce synthesis of tau protein.

“The first clinical trial is set up in 12 centers in Canada and five European countries,” Dr. Lane said. “Patients aged 50 to 75 with mild Alzheimer’s disease are being randomized to multiple ascending doses of lonis-MAPT_RX administered intrathecally.” The study drug will be given four times at monthly intervals, and there will be six months of follow-up. End points include CSF biomarkers, neuroimaging, and clinical outcomes. “We are expecting a 50–85% reduction in tau production in the cerebral cortex,” Dr. Lane said.

—Adriene Marshall

Suggested Reading

DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374).

IDWeek 2017 kicks off Oct. 3 at the San Diego Convention Center, with a focus on pandemic preparedness and other challenges facing infectious diseases clinicians and researchers in the 21st century.

Premeeting workshops and symposia occupy most of the first 2 days of the event, with highlights including a session on managing infections in opioid users and a “late breaker” symposium addressing the latest on the H7N9 outbreak in China, the current findings and recommendations regarding Candida auris, and the epidemiology of the recent Legionella outbreaks in the United States. Another late breaker session focuses on the recent spate of hepatitis A outbreaks, including one in conference host city San Diego, primarily among the homeless population.

IDWeek is the combined annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS). The first IDWeek was held in 2012.

[email protected]

On Twitter @richpizzi

IDWeek 2017 kicks off Oct. 3 at the San Diego Convention Center, with a focus on pandemic preparedness and other challenges facing infectious diseases clinicians and researchers in the 21st century.

Premeeting workshops and symposia occupy most of the first 2 days of the event, with highlights including a session on managing infections in opioid users and a “late breaker” symposium addressing the latest on the H7N9 outbreak in China, the current findings and recommendations regarding Candida auris, and the epidemiology of the recent Legionella outbreaks in the United States. Another late breaker session focuses on the recent spate of hepatitis A outbreaks, including one in conference host city San Diego, primarily among the homeless population.

IDWeek is the combined annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS). The first IDWeek was held in 2012.

[email protected]

On Twitter @richpizzi

IDWeek 2017 kicks off Oct. 3 at the San Diego Convention Center, with a focus on pandemic preparedness and other challenges facing infectious diseases clinicians and researchers in the 21st century.

Premeeting workshops and symposia occupy most of the first 2 days of the event, with highlights including a session on managing infections in opioid users and a “late breaker” symposium addressing the latest on the H7N9 outbreak in China, the current findings and recommendations regarding Candida auris, and the epidemiology of the recent Legionella outbreaks in the United States. Another late breaker session focuses on the recent spate of hepatitis A outbreaks, including one in conference host city San Diego, primarily among the homeless population.

IDWeek is the combined annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS). The first IDWeek was held in 2012.

[email protected]

On Twitter @richpizzi