Original Research

In an era of potent antiretroviral therapy (ART), end stage liver disease (ESLD) is the second leading cause of death among patients with human immumodeficiency virus (HIV) infections who are co-infected with hepatitis C virus (HCV).^1,2 In the U.S., HCV infection is the major cause of liver failure, liver transplantation, and liver disease associated death, with an annual mortality that now exceeds that of HIV.^1,2 It is estimated that 30% to 35% of persons with HIV infection also have HCV infection.^1,2 Interestingly, patients with underlying HIV have a lower rate of spontaneous hepatitis C virologic clearance during acute infection, which is thought to be directly related to their level of underlying immune suppression and immune function.³ The consequences of HCV infection in this population are significant and include accelerated liver disease and fibrosis progression, higher rates of ESLD, and shortened life span after hepatic decompensation.^4,5 Because of these complications, the U.S. Department of Health and Human Services (DHHS) recommends that all HIV-infected patients should be screened for HCV infection, preferably before starting ART.⁶

HCV Treatment for HIV-HCV Co-Infection

The higher rates of fibrosis progression, decompensated liver disease, and morbidity and mortality secondary to ESLD compared with patients with HCV monoinfection are a major impetus to treat HCV in patients with HIV-HCV co-infection. However, there are very limited data on the safety and efficacy of the available antiviral agents for co-infection. The current paradigm is to stage patients before HCV treatment since those patients with minimal fibrosis may be able to wait for future less toxic or complex therapies, while HCV therapy should be offered to patients with portal or higher stages of fibrosis.⁷ Today with simpler and more effective therapies, even this paradigm is rapidly shifting to offering treatment for all infected patients.

The goal of HCV therapy is to achieve sustained virologic response (SVR), undetectable HCV RNA levels 24 weeks after the end of treatment. This endpoint is the gold standard of treatment-induced viral eradication and is used as the primary endpoint for treatment of HCV regardless of HIV status. Secondary goals are achieved upon viral eradication, including the reduction in morbidity and mortality associated with liver disease (eg, fibrosis/inflammation, hepatocellular carcinoma [HCC]).⁸ Failure to achieve SVR leaves the patient with continued risk of liver disease progression, including fibrosis and liver decompensation. Interestingly, in patients who have received treatment with peginterferon and ribavirin, there are data supporting a lower risk of liver-related mortality, hepatic decompensation, and liver stiffness when initial SVR is achieved, but there is a subsequent relapse (reappearance of HCV RNA).⁹

The complex decision to treat a patient with HIV infection for HCV is based on the stage of liver disease along with HCV genotype, viral load (VL), presence of comorbidities, and stability of the patient’s HIV regimen (if any). This is a long-term commitment for the patient, and his or her readiness to undergo and adhere to therapy is as important as the regimen. Given this complexity, it is also clear that treatment of HCV in either HCV alone or HIV-HCV co-infection should not be attempted without consultation and guidance from an infectious diseases or gastroenterology physician who has experience and training in the management of HCV and HIV. In general, a team of providers, including the physician, pharmacist, and social worker are required to ensure safety, compliance, and efficacy.

The timing of treatment is important in patients with bridging fibrosis or cirrhosis. However, treatment of mild to moderate disease can also be justified given the data supporting more rapid disease progression in patients with HIV-HCV co-infection, although not as pressing.^4,5 The best indicator for disease stage remains liver biopsy, which is assessed for grade and stage of the liver injury. There are 3 primary reasons for performing a liver biopsy: (1) It provides useful information on the status of the liver injury; (2) It identifies features useful in the decision to initiate therapy; and (3) It may reveal advanced fibrosis or cirrhosis that necessitates surveillance for HCC. The biopsy also provides information on other histologic features that might have a bearing on liver disease progression.10 However, there are clear contraindications to treatment, including a history of decompensated cirrhosis (may be exacerbated by treatment), pregnancy (teratogenicity of ribavirin), or uncontrolled depression and unstable cardiac or pulmonary conditions.⁶ Patients with untreated/uncontrolled HIV and/or AIDS are not optimal for treatment.¹⁰

In patients presenting with HIV and HCV coinfection the order of HIV or HCV treatment does affect patient outcomes.⁶ Recommendations from the DHHS HIV task force are that all treatment-naive HIV/HCV coinfected patients be initiated on HIV ART regardless of their CD4 cell count.6 In patients with lower CD4 counts (eg, < 200 cells/mm3), it may be preferable to initiate ART and delay HCV therapy until CD4 count increases. The importance of immune reconstitution and function has been demonstrated by studies that show ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation.

There is also evidence to support the model that HCV viremia increase proportionally to the extent of CD4 cell count decline; although there is no direct correlation between extent of liver damage and viremia there are direct implications for therapy.¹⁰ For most HIV-HCV co-infected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be considered for patients with HIV-HCV co-infection, regardless of CD4 count, and treatment of HCV may be deferred until there is a rise in the CD4 count.^11,12

Current Treatment Regimens

Antiretroviral regimens for patients with HIV-HCV coinfection are generally the same as those for individuals without HIV infection (Table).^13-20 Importantly, when treating both infections the provider must consider the large pill burden, drug-drug interactions, and overlapping toxicities (in particular hepatic) prior to
starting therapy. The same predictors as those for monoinfection apply to co-infected patients, including the level of baseline viremia, with high-level viremia having a negative impact on overall SVR rates in clinical trials with the new protease inhibitor boceprevir (although it did not impact telaprevircontaining
regimens).^21,22 Another factor that predicts treatment response is the HCV genotype (total of 6). In the U.S., genotype 1 accounts for 70% to 75% of HCV infections. Genotype 1a is responsible for two-thirds, and genotype 1b for one-third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a.

Treatment success with interferon-based regimens is also influenced by the patient’s interleukin 28B gene (IL28B) polymorphism. Patients with the IL28B CC genotype have a greater response than those with IL28B TT genotype.²³ IL28B is a member of the type III interferon system. Interferons are part of the innate immune response of host cells to pathogens in particular viruses. They establish an antiviral state by inhibiting protein synthesis, alerting the immune system to the presence of pathogen, and inducing proteins with antiviral activity. Interferons are pivotal factors in fighting viral infections and establishing an antiviral state
in the infected and surrounding cells.²⁴ Currently, we do not routinely determine IL28B genotypes; however, as technology improves and genotyping becomes more commercially available, this may be incorporated into routine practice. Moreover, with the second generation HCV drugs, including simpeprevir and sofosbuvir, the IL28 genotype is not a factor as new recommendations include interferon-free regimens.²⁵

Peginterferon alpha plus ribavirin has been the mainstay of therapy since 2001, producing an overall 40% response in treated patients with HCV genotype 1.²⁶ More recently, 4 classes of direct-acting antiviral (DAA) agents have been developed, including nonstructural protein 3/4A (NS3/4A) protease inhibitors (PIs), nonstructural protein 5B (NS5B) nucleoside inhibitors, NS5B non-nucleoside inhibitors, and nonstructural protein 5A (NS5A) inhibitors. Of these classes, the PIs boceprevir and telaprevir have been in use since 2011 and have significantly improved response rates to therapy for genotype 1 infection. These drugs, however, continue to require peginterferon and ribavirin therapy; therefore many of the barriers to therapy that existed previously remain.

Several clinical trials demonstrated significantly increased efficacy with PI backed therapy when compared with standard interferon ribavirin regimens in treatment-naive and treatment-experienced nonresponders/patients who have relapsed.^21,22,27 Previously one of the main treatment predictors was the rapidity of viral suppression assessed at 4 weeks of therapy. If patients have a rapid virologic response (ie, > 2 log decrease in VL), they generally do well with sustained viral suppression. However, this predictor becomes unclear as the DAA are used. Because of their potency with rapid viral suppression, the durability of the rapid virologic response and its use as a predictor of treatment success becomes uncertain. To date, there have been few clinical trials completed and published on the efficacy and safety of this triple drug regimen in the HIV-HCV co-infected patient. However, what data there is available is encouraging.

In a phase 2 clinical trial of genotype 1 co-infected patients after a 4-week peginterferon and ribavirin leadin, boceprevir was initiated and continued for 44 weeks vs continuation of standard of care with peginterferon and ribavirin. In this cohort 42% of patients in the boceprevir arm achieved viral suppression at week 8 vs 15% in the standard therapy arm. At 24 weeks postcompletion of therapy, 63% of patient maintained SVR compared with 29% in the standard arm. Importantly, co-infected patients did not have new previously unreported adverse events (AEs), and the percentage of patients with AEs seemed to be similar to those with HCV infection alone.²⁸ Similar studies of telaprevir also demonstrated more effective therapy than did the standard of care in co-infected patients. Another study evaluating telaprevir utilized a small cohort of 60 patients with genotype 1 infection. They were treated for 12 weeks with peginterferon, ribavirin, and telaprevir followed by an additional 36 weeks of peginterferon and ribavirin. After 4 weeks of therapy, 68% of patients in the telaprevir arm had rapid virologic response compared with none of the patients in the standard therapy arm. Patients included in this cohort had higher VL and advanced liver disease. Upon completion of the study at both 12 and 24 weeks posttherapy, 74% vs 24% of patients had SVR, respectively. Safety data in this study also demonstrated  similar toxicity profiles as those with HCV monoinfection.²⁹

In recent months the FDA approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3. Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/μL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.³⁰ The sofosbuvir regimen utilized in the PHOTON-1 trial is an interferon-free regimen, the first time there has been success with interferon-free regimens in this population.³⁰ A new study released in early November at the American Association for the Study of Liver Diseases meeting presented data from the ERADICATE trial, which was designed to test a simple once daily regimen of sofosbuvir and ledipasvir (a new inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion) in 50 patients. Results presented demonstrated that at 12 weeks posttreatment all patients in the ART untreated group and all but one in the ART treated group had undetectable HCV RNA. The overall SVR rate was 98% for this study. This is the first time an interferon and ribavirin-free regimen has shown clear efficacy in the treatment and cure of HCV infection.²⁵ New guidelines for the treatment of patients with HCV-HIV co-infection are expected to be released in the immediate future.

Conclusion

The sudden and dramatic change in hepatitis C management is now here, with an extraordinary array of new drugs expected to cure the majority of hepatitis C-infected patients.³¹ It remains an exciting time in the field as for the first time we may be able to reach solid cure rates with simpler, more accessible regimens, in particular as we are on the threshold of totally oral therapy. One of the greatest limitations has been and will remain the economics of therapy (Table), which is not discussed here but remains at the forefront of barriers to care and cure.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

 Click here to read the digital edition.

In an era of potent antiretroviral therapy (ART), end stage liver disease (ESLD) is the second leading cause of death among patients with human immumodeficiency virus (HIV) infections who are co-infected with hepatitis C virus (HCV).^1,2 In the U.S., HCV infection is the major cause of liver failure, liver transplantation, and liver disease associated death, with an annual mortality that now exceeds that of HIV.^1,2 It is estimated that 30% to 35% of persons with HIV infection also have HCV infection.^1,2 Interestingly, patients with underlying HIV have a lower rate of spontaneous hepatitis C virologic clearance during acute infection, which is thought to be directly related to their level of underlying immune suppression and immune function.³ The consequences of HCV infection in this population are significant and include accelerated liver disease and fibrosis progression, higher rates of ESLD, and shortened life span after hepatic decompensation.^4,5 Because of these complications, the U.S. Department of Health and Human Services (DHHS) recommends that all HIV-infected patients should be screened for HCV infection, preferably before starting ART.⁶

HCV Treatment for HIV-HCV Co-Infection

The higher rates of fibrosis progression, decompensated liver disease, and morbidity and mortality secondary to ESLD compared with patients with HCV monoinfection are a major impetus to treat HCV in patients with HIV-HCV co-infection. However, there are very limited data on the safety and efficacy of the available antiviral agents for co-infection. The current paradigm is to stage patients before HCV treatment since those patients with minimal fibrosis may be able to wait for future less toxic or complex therapies, while HCV therapy should be offered to patients with portal or higher stages of fibrosis.⁷ Today with simpler and more effective therapies, even this paradigm is rapidly shifting to offering treatment for all infected patients.

The goal of HCV therapy is to achieve sustained virologic response (SVR), undetectable HCV RNA levels 24 weeks after the end of treatment. This endpoint is the gold standard of treatment-induced viral eradication and is used as the primary endpoint for treatment of HCV regardless of HIV status. Secondary goals are achieved upon viral eradication, including the reduction in morbidity and mortality associated with liver disease (eg, fibrosis/inflammation, hepatocellular carcinoma [HCC]).⁸ Failure to achieve SVR leaves the patient with continued risk of liver disease progression, including fibrosis and liver decompensation. Interestingly, in patients who have received treatment with peginterferon and ribavirin, there are data supporting a lower risk of liver-related mortality, hepatic decompensation, and liver stiffness when initial SVR is achieved, but there is a subsequent relapse (reappearance of HCV RNA).⁹

The complex decision to treat a patient with HIV infection for HCV is based on the stage of liver disease along with HCV genotype, viral load (VL), presence of comorbidities, and stability of the patient’s HIV regimen (if any). This is a long-term commitment for the patient, and his or her readiness to undergo and adhere to therapy is as important as the regimen. Given this complexity, it is also clear that treatment of HCV in either HCV alone or HIV-HCV co-infection should not be attempted without consultation and guidance from an infectious diseases or gastroenterology physician who has experience and training in the management of HCV and HIV. In general, a team of providers, including the physician, pharmacist, and social worker are required to ensure safety, compliance, and efficacy.

The timing of treatment is important in patients with bridging fibrosis or cirrhosis. However, treatment of mild to moderate disease can also be justified given the data supporting more rapid disease progression in patients with HIV-HCV co-infection, although not as pressing.^4,5 The best indicator for disease stage remains liver biopsy, which is assessed for grade and stage of the liver injury. There are 3 primary reasons for performing a liver biopsy: (1) It provides useful information on the status of the liver injury; (2) It identifies features useful in the decision to initiate therapy; and (3) It may reveal advanced fibrosis or cirrhosis that necessitates surveillance for HCC. The biopsy also provides information on other histologic features that might have a bearing on liver disease progression.10 However, there are clear contraindications to treatment, including a history of decompensated cirrhosis (may be exacerbated by treatment), pregnancy (teratogenicity of ribavirin), or uncontrolled depression and unstable cardiac or pulmonary conditions.⁶ Patients with untreated/uncontrolled HIV and/or AIDS are not optimal for treatment.¹⁰

In patients presenting with HIV and HCV coinfection the order of HIV or HCV treatment does affect patient outcomes.⁶ Recommendations from the DHHS HIV task force are that all treatment-naive HIV/HCV coinfected patients be initiated on HIV ART regardless of their CD4 cell count.6 In patients with lower CD4 counts (eg, < 200 cells/mm3), it may be preferable to initiate ART and delay HCV therapy until CD4 count increases. The importance of immune reconstitution and function has been demonstrated by studies that show ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation.

There is also evidence to support the model that HCV viremia increase proportionally to the extent of CD4 cell count decline; although there is no direct correlation between extent of liver damage and viremia there are direct implications for therapy.¹⁰ For most HIV-HCV co-infected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be considered for patients with HIV-HCV co-infection, regardless of CD4 count, and treatment of HCV may be deferred until there is a rise in the CD4 count.^11,12

Current Treatment Regimens

Antiretroviral regimens for patients with HIV-HCV coinfection are generally the same as those for individuals without HIV infection (Table).^13-20 Importantly, when treating both infections the provider must consider the large pill burden, drug-drug interactions, and overlapping toxicities (in particular hepatic) prior to
starting therapy. The same predictors as those for monoinfection apply to co-infected patients, including the level of baseline viremia, with high-level viremia having a negative impact on overall SVR rates in clinical trials with the new protease inhibitor boceprevir (although it did not impact telaprevircontaining
regimens).^21,22 Another factor that predicts treatment response is the HCV genotype (total of 6). In the U.S., genotype 1 accounts for 70% to 75% of HCV infections. Genotype 1a is responsible for two-thirds, and genotype 1b for one-third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a.

Treatment success with interferon-based regimens is also influenced by the patient’s interleukin 28B gene (IL28B) polymorphism. Patients with the IL28B CC genotype have a greater response than those with IL28B TT genotype.²³ IL28B is a member of the type III interferon system. Interferons are part of the innate immune response of host cells to pathogens in particular viruses. They establish an antiviral state by inhibiting protein synthesis, alerting the immune system to the presence of pathogen, and inducing proteins with antiviral activity. Interferons are pivotal factors in fighting viral infections and establishing an antiviral state
in the infected and surrounding cells.²⁴ Currently, we do not routinely determine IL28B genotypes; however, as technology improves and genotyping becomes more commercially available, this may be incorporated into routine practice. Moreover, with the second generation HCV drugs, including simpeprevir and sofosbuvir, the IL28 genotype is not a factor as new recommendations include interferon-free regimens.²⁵

Peginterferon alpha plus ribavirin has been the mainstay of therapy since 2001, producing an overall 40% response in treated patients with HCV genotype 1.²⁶ More recently, 4 classes of direct-acting antiviral (DAA) agents have been developed, including nonstructural protein 3/4A (NS3/4A) protease inhibitors (PIs), nonstructural protein 5B (NS5B) nucleoside inhibitors, NS5B non-nucleoside inhibitors, and nonstructural protein 5A (NS5A) inhibitors. Of these classes, the PIs boceprevir and telaprevir have been in use since 2011 and have significantly improved response rates to therapy for genotype 1 infection. These drugs, however, continue to require peginterferon and ribavirin therapy; therefore many of the barriers to therapy that existed previously remain.

Several clinical trials demonstrated significantly increased efficacy with PI backed therapy when compared with standard interferon ribavirin regimens in treatment-naive and treatment-experienced nonresponders/patients who have relapsed.^21,22,27 Previously one of the main treatment predictors was the rapidity of viral suppression assessed at 4 weeks of therapy. If patients have a rapid virologic response (ie, > 2 log decrease in VL), they generally do well with sustained viral suppression. However, this predictor becomes unclear as the DAA are used. Because of their potency with rapid viral suppression, the durability of the rapid virologic response and its use as a predictor of treatment success becomes uncertain. To date, there have been few clinical trials completed and published on the efficacy and safety of this triple drug regimen in the HIV-HCV co-infected patient. However, what data there is available is encouraging.

In a phase 2 clinical trial of genotype 1 co-infected patients after a 4-week peginterferon and ribavirin leadin, boceprevir was initiated and continued for 44 weeks vs continuation of standard of care with peginterferon and ribavirin. In this cohort 42% of patients in the boceprevir arm achieved viral suppression at week 8 vs 15% in the standard therapy arm. At 24 weeks postcompletion of therapy, 63% of patient maintained SVR compared with 29% in the standard arm. Importantly, co-infected patients did not have new previously unreported adverse events (AEs), and the percentage of patients with AEs seemed to be similar to those with HCV infection alone.²⁸ Similar studies of telaprevir also demonstrated more effective therapy than did the standard of care in co-infected patients. Another study evaluating telaprevir utilized a small cohort of 60 patients with genotype 1 infection. They were treated for 12 weeks with peginterferon, ribavirin, and telaprevir followed by an additional 36 weeks of peginterferon and ribavirin. After 4 weeks of therapy, 68% of patients in the telaprevir arm had rapid virologic response compared with none of the patients in the standard therapy arm. Patients included in this cohort had higher VL and advanced liver disease. Upon completion of the study at both 12 and 24 weeks posttherapy, 74% vs 24% of patients had SVR, respectively. Safety data in this study also demonstrated  similar toxicity profiles as those with HCV monoinfection.²⁹

In recent months the FDA approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3. Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/μL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.³⁰ The sofosbuvir regimen utilized in the PHOTON-1 trial is an interferon-free regimen, the first time there has been success with interferon-free regimens in this population.³⁰ A new study released in early November at the American Association for the Study of Liver Diseases meeting presented data from the ERADICATE trial, which was designed to test a simple once daily regimen of sofosbuvir and ledipasvir (a new inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion) in 50 patients. Results presented demonstrated that at 12 weeks posttreatment all patients in the ART untreated group and all but one in the ART treated group had undetectable HCV RNA. The overall SVR rate was 98% for this study. This is the first time an interferon and ribavirin-free regimen has shown clear efficacy in the treatment and cure of HCV infection.²⁵ New guidelines for the treatment of patients with HCV-HIV co-infection are expected to be released in the immediate future.

Conclusion

The sudden and dramatic change in hepatitis C management is now here, with an extraordinary array of new drugs expected to cure the majority of hepatitis C-infected patients.³¹ It remains an exciting time in the field as for the first time we may be able to reach solid cure rates with simpler, more accessible regimens, in particular as we are on the threshold of totally oral therapy. One of the greatest limitations has been and will remain the economics of therapy (Table), which is not discussed here but remains at the forefront of barriers to care and cure.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

 Click here to read the digital edition.

In an era of potent antiretroviral therapy (ART), end stage liver disease (ESLD) is the second leading cause of death among patients with human immumodeficiency virus (HIV) infections who are co-infected with hepatitis C virus (HCV).^1,2 In the U.S., HCV infection is the major cause of liver failure, liver transplantation, and liver disease associated death, with an annual mortality that now exceeds that of HIV.^1,2 It is estimated that 30% to 35% of persons with HIV infection also have HCV infection.^1,2 Interestingly, patients with underlying HIV have a lower rate of spontaneous hepatitis C virologic clearance during acute infection, which is thought to be directly related to their level of underlying immune suppression and immune function.³ The consequences of HCV infection in this population are significant and include accelerated liver disease and fibrosis progression, higher rates of ESLD, and shortened life span after hepatic decompensation.^4,5 Because of these complications, the U.S. Department of Health and Human Services (DHHS) recommends that all HIV-infected patients should be screened for HCV infection, preferably before starting ART.⁶

HCV Treatment for HIV-HCV Co-Infection

The higher rates of fibrosis progression, decompensated liver disease, and morbidity and mortality secondary to ESLD compared with patients with HCV monoinfection are a major impetus to treat HCV in patients with HIV-HCV co-infection. However, there are very limited data on the safety and efficacy of the available antiviral agents for co-infection. The current paradigm is to stage patients before HCV treatment since those patients with minimal fibrosis may be able to wait for future less toxic or complex therapies, while HCV therapy should be offered to patients with portal or higher stages of fibrosis.⁷ Today with simpler and more effective therapies, even this paradigm is rapidly shifting to offering treatment for all infected patients.

The goal of HCV therapy is to achieve sustained virologic response (SVR), undetectable HCV RNA levels 24 weeks after the end of treatment. This endpoint is the gold standard of treatment-induced viral eradication and is used as the primary endpoint for treatment of HCV regardless of HIV status. Secondary goals are achieved upon viral eradication, including the reduction in morbidity and mortality associated with liver disease (eg, fibrosis/inflammation, hepatocellular carcinoma [HCC]).⁸ Failure to achieve SVR leaves the patient with continued risk of liver disease progression, including fibrosis and liver decompensation. Interestingly, in patients who have received treatment with peginterferon and ribavirin, there are data supporting a lower risk of liver-related mortality, hepatic decompensation, and liver stiffness when initial SVR is achieved, but there is a subsequent relapse (reappearance of HCV RNA).⁹

The complex decision to treat a patient with HIV infection for HCV is based on the stage of liver disease along with HCV genotype, viral load (VL), presence of comorbidities, and stability of the patient’s HIV regimen (if any). This is a long-term commitment for the patient, and his or her readiness to undergo and adhere to therapy is as important as the regimen. Given this complexity, it is also clear that treatment of HCV in either HCV alone or HIV-HCV co-infection should not be attempted without consultation and guidance from an infectious diseases or gastroenterology physician who has experience and training in the management of HCV and HIV. In general, a team of providers, including the physician, pharmacist, and social worker are required to ensure safety, compliance, and efficacy.

The timing of treatment is important in patients with bridging fibrosis or cirrhosis. However, treatment of mild to moderate disease can also be justified given the data supporting more rapid disease progression in patients with HIV-HCV co-infection, although not as pressing.^4,5 The best indicator for disease stage remains liver biopsy, which is assessed for grade and stage of the liver injury. There are 3 primary reasons for performing a liver biopsy: (1) It provides useful information on the status of the liver injury; (2) It identifies features useful in the decision to initiate therapy; and (3) It may reveal advanced fibrosis or cirrhosis that necessitates surveillance for HCC. The biopsy also provides information on other histologic features that might have a bearing on liver disease progression.10 However, there are clear contraindications to treatment, including a history of decompensated cirrhosis (may be exacerbated by treatment), pregnancy (teratogenicity of ribavirin), or uncontrolled depression and unstable cardiac or pulmonary conditions.⁶ Patients with untreated/uncontrolled HIV and/or AIDS are not optimal for treatment.¹⁰

In patients presenting with HIV and HCV coinfection the order of HIV or HCV treatment does affect patient outcomes.⁶ Recommendations from the DHHS HIV task force are that all treatment-naive HIV/HCV coinfected patients be initiated on HIV ART regardless of their CD4 cell count.6 In patients with lower CD4 counts (eg, < 200 cells/mm3), it may be preferable to initiate ART and delay HCV therapy until CD4 count increases. The importance of immune reconstitution and function has been demonstrated by studies that show ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation.

There is also evidence to support the model that HCV viremia increase proportionally to the extent of CD4 cell count decline; although there is no direct correlation between extent of liver damage and viremia there are direct implications for therapy.¹⁰ For most HIV-HCV co-infected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be considered for patients with HIV-HCV co-infection, regardless of CD4 count, and treatment of HCV may be deferred until there is a rise in the CD4 count.^11,12

Current Treatment Regimens

Antiretroviral regimens for patients with HIV-HCV coinfection are generally the same as those for individuals without HIV infection (Table).^13-20 Importantly, when treating both infections the provider must consider the large pill burden, drug-drug interactions, and overlapping toxicities (in particular hepatic) prior to
starting therapy. The same predictors as those for monoinfection apply to co-infected patients, including the level of baseline viremia, with high-level viremia having a negative impact on overall SVR rates in clinical trials with the new protease inhibitor boceprevir (although it did not impact telaprevircontaining
regimens).^21,22 Another factor that predicts treatment response is the HCV genotype (total of 6). In the U.S., genotype 1 accounts for 70% to 75% of HCV infections. Genotype 1a is responsible for two-thirds, and genotype 1b for one-third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a.

Treatment success with interferon-based regimens is also influenced by the patient’s interleukin 28B gene (IL28B) polymorphism. Patients with the IL28B CC genotype have a greater response than those with IL28B TT genotype.²³ IL28B is a member of the type III interferon system. Interferons are part of the innate immune response of host cells to pathogens in particular viruses. They establish an antiviral state by inhibiting protein synthesis, alerting the immune system to the presence of pathogen, and inducing proteins with antiviral activity. Interferons are pivotal factors in fighting viral infections and establishing an antiviral state
in the infected and surrounding cells.²⁴ Currently, we do not routinely determine IL28B genotypes; however, as technology improves and genotyping becomes more commercially available, this may be incorporated into routine practice. Moreover, with the second generation HCV drugs, including simpeprevir and sofosbuvir, the IL28 genotype is not a factor as new recommendations include interferon-free regimens.²⁵

Peginterferon alpha plus ribavirin has been the mainstay of therapy since 2001, producing an overall 40% response in treated patients with HCV genotype 1.²⁶ More recently, 4 classes of direct-acting antiviral (DAA) agents have been developed, including nonstructural protein 3/4A (NS3/4A) protease inhibitors (PIs), nonstructural protein 5B (NS5B) nucleoside inhibitors, NS5B non-nucleoside inhibitors, and nonstructural protein 5A (NS5A) inhibitors. Of these classes, the PIs boceprevir and telaprevir have been in use since 2011 and have significantly improved response rates to therapy for genotype 1 infection. These drugs, however, continue to require peginterferon and ribavirin therapy; therefore many of the barriers to therapy that existed previously remain.

Several clinical trials demonstrated significantly increased efficacy with PI backed therapy when compared with standard interferon ribavirin regimens in treatment-naive and treatment-experienced nonresponders/patients who have relapsed.^21,22,27 Previously one of the main treatment predictors was the rapidity of viral suppression assessed at 4 weeks of therapy. If patients have a rapid virologic response (ie, > 2 log decrease in VL), they generally do well with sustained viral suppression. However, this predictor becomes unclear as the DAA are used. Because of their potency with rapid viral suppression, the durability of the rapid virologic response and its use as a predictor of treatment success becomes uncertain. To date, there have been few clinical trials completed and published on the efficacy and safety of this triple drug regimen in the HIV-HCV co-infected patient. However, what data there is available is encouraging.

In a phase 2 clinical trial of genotype 1 co-infected patients after a 4-week peginterferon and ribavirin leadin, boceprevir was initiated and continued for 44 weeks vs continuation of standard of care with peginterferon and ribavirin. In this cohort 42% of patients in the boceprevir arm achieved viral suppression at week 8 vs 15% in the standard therapy arm. At 24 weeks postcompletion of therapy, 63% of patient maintained SVR compared with 29% in the standard arm. Importantly, co-infected patients did not have new previously unreported adverse events (AEs), and the percentage of patients with AEs seemed to be similar to those with HCV infection alone.²⁸ Similar studies of telaprevir also demonstrated more effective therapy than did the standard of care in co-infected patients. Another study evaluating telaprevir utilized a small cohort of 60 patients with genotype 1 infection. They were treated for 12 weeks with peginterferon, ribavirin, and telaprevir followed by an additional 36 weeks of peginterferon and ribavirin. After 4 weeks of therapy, 68% of patients in the telaprevir arm had rapid virologic response compared with none of the patients in the standard therapy arm. Patients included in this cohort had higher VL and advanced liver disease. Upon completion of the study at both 12 and 24 weeks posttherapy, 74% vs 24% of patients had SVR, respectively. Safety data in this study also demonstrated  similar toxicity profiles as those with HCV monoinfection.²⁹

In recent months the FDA approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3. Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/μL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.³⁰ The sofosbuvir regimen utilized in the PHOTON-1 trial is an interferon-free regimen, the first time there has been success with interferon-free regimens in this population.³⁰ A new study released in early November at the American Association for the Study of Liver Diseases meeting presented data from the ERADICATE trial, which was designed to test a simple once daily regimen of sofosbuvir and ledipasvir (a new inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion) in 50 patients. Results presented demonstrated that at 12 weeks posttreatment all patients in the ART untreated group and all but one in the ART treated group had undetectable HCV RNA. The overall SVR rate was 98% for this study. This is the first time an interferon and ribavirin-free regimen has shown clear efficacy in the treatment and cure of HCV infection.²⁵ New guidelines for the treatment of patients with HCV-HIV co-infection are expected to be released in the immediate future.

Conclusion

The sudden and dramatic change in hepatitis C management is now here, with an extraordinary array of new drugs expected to cure the majority of hepatitis C-infected patients.³¹ It remains an exciting time in the field as for the first time we may be able to reach solid cure rates with simpler, more accessible regimens, in particular as we are on the threshold of totally oral therapy. One of the greatest limitations has been and will remain the economics of therapy (Table), which is not discussed here but remains at the forefront of barriers to care and cure.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

 Click here to read the digital edition.

Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are considered the signature injuries in veterans of the military operations in Iraq and Afghanistan.¹ In 2007, the VA implemented the Polytrauma System of Care (PSC) to provide comprehensive screening, evaluation, and treatment of these multifaceted injuries.^2,3 The VA defined polytrauma as “two or more injuries to physical regions or organ systems, one of which may be life threatening, resulting in physical, cognitive, psychological, or psychosocial impairments and functional disability.”³ The VA intended the PSC to provide a national system of integrated care to meet the unique needs of these combat service members.

In addition to the comprehensive evaluation and treatment of traumatic injuries, a critical mission of the PSC is to facilitate the reintegration of injured combat veterans into their home communities. Optimal community reintegration requires that the clinician also assess premorbid comorbidities, which may affect postdeployment adjustments. Attention-deficit/hyperactivity disorder (ADHD), with an estimated adult prevalence of 4.4% in the U.S. and 2.5% to 3.4% worldwide, is a common disorder in the general adult population that often is associated with chronic social and vocational adjustment difficulties.^4-6 The increasing recognition that this disorder often persists into adulthood is of significance to veterans, largely young and male, who have left military service and are reintegrating into college and community job settings.⁷ Despite growing interest in adult ADHD, little is known about its prevalence and correlates in the veteran population.

The prevalence of ADHD in the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veteran polytrauma population has not been adequately studied. Studies have found that combat veterans with or without confirmed TBI diagnosis commonly have similar overlapping symptoms, such as memory problems, difficulty concentrating, poor attention, and sleep problems associated with other comorbidities such as pain, PTSD, ADHD, and other mental health diagnoses.^8-14 Increased awareness of various clinical variables would enhance understanding of the population characteristics and specific needs for education and management.

Related: Preparing the Military Health System for the 21st Century

To begin to address the lack of information about ADHD in the VA polytrauma population, this study aimed to (1) identify the prevalence of ADHD in veterans referred to the Clement J. Zablocki (CJZ) VAMC Polytrauma Clinic (PC) in Milwaukee, Wisconsin; (2) describe demographic characteristics of polytrauma veterans with ADHD; (3) determine the comorbidity relationship between ADHD and TBI, PTSD, depression and anxiety disorders, and substance abuse; and (4) determine whether individuals with ADHD compared with those without ADHD report more physical and emotional symptomatic distress with particular attention given to reports of pain, headaches, and problems with attention and concentration, memory, and sleep.

Methods

The study population consisted of 690 OEF/OIF/OND soldiers and veterans who received a comprehensive TBI evaluation in the CJZVAMC PC from January 1, 2008, to December 31, 2012. Referrals to the PC were made by primary care physicians (PCPs) when OEF/OIF/OND veterans or service members enrolled at a VA facility for health care or transferred their care from another VA facility.

Either a prior diagnosis of TBI established by a qualified provider or positive responses to a 4-question screening tool for TBI prompted a referral to the PC. The 4 questions sought to establish (1) events that may increase risk of TBIs; (2) immediate symptoms following the event; (3) new or worsening symptoms following the event; and (4) current symptoms.¹ Referrals to the clinic most commonly came from PCPs at the CJZVAMC and its associated community-based outpatient clinics but occasionally came from mental health service providers.

Study Design

The CJZVAMC Institutional Review Board approved this study. A population database was developed from a review of medical records, clinical interviews of patients, and completion of standard intake forms during the veterans’ initial evaluations in the CJZVAMC PC. The database aimed to abstract patient information relevant for understanding and treating the population seen in the clinic. The database contained information related to demographics, injury parameters, neurobehavioral and PTSD symptoms, past and current mental health disorders, substance abuse history, pain symptoms, and developmental history (eg, ADHD, learning disability).

Related: First Brain Wave Test to Diagnose ADHD

Prior to the PC intake interview, each veteran completed a packet of preclinic questionnaires that included information concerning deployment-related injury exposure and history; the 22-item Neurobehavioral Symptom Inventory (NSI), which assessed physical, cognitive, and emotional symptoms; current pain symptoms; and the Posttraumatic Stress Disorder Checklist-Civilian Version (PCLC).^15,16 Intake interviews in the CJZVAMC PC were typically conducted with a minimum of 2 specialties present (physical medicine/rehabilitation and neuropsychology) and occasionally as many as 4 specialties present (also including health psychology and social work). Data collection and abstraction for the database were derived by all specialties present and assisted by the polytrauma program technician.

Diagnoses

The diagnosis of ADHD in a veteran was established through 1 of 2 methods: (1) report of a developmental history of behavioral adjustment difficulties consistent with ADHD that was coupled with formal psychiatric diagnosis and recommended treatment of ADHD in childhood; or (2) current diagnosis of ADHD as identified in the veteran’s active problem list. In most cases of report of developmental diagnosis, the veteran reported having been diagnosed and having received treatment with a stimulant medication for a period of time. In a few cases, the veteran reported having been diagnosed and stimulant medication was recommended, but the veteran’s parents declined the pharmacologic treatment in favor of behavioral treatment strategies.

In cases of current diagnosis, Diagnostic and Statistical Manual of Mental Disorders, Text Revision, 4th Edition (DSM-IV-TR), criteria were applied and supported by formal clinical examinations for ADHD conducted by psychologists, psychiatrists or neuropsychologists, or through VA disability (Compensation and Pension) evaluations where an issue related to ADHD diagnosis was raised.¹⁷ There was considerable overlap between these 2 diagnostic criteria (ie, through report of developmental history of diagnosis or formal adult evaluation) with 93% of cases being positive on both diagnostic methods.

Other comorbid psychiatric (eg, depression, anxiety, PTSD, substance abuse) and medical (eg, headache, pain) conditions also were abstracted from the veteran’s medical records at the time of the intake evaluation. Documentation of these conditions was derived from the veteran’s problem list and clinical notes that identified the condition as a diagnostic conclusion or focus of treatment. The comorbid conditions were not otherwise independently documented. Many veterans were taking psychotropic medications for mood, sleep, or chronic pain problems at the time of evaluation in the PC; however, use of medication and their effects were not systematically evaluated.

Statistical Analysis

In addition to documentation of the population prevalence for ADHD, analysis for disproportionate prevalence of comorbid conditions in individuals with ADHD compared with those without ADHD was done through the use of the chi-square test and/or Fisher exact test. For continuous variables, t tests were used to compare individuals with ADHD with individuals without ADHD. To control family-wise type I error to a P value of .05, a false discovery rate (FDR) was applied to studies of demographics, comorbidities, and ratings of symptomatic distress.

Results

The general population characteristics of the 690 veterans and soldiers are summarized in Table 1. The sample was predominantly male (96%), white (88%), and ranged in age from 22 to 55 years with a mean of 28 years. Active-duty service members and reservists from the U.S. Army, Marines, Navy, and Air Force were represented, but most were Army veterans (72%). Most (63%) had a high school education. About two-thirds of the veterans had a single deployment, and the remaining had multiple deployments.

The TBI clinic evaluations found that 58% of the patients had ≥ 1 TBI during their deployments, almost exclusively mild in severity. Seventy-three patients met study criteria for ADHD: 69 with an identified history of diagnosis in childhood and 68 with a current diagnosis, with 93% overlap of these groups. Table 2 provides a breakdown of demographic characteristics, comorbidities, and symptomatic distress in veterans with ADHD compared with those without the diagnosis.

Demographic Characteristics

Veterans with ADHD were found to be slightly younger (2.3 years younger, P = .003) and to have less education (greater frequency of less than high school and high school only, P = .003) compared with those who did not have the diagnosis. No significant group differences in sex, employment/school status, marital status, or number of deployments were identified in veterans with ADHD compared with non-ADHD veterans. Individuals with ADHD did not experience more physical, emotional, or sexual abuse as children than did their non-ADHD counterparts. The prevalence of TBI during deployment was similar in veterans with ADHD compared with that of non-ADHD veterans. There was a trend for veterans with ADHD to have more TBIs prior to military service than in non-ADHD veterans; however, this trend did not reach statistical significance (P = .188).

Comorbidities

After application of the FDR threshold, veterans with ADHD did not show a disproportionate prevalence of mental health diagnoses (eg, PTSD, depression and anxiety disorders, or substance abuse). There was a nonsignificant trend for more veterans with ADHD to report pain during the previous 30 days (P = .035) and more issues with substance abuse (P = .10) than for non-ADHD veterans, but these trends did not meet the FDR threshold of < .05. 

Symptomatic Distress

Veterans with ADHD did not report significantly greater levels of distress on either the NSI or the PCLC survey compared with non-ADHD veterans.Not surprisingly, when select symptoms were investigated, veterans with ADHD reported more problems with attention and concentration than for non-ADHD veterans (P = .015). No group differences were identified for sleep issues, headaches, or memory, although there was a trend for the latter (P = .14).

Discussion

In this study, there was a 10.6% prevalence of ADHD in 690 OEF/OIF/OND combat veterans. This rate is considerably higher than estimates of prevalence of ADHD in adults (4.4%) made from a nationwide survey and worldwide prevalence estimates of 2.5% to 3.5%.^4-6 Still, the current prevalence finding is consistent with a recent finding of ADHD in previous deploying U.S. soldiers military samples (10.4%).¹⁸ The high prevalence of ADHD in the current clinic population argues for increased provider awareness of this condition as a possible factor in postdeployment adjustment assessments.

Changes in prevalence estimates of ADHD may represent increased awareness of the condition over this interval of time, professional drift in the application of diagnostic criteria, or changes in societal attitudes about acceptability in pursuing treatment for the condition. For example, in nationwide surveys in 2003, 2007, and 2011, the CDC identified an increase from 7.8% to 9.5% to 11%, respectively, in diagnoses of ADHD in childhood.¹⁹ Also, considering that the current sample was predominantly male and the prevalence of ADHD in males is higher than in females, one might expect a higher ADHD prevalence rate in this study than that in the general population. In this regard, the ADHD prevalence rate in males remains comparable to that estimated by recent CDC survey data.¹⁹

When estimating ADHD population prevalence in the future, it is worth noting that a change in the diagnostic criteria for ADHD has occurred in DSM-5. Specifically, the age at which critical symptoms must be present to make the diagnosis of ADHD has been increased from age 7 years to age 12 years, and the number of critical symptoms to meet hyperactivity-impulsivity criteria has been lowered from 6 to 5 in older adolescents and adults.²⁰ These changes in the diagnostic criteria for ADHD will have the net effect of increasing estimates of prevalence of ADHD.

Changes in prevalence estimates of ADHD may represent increased awareness of the condition over this interval of time, professional drift in the application of diagnostic criteria, or changes in societal attitudes about acceptability in pursuing treatment for the condition.

The 73 individuals with an ADHD diagnoses in this study were found to have less education and be slightly younger than were the veterans who did not have an ADHD diagnosis. This finding is not unexpected, as individuals with ADHD are known to struggle in school and often drop out of high school and pursue alternative means of getting an equivalency degree or certification.²¹ Early departure from high school can be followed by earlier enlistment in the military. Prior studies by Krauss and colleagues found similar findings in an ADHD study of military recruits (ie, they were less likely to have education beyond a high school degree).⁷

ADHD and TBI

Given problems with attention, impulsivity, and high levels of aggressive behaviors associated with ADHD, individuals with ADHD have been found to be at higher risk for accidental injuries, including TBI, than are individuals without ADHD.^21,22 Thus, soldiers with ADHD may be at greater risk for TBI during their time in the military. In the current sample, although veterans with ADHD showed a trend toward having more TBIs prior to joining the military relative to non-ADHD veterans, the veterans with ADHD had a similar rate of TBIs during their time in the military relative to non-ADHD veterans.

Although individuals with ADHD are reported to have a higher prevalence of mental health issues than does the general public, this was not evident in the current sample.²¹ Veterans with ADHD in this study did not have a disproportionate prevalence of PTSD, depression, anxiety, or substance abuse.

There was a nonsignificant trend for more individuals with an ADHD diagnosis compared with those without the diagnosis to report experiencing pain during the 30 days prior to their evaluation in the PC. Although not statistically significant, this finding would not be unexpected, in that individuals with ADHD are known to show less tolerance for frustration relative to that of the general population.²¹ In the current study, reports of pain in the ADHD group correlated with reports of being irritable and easily annoyed (r = .27, P = .024), but no correlation was observed with reports of poor frustration tolerance (r = .04, P = .74). Still, of note, > 90% of the OEF/OIF/OND veterans in this study, regardless of their ADHD diagnosis, reported pain symptoms of some type. The high prevalence of pain symptoms in this sample is consistent with a previous study that found pain to be one of the most common problems in polytrauma patients.¹⁰

Related: Civilian Stress Compounds Service-Related Stress

Not surprisingly, as shown in Table 2, veterans with ADHD compared with those without the diagnosis reported more problems with attention and concentration. The report of more attentional problems is seemingly not accounted for by group differences in reports of pain in general, headaches, sleep disturbance, or memory problems.

Study Strengths

A large sample of veterans constituted this study, and the data were gathered in consecutive referrals to the CJZVAMC PC over a 5-year period. Also, information on a number of comorbidities were captured simultaneously with the polytrauma and ADHD diagnoses, allowing much greater ability to investigate the interaction of multiple comorbidities as well as lingering reports of symptoms following discharge from active military service.

In these authors’ experience, veterans with ADHD benefit substantially from structured treatment interventions that are focused on developing compensatory skills for their problems with attention and impulsivity. Individuals with ADHD typically have a greater need for assistance with planning and organizing, making decisions, problem solving, and regulating their attention and affect. Individuals with ADHD may benefit from treatment strategies focused on ADHD behaviors in conjunction with traditional treatment strategies frequently used in the PC. These strategies include increased case management, medication trials, education regarding ADHD, vocational assistance, and consideration of both the school and work accommodations.

Studies have shown that treatments with stimulants improve functioning and reduce depression and substance use.²¹ In this study, < 5% of individuals with ADHD were taking stimulants at the time they were initially assessed in the PC, whereas the majority were taking stimulants after being referred for ADHD evaluation. Thus, identification of veterans with ADHD has clinical relevance in understanding the specific needs that guide development of individualized treatment plans to promote successful community reintegration.

Limitations

One limitation of the study is the lack of available medical records of historical ADHD diagnoses prior to military service. Also, although DSM-IV criteria for ADHD were operational in the psychodiagnostic clinics for these subjects, because the polytrauma study team did not conduct the evaluations in this sample, uniform diagnostic standards may not have been consistently applied when establishing the ADHD diagnosis. There was a 93% agreement between the 2 methods of diagnosis (ie, report of developmental diagnosis or positive adult evaluation), suggesting that diagnostic precision for ADHD in this study was reasonably accurate.

Community reintegration of individuals with ADHD will likely be challenging, as these individuals often have struggled with functioning in their communities prior to their military service.

Another significant limitation of this study, apart from establishing medical and psychiatric status at the time of the initial referral to the PC, is the omission of functional outcome assessments regarding success of polytrauma treatment initiatives or ultimate community reintegration of successful psychosocial participation or academic and vocational achievements. Future longitudinal outcome studies are needed to determine whether ADHD has a significant impact on clinical outcomes. Of interest, pain was an overwhelmingly common factor (> 90%) for the military population studied at this site. Some degree of disturbance in attentional capacities is common in patients with chronic pain, which may aggravate ADHD symptoms and vice versa. Further investigations are needed to determine the potential functional impact of pain, including use of pain and psychotropic medications, on ADHD symptoms and the combined effect of these symptoms on overall outcome from rehabilitation and reintegration efforts.

Although these findings suggest that polytrauma veterans with ADHD do not have more psychiatric or physical comorbidities than do veterans without ADHD, it is premature to conclude that community reintegration can be optimally managed in the same way for both groups. Community reintegration of individuals with ADHD will likely be challenging, as these individuals often have struggled with functioning in their communities prior to their military service.

Studies of adult ADHD in the U.S. and in other countries have found that it is often associated with substantial impairment in managing the demands of functioning as an adult in society.⁴ Although some theorists have speculated that symptoms of ADHD may have been evolutionarily adaptive to survival in select environments (eg, predatory hunting environments), there is no clear evidence to support such adaptive benefits of the symptom in modern combat environments.^23,24 Symptoms of ADHD are typically maladaptive to soldiers transitioning to civilian lives.

Conclusions

This investigation described the demographic and clinical characteristics of OEF/OIF/OND veterans referred for evaluation of TBI to the CJZVAMC PC during 5 years of operation from 2008 through 2012. The aim was to increase provider awareness of possible important variables that may influence recovery and community reintegration. This study may help to form the foundation for future lines of research into variables such as ADHD that may influence outcomes of rehabilitation and reintegration interventions.

To better understand the treatment needs of young veterans returning home from the wars in Iraq and Afghanistan, this study sought to identify the prevalence rate of ADHD, a condition known to complicate community adjustment. In this study, there was a 10.6% prevalence of ADHD among the 690 OEF/OIF/OND combat veterans seen over the 5-year period in the CJZVAMC PC, which is substantially higher than prevalence estimates in the U.S. general population but similar to estimates in previous military samples.

Compared with veterans who did not have ADHD, veterans with ADHD were younger, less well educated, and reported more problems with attention and concentration but did not have a greater incidence of military TBI or mental health comorbidities. The high prevalence of ADHD in this group argues for greater awareness of this clinical variable and development of intervention programs tailored to the specific skill deficiencies found in the condition, which can be included as part of the comprehensive treatment interventions.

Veterans with ADHD treated in the PC seem to benefit from structured treatment plans and education to promote self-awareness and veteran-centered self-management for effective symptom reduction and coping strategies. Development of effective integrated treatment options with a focus on educational and vocational resources and assistance could facilitate successful community reintegration. Future studies are needed to further assess outcomes of community reintegration, including academic and occupational outcomes, in this population.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are considered the signature injuries in veterans of the military operations in Iraq and Afghanistan.¹ In 2007, the VA implemented the Polytrauma System of Care (PSC) to provide comprehensive screening, evaluation, and treatment of these multifaceted injuries.^2,3 The VA defined polytrauma as “two or more injuries to physical regions or organ systems, one of which may be life threatening, resulting in physical, cognitive, psychological, or psychosocial impairments and functional disability.”³ The VA intended the PSC to provide a national system of integrated care to meet the unique needs of these combat service members.

In addition to the comprehensive evaluation and treatment of traumatic injuries, a critical mission of the PSC is to facilitate the reintegration of injured combat veterans into their home communities. Optimal community reintegration requires that the clinician also assess premorbid comorbidities, which may affect postdeployment adjustments. Attention-deficit/hyperactivity disorder (ADHD), with an estimated adult prevalence of 4.4% in the U.S. and 2.5% to 3.4% worldwide, is a common disorder in the general adult population that often is associated with chronic social and vocational adjustment difficulties.^4-6 The increasing recognition that this disorder often persists into adulthood is of significance to veterans, largely young and male, who have left military service and are reintegrating into college and community job settings.⁷ Despite growing interest in adult ADHD, little is known about its prevalence and correlates in the veteran population.

The prevalence of ADHD in the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veteran polytrauma population has not been adequately studied. Studies have found that combat veterans with or without confirmed TBI diagnosis commonly have similar overlapping symptoms, such as memory problems, difficulty concentrating, poor attention, and sleep problems associated with other comorbidities such as pain, PTSD, ADHD, and other mental health diagnoses.^8-14 Increased awareness of various clinical variables would enhance understanding of the population characteristics and specific needs for education and management.

Related: Preparing the Military Health System for the 21st Century

To begin to address the lack of information about ADHD in the VA polytrauma population, this study aimed to (1) identify the prevalence of ADHD in veterans referred to the Clement J. Zablocki (CJZ) VAMC Polytrauma Clinic (PC) in Milwaukee, Wisconsin; (2) describe demographic characteristics of polytrauma veterans with ADHD; (3) determine the comorbidity relationship between ADHD and TBI, PTSD, depression and anxiety disorders, and substance abuse; and (4) determine whether individuals with ADHD compared with those without ADHD report more physical and emotional symptomatic distress with particular attention given to reports of pain, headaches, and problems with attention and concentration, memory, and sleep.

Methods

The study population consisted of 690 OEF/OIF/OND soldiers and veterans who received a comprehensive TBI evaluation in the CJZVAMC PC from January 1, 2008, to December 31, 2012. Referrals to the PC were made by primary care physicians (PCPs) when OEF/OIF/OND veterans or service members enrolled at a VA facility for health care or transferred their care from another VA facility.

Either a prior diagnosis of TBI established by a qualified provider or positive responses to a 4-question screening tool for TBI prompted a referral to the PC. The 4 questions sought to establish (1) events that may increase risk of TBIs; (2) immediate symptoms following the event; (3) new or worsening symptoms following the event; and (4) current symptoms.¹ Referrals to the clinic most commonly came from PCPs at the CJZVAMC and its associated community-based outpatient clinics but occasionally came from mental health service providers.

Study Design

The CJZVAMC Institutional Review Board approved this study. A population database was developed from a review of medical records, clinical interviews of patients, and completion of standard intake forms during the veterans’ initial evaluations in the CJZVAMC PC. The database aimed to abstract patient information relevant for understanding and treating the population seen in the clinic. The database contained information related to demographics, injury parameters, neurobehavioral and PTSD symptoms, past and current mental health disorders, substance abuse history, pain symptoms, and developmental history (eg, ADHD, learning disability).

Related: First Brain Wave Test to Diagnose ADHD

Prior to the PC intake interview, each veteran completed a packet of preclinic questionnaires that included information concerning deployment-related injury exposure and history; the 22-item Neurobehavioral Symptom Inventory (NSI), which assessed physical, cognitive, and emotional symptoms; current pain symptoms; and the Posttraumatic Stress Disorder Checklist-Civilian Version (PCLC).^15,16 Intake interviews in the CJZVAMC PC were typically conducted with a minimum of 2 specialties present (physical medicine/rehabilitation and neuropsychology) and occasionally as many as 4 specialties present (also including health psychology and social work). Data collection and abstraction for the database were derived by all specialties present and assisted by the polytrauma program technician.

Diagnoses

The diagnosis of ADHD in a veteran was established through 1 of 2 methods: (1) report of a developmental history of behavioral adjustment difficulties consistent with ADHD that was coupled with formal psychiatric diagnosis and recommended treatment of ADHD in childhood; or (2) current diagnosis of ADHD as identified in the veteran’s active problem list. In most cases of report of developmental diagnosis, the veteran reported having been diagnosed and having received treatment with a stimulant medication for a period of time. In a few cases, the veteran reported having been diagnosed and stimulant medication was recommended, but the veteran’s parents declined the pharmacologic treatment in favor of behavioral treatment strategies.

In cases of current diagnosis, Diagnostic and Statistical Manual of Mental Disorders, Text Revision, 4th Edition (DSM-IV-TR), criteria were applied and supported by formal clinical examinations for ADHD conducted by psychologists, psychiatrists or neuropsychologists, or through VA disability (Compensation and Pension) evaluations where an issue related to ADHD diagnosis was raised.¹⁷ There was considerable overlap between these 2 diagnostic criteria (ie, through report of developmental history of diagnosis or formal adult evaluation) with 93% of cases being positive on both diagnostic methods.

Other comorbid psychiatric (eg, depression, anxiety, PTSD, substance abuse) and medical (eg, headache, pain) conditions also were abstracted from the veteran’s medical records at the time of the intake evaluation. Documentation of these conditions was derived from the veteran’s problem list and clinical notes that identified the condition as a diagnostic conclusion or focus of treatment. The comorbid conditions were not otherwise independently documented. Many veterans were taking psychotropic medications for mood, sleep, or chronic pain problems at the time of evaluation in the PC; however, use of medication and their effects were not systematically evaluated.

Statistical Analysis

In addition to documentation of the population prevalence for ADHD, analysis for disproportionate prevalence of comorbid conditions in individuals with ADHD compared with those without ADHD was done through the use of the chi-square test and/or Fisher exact test. For continuous variables, t tests were used to compare individuals with ADHD with individuals without ADHD. To control family-wise type I error to a P value of .05, a false discovery rate (FDR) was applied to studies of demographics, comorbidities, and ratings of symptomatic distress.

Results

The general population characteristics of the 690 veterans and soldiers are summarized in Table 1. The sample was predominantly male (96%), white (88%), and ranged in age from 22 to 55 years with a mean of 28 years. Active-duty service members and reservists from the U.S. Army, Marines, Navy, and Air Force were represented, but most were Army veterans (72%). Most (63%) had a high school education. About two-thirds of the veterans had a single deployment, and the remaining had multiple deployments.

The TBI clinic evaluations found that 58% of the patients had ≥ 1 TBI during their deployments, almost exclusively mild in severity. Seventy-three patients met study criteria for ADHD: 69 with an identified history of diagnosis in childhood and 68 with a current diagnosis, with 93% overlap of these groups. Table 2 provides a breakdown of demographic characteristics, comorbidities, and symptomatic distress in veterans with ADHD compared with those without the diagnosis.

Demographic Characteristics

Veterans with ADHD were found to be slightly younger (2.3 years younger, P = .003) and to have less education (greater frequency of less than high school and high school only, P = .003) compared with those who did not have the diagnosis. No significant group differences in sex, employment/school status, marital status, or number of deployments were identified in veterans with ADHD compared with non-ADHD veterans. Individuals with ADHD did not experience more physical, emotional, or sexual abuse as children than did their non-ADHD counterparts. The prevalence of TBI during deployment was similar in veterans with ADHD compared with that of non-ADHD veterans. There was a trend for veterans with ADHD to have more TBIs prior to military service than in non-ADHD veterans; however, this trend did not reach statistical significance (P = .188).

Comorbidities

After application of the FDR threshold, veterans with ADHD did not show a disproportionate prevalence of mental health diagnoses (eg, PTSD, depression and anxiety disorders, or substance abuse). There was a nonsignificant trend for more veterans with ADHD to report pain during the previous 30 days (P = .035) and more issues with substance abuse (P = .10) than for non-ADHD veterans, but these trends did not meet the FDR threshold of < .05. 

Symptomatic Distress

Veterans with ADHD did not report significantly greater levels of distress on either the NSI or the PCLC survey compared with non-ADHD veterans.Not surprisingly, when select symptoms were investigated, veterans with ADHD reported more problems with attention and concentration than for non-ADHD veterans (P = .015). No group differences were identified for sleep issues, headaches, or memory, although there was a trend for the latter (P = .14).

Discussion

In this study, there was a 10.6% prevalence of ADHD in 690 OEF/OIF/OND combat veterans. This rate is considerably higher than estimates of prevalence of ADHD in adults (4.4%) made from a nationwide survey and worldwide prevalence estimates of 2.5% to 3.5%.^4-6 Still, the current prevalence finding is consistent with a recent finding of ADHD in previous deploying U.S. soldiers military samples (10.4%).¹⁸ The high prevalence of ADHD in the current clinic population argues for increased provider awareness of this condition as a possible factor in postdeployment adjustment assessments.

Changes in prevalence estimates of ADHD may represent increased awareness of the condition over this interval of time, professional drift in the application of diagnostic criteria, or changes in societal attitudes about acceptability in pursuing treatment for the condition. For example, in nationwide surveys in 2003, 2007, and 2011, the CDC identified an increase from 7.8% to 9.5% to 11%, respectively, in diagnoses of ADHD in childhood.¹⁹ Also, considering that the current sample was predominantly male and the prevalence of ADHD in males is higher than in females, one might expect a higher ADHD prevalence rate in this study than that in the general population. In this regard, the ADHD prevalence rate in males remains comparable to that estimated by recent CDC survey data.¹⁹

When estimating ADHD population prevalence in the future, it is worth noting that a change in the diagnostic criteria for ADHD has occurred in DSM-5. Specifically, the age at which critical symptoms must be present to make the diagnosis of ADHD has been increased from age 7 years to age 12 years, and the number of critical symptoms to meet hyperactivity-impulsivity criteria has been lowered from 6 to 5 in older adolescents and adults.²⁰ These changes in the diagnostic criteria for ADHD will have the net effect of increasing estimates of prevalence of ADHD.

Changes in prevalence estimates of ADHD may represent increased awareness of the condition over this interval of time, professional drift in the application of diagnostic criteria, or changes in societal attitudes about acceptability in pursuing treatment for the condition.

The 73 individuals with an ADHD diagnoses in this study were found to have less education and be slightly younger than were the veterans who did not have an ADHD diagnosis. This finding is not unexpected, as individuals with ADHD are known to struggle in school and often drop out of high school and pursue alternative means of getting an equivalency degree or certification.²¹ Early departure from high school can be followed by earlier enlistment in the military. Prior studies by Krauss and colleagues found similar findings in an ADHD study of military recruits (ie, they were less likely to have education beyond a high school degree).⁷

ADHD and TBI

Given problems with attention, impulsivity, and high levels of aggressive behaviors associated with ADHD, individuals with ADHD have been found to be at higher risk for accidental injuries, including TBI, than are individuals without ADHD.^21,22 Thus, soldiers with ADHD may be at greater risk for TBI during their time in the military. In the current sample, although veterans with ADHD showed a trend toward having more TBIs prior to joining the military relative to non-ADHD veterans, the veterans with ADHD had a similar rate of TBIs during their time in the military relative to non-ADHD veterans.

Although individuals with ADHD are reported to have a higher prevalence of mental health issues than does the general public, this was not evident in the current sample.²¹ Veterans with ADHD in this study did not have a disproportionate prevalence of PTSD, depression, anxiety, or substance abuse.

There was a nonsignificant trend for more individuals with an ADHD diagnosis compared with those without the diagnosis to report experiencing pain during the 30 days prior to their evaluation in the PC. Although not statistically significant, this finding would not be unexpected, in that individuals with ADHD are known to show less tolerance for frustration relative to that of the general population.²¹ In the current study, reports of pain in the ADHD group correlated with reports of being irritable and easily annoyed (r = .27, P = .024), but no correlation was observed with reports of poor frustration tolerance (r = .04, P = .74). Still, of note, > 90% of the OEF/OIF/OND veterans in this study, regardless of their ADHD diagnosis, reported pain symptoms of some type. The high prevalence of pain symptoms in this sample is consistent with a previous study that found pain to be one of the most common problems in polytrauma patients.¹⁰

Related: Civilian Stress Compounds Service-Related Stress

Not surprisingly, as shown in Table 2, veterans with ADHD compared with those without the diagnosis reported more problems with attention and concentration. The report of more attentional problems is seemingly not accounted for by group differences in reports of pain in general, headaches, sleep disturbance, or memory problems.

Study Strengths

A large sample of veterans constituted this study, and the data were gathered in consecutive referrals to the CJZVAMC PC over a 5-year period. Also, information on a number of comorbidities were captured simultaneously with the polytrauma and ADHD diagnoses, allowing much greater ability to investigate the interaction of multiple comorbidities as well as lingering reports of symptoms following discharge from active military service.

In these authors’ experience, veterans with ADHD benefit substantially from structured treatment interventions that are focused on developing compensatory skills for their problems with attention and impulsivity. Individuals with ADHD typically have a greater need for assistance with planning and organizing, making decisions, problem solving, and regulating their attention and affect. Individuals with ADHD may benefit from treatment strategies focused on ADHD behaviors in conjunction with traditional treatment strategies frequently used in the PC. These strategies include increased case management, medication trials, education regarding ADHD, vocational assistance, and consideration of both the school and work accommodations.

Studies have shown that treatments with stimulants improve functioning and reduce depression and substance use.²¹ In this study, < 5% of individuals with ADHD were taking stimulants at the time they were initially assessed in the PC, whereas the majority were taking stimulants after being referred for ADHD evaluation. Thus, identification of veterans with ADHD has clinical relevance in understanding the specific needs that guide development of individualized treatment plans to promote successful community reintegration.

Limitations

One limitation of the study is the lack of available medical records of historical ADHD diagnoses prior to military service. Also, although DSM-IV criteria for ADHD were operational in the psychodiagnostic clinics for these subjects, because the polytrauma study team did not conduct the evaluations in this sample, uniform diagnostic standards may not have been consistently applied when establishing the ADHD diagnosis. There was a 93% agreement between the 2 methods of diagnosis (ie, report of developmental diagnosis or positive adult evaluation), suggesting that diagnostic precision for ADHD in this study was reasonably accurate.

Community reintegration of individuals with ADHD will likely be challenging, as these individuals often have struggled with functioning in their communities prior to their military service.

Another significant limitation of this study, apart from establishing medical and psychiatric status at the time of the initial referral to the PC, is the omission of functional outcome assessments regarding success of polytrauma treatment initiatives or ultimate community reintegration of successful psychosocial participation or academic and vocational achievements. Future longitudinal outcome studies are needed to determine whether ADHD has a significant impact on clinical outcomes. Of interest, pain was an overwhelmingly common factor (> 90%) for the military population studied at this site. Some degree of disturbance in attentional capacities is common in patients with chronic pain, which may aggravate ADHD symptoms and vice versa. Further investigations are needed to determine the potential functional impact of pain, including use of pain and psychotropic medications, on ADHD symptoms and the combined effect of these symptoms on overall outcome from rehabilitation and reintegration efforts.

Although these findings suggest that polytrauma veterans with ADHD do not have more psychiatric or physical comorbidities than do veterans without ADHD, it is premature to conclude that community reintegration can be optimally managed in the same way for both groups. Community reintegration of individuals with ADHD will likely be challenging, as these individuals often have struggled with functioning in their communities prior to their military service.

Studies of adult ADHD in the U.S. and in other countries have found that it is often associated with substantial impairment in managing the demands of functioning as an adult in society.⁴ Although some theorists have speculated that symptoms of ADHD may have been evolutionarily adaptive to survival in select environments (eg, predatory hunting environments), there is no clear evidence to support such adaptive benefits of the symptom in modern combat environments.^23,24 Symptoms of ADHD are typically maladaptive to soldiers transitioning to civilian lives.

Conclusions

This investigation described the demographic and clinical characteristics of OEF/OIF/OND veterans referred for evaluation of TBI to the CJZVAMC PC during 5 years of operation from 2008 through 2012. The aim was to increase provider awareness of possible important variables that may influence recovery and community reintegration. This study may help to form the foundation for future lines of research into variables such as ADHD that may influence outcomes of rehabilitation and reintegration interventions.

To better understand the treatment needs of young veterans returning home from the wars in Iraq and Afghanistan, this study sought to identify the prevalence rate of ADHD, a condition known to complicate community adjustment. In this study, there was a 10.6% prevalence of ADHD among the 690 OEF/OIF/OND combat veterans seen over the 5-year period in the CJZVAMC PC, which is substantially higher than prevalence estimates in the U.S. general population but similar to estimates in previous military samples.

Compared with veterans who did not have ADHD, veterans with ADHD were younger, less well educated, and reported more problems with attention and concentration but did not have a greater incidence of military TBI or mental health comorbidities. The high prevalence of ADHD in this group argues for greater awareness of this clinical variable and development of intervention programs tailored to the specific skill deficiencies found in the condition, which can be included as part of the comprehensive treatment interventions.

Veterans with ADHD treated in the PC seem to benefit from structured treatment plans and education to promote self-awareness and veteran-centered self-management for effective symptom reduction and coping strategies. Development of effective integrated treatment options with a focus on educational and vocational resources and assistance could facilitate successful community reintegration. Future studies are needed to further assess outcomes of community reintegration, including academic and occupational outcomes, in this population.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are considered the signature injuries in veterans of the military operations in Iraq and Afghanistan.¹ In 2007, the VA implemented the Polytrauma System of Care (PSC) to provide comprehensive screening, evaluation, and treatment of these multifaceted injuries.^2,3 The VA defined polytrauma as “two or more injuries to physical regions or organ systems, one of which may be life threatening, resulting in physical, cognitive, psychological, or psychosocial impairments and functional disability.”³ The VA intended the PSC to provide a national system of integrated care to meet the unique needs of these combat service members.

In addition to the comprehensive evaluation and treatment of traumatic injuries, a critical mission of the PSC is to facilitate the reintegration of injured combat veterans into their home communities. Optimal community reintegration requires that the clinician also assess premorbid comorbidities, which may affect postdeployment adjustments. Attention-deficit/hyperactivity disorder (ADHD), with an estimated adult prevalence of 4.4% in the U.S. and 2.5% to 3.4% worldwide, is a common disorder in the general adult population that often is associated with chronic social and vocational adjustment difficulties.^4-6 The increasing recognition that this disorder often persists into adulthood is of significance to veterans, largely young and male, who have left military service and are reintegrating into college and community job settings.⁷ Despite growing interest in adult ADHD, little is known about its prevalence and correlates in the veteran population.

The prevalence of ADHD in the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veteran polytrauma population has not been adequately studied. Studies have found that combat veterans with or without confirmed TBI diagnosis commonly have similar overlapping symptoms, such as memory problems, difficulty concentrating, poor attention, and sleep problems associated with other comorbidities such as pain, PTSD, ADHD, and other mental health diagnoses.^8-14 Increased awareness of various clinical variables would enhance understanding of the population characteristics and specific needs for education and management.

Related: Preparing the Military Health System for the 21st Century

To begin to address the lack of information about ADHD in the VA polytrauma population, this study aimed to (1) identify the prevalence of ADHD in veterans referred to the Clement J. Zablocki (CJZ) VAMC Polytrauma Clinic (PC) in Milwaukee, Wisconsin; (2) describe demographic characteristics of polytrauma veterans with ADHD; (3) determine the comorbidity relationship between ADHD and TBI, PTSD, depression and anxiety disorders, and substance abuse; and (4) determine whether individuals with ADHD compared with those without ADHD report more physical and emotional symptomatic distress with particular attention given to reports of pain, headaches, and problems with attention and concentration, memory, and sleep.

Methods

The study population consisted of 690 OEF/OIF/OND soldiers and veterans who received a comprehensive TBI evaluation in the CJZVAMC PC from January 1, 2008, to December 31, 2012. Referrals to the PC were made by primary care physicians (PCPs) when OEF/OIF/OND veterans or service members enrolled at a VA facility for health care or transferred their care from another VA facility.

Either a prior diagnosis of TBI established by a qualified provider or positive responses to a 4-question screening tool for TBI prompted a referral to the PC. The 4 questions sought to establish (1) events that may increase risk of TBIs; (2) immediate symptoms following the event; (3) new or worsening symptoms following the event; and (4) current symptoms.¹ Referrals to the clinic most commonly came from PCPs at the CJZVAMC and its associated community-based outpatient clinics but occasionally came from mental health service providers.

Study Design

The CJZVAMC Institutional Review Board approved this study. A population database was developed from a review of medical records, clinical interviews of patients, and completion of standard intake forms during the veterans’ initial evaluations in the CJZVAMC PC. The database aimed to abstract patient information relevant for understanding and treating the population seen in the clinic. The database contained information related to demographics, injury parameters, neurobehavioral and PTSD symptoms, past and current mental health disorders, substance abuse history, pain symptoms, and developmental history (eg, ADHD, learning disability).

Related: First Brain Wave Test to Diagnose ADHD

Prior to the PC intake interview, each veteran completed a packet of preclinic questionnaires that included information concerning deployment-related injury exposure and history; the 22-item Neurobehavioral Symptom Inventory (NSI), which assessed physical, cognitive, and emotional symptoms; current pain symptoms; and the Posttraumatic Stress Disorder Checklist-Civilian Version (PCLC).^15,16 Intake interviews in the CJZVAMC PC were typically conducted with a minimum of 2 specialties present (physical medicine/rehabilitation and neuropsychology) and occasionally as many as 4 specialties present (also including health psychology and social work). Data collection and abstraction for the database were derived by all specialties present and assisted by the polytrauma program technician.

Diagnoses

The diagnosis of ADHD in a veteran was established through 1 of 2 methods: (1) report of a developmental history of behavioral adjustment difficulties consistent with ADHD that was coupled with formal psychiatric diagnosis and recommended treatment of ADHD in childhood; or (2) current diagnosis of ADHD as identified in the veteran’s active problem list. In most cases of report of developmental diagnosis, the veteran reported having been diagnosed and having received treatment with a stimulant medication for a period of time. In a few cases, the veteran reported having been diagnosed and stimulant medication was recommended, but the veteran’s parents declined the pharmacologic treatment in favor of behavioral treatment strategies.

In cases of current diagnosis, Diagnostic and Statistical Manual of Mental Disorders, Text Revision, 4th Edition (DSM-IV-TR), criteria were applied and supported by formal clinical examinations for ADHD conducted by psychologists, psychiatrists or neuropsychologists, or through VA disability (Compensation and Pension) evaluations where an issue related to ADHD diagnosis was raised.¹⁷ There was considerable overlap between these 2 diagnostic criteria (ie, through report of developmental history of diagnosis or formal adult evaluation) with 93% of cases being positive on both diagnostic methods.

Other comorbid psychiatric (eg, depression, anxiety, PTSD, substance abuse) and medical (eg, headache, pain) conditions also were abstracted from the veteran’s medical records at the time of the intake evaluation. Documentation of these conditions was derived from the veteran’s problem list and clinical notes that identified the condition as a diagnostic conclusion or focus of treatment. The comorbid conditions were not otherwise independently documented. Many veterans were taking psychotropic medications for mood, sleep, or chronic pain problems at the time of evaluation in the PC; however, use of medication and their effects were not systematically evaluated.

Statistical Analysis

In addition to documentation of the population prevalence for ADHD, analysis for disproportionate prevalence of comorbid conditions in individuals with ADHD compared with those without ADHD was done through the use of the chi-square test and/or Fisher exact test. For continuous variables, t tests were used to compare individuals with ADHD with individuals without ADHD. To control family-wise type I error to a P value of .05, a false discovery rate (FDR) was applied to studies of demographics, comorbidities, and ratings of symptomatic distress.

Results

The general population characteristics of the 690 veterans and soldiers are summarized in Table 1. The sample was predominantly male (96%), white (88%), and ranged in age from 22 to 55 years with a mean of 28 years. Active-duty service members and reservists from the U.S. Army, Marines, Navy, and Air Force were represented, but most were Army veterans (72%). Most (63%) had a high school education. About two-thirds of the veterans had a single deployment, and the remaining had multiple deployments.

The TBI clinic evaluations found that 58% of the patients had ≥ 1 TBI during their deployments, almost exclusively mild in severity. Seventy-three patients met study criteria for ADHD: 69 with an identified history of diagnosis in childhood and 68 with a current diagnosis, with 93% overlap of these groups. Table 2 provides a breakdown of demographic characteristics, comorbidities, and symptomatic distress in veterans with ADHD compared with those without the diagnosis.

Demographic Characteristics

Veterans with ADHD were found to be slightly younger (2.3 years younger, P = .003) and to have less education (greater frequency of less than high school and high school only, P = .003) compared with those who did not have the diagnosis. No significant group differences in sex, employment/school status, marital status, or number of deployments were identified in veterans with ADHD compared with non-ADHD veterans. Individuals with ADHD did not experience more physical, emotional, or sexual abuse as children than did their non-ADHD counterparts. The prevalence of TBI during deployment was similar in veterans with ADHD compared with that of non-ADHD veterans. There was a trend for veterans with ADHD to have more TBIs prior to military service than in non-ADHD veterans; however, this trend did not reach statistical significance (P = .188).

Comorbidities

After application of the FDR threshold, veterans with ADHD did not show a disproportionate prevalence of mental health diagnoses (eg, PTSD, depression and anxiety disorders, or substance abuse). There was a nonsignificant trend for more veterans with ADHD to report pain during the previous 30 days (P = .035) and more issues with substance abuse (P = .10) than for non-ADHD veterans, but these trends did not meet the FDR threshold of < .05. 

Symptomatic Distress

Veterans with ADHD did not report significantly greater levels of distress on either the NSI or the PCLC survey compared with non-ADHD veterans.Not surprisingly, when select symptoms were investigated, veterans with ADHD reported more problems with attention and concentration than for non-ADHD veterans (P = .015). No group differences were identified for sleep issues, headaches, or memory, although there was a trend for the latter (P = .14).

Discussion

In this study, there was a 10.6% prevalence of ADHD in 690 OEF/OIF/OND combat veterans. This rate is considerably higher than estimates of prevalence of ADHD in adults (4.4%) made from a nationwide survey and worldwide prevalence estimates of 2.5% to 3.5%.^4-6 Still, the current prevalence finding is consistent with a recent finding of ADHD in previous deploying U.S. soldiers military samples (10.4%).¹⁸ The high prevalence of ADHD in the current clinic population argues for increased provider awareness of this condition as a possible factor in postdeployment adjustment assessments.

Changes in prevalence estimates of ADHD may represent increased awareness of the condition over this interval of time, professional drift in the application of diagnostic criteria, or changes in societal attitudes about acceptability in pursuing treatment for the condition. For example, in nationwide surveys in 2003, 2007, and 2011, the CDC identified an increase from 7.8% to 9.5% to 11%, respectively, in diagnoses of ADHD in childhood.¹⁹ Also, considering that the current sample was predominantly male and the prevalence of ADHD in males is higher than in females, one might expect a higher ADHD prevalence rate in this study than that in the general population. In this regard, the ADHD prevalence rate in males remains comparable to that estimated by recent CDC survey data.¹⁹

When estimating ADHD population prevalence in the future, it is worth noting that a change in the diagnostic criteria for ADHD has occurred in DSM-5. Specifically, the age at which critical symptoms must be present to make the diagnosis of ADHD has been increased from age 7 years to age 12 years, and the number of critical symptoms to meet hyperactivity-impulsivity criteria has been lowered from 6 to 5 in older adolescents and adults.²⁰ These changes in the diagnostic criteria for ADHD will have the net effect of increasing estimates of prevalence of ADHD.

Changes in prevalence estimates of ADHD may represent increased awareness of the condition over this interval of time, professional drift in the application of diagnostic criteria, or changes in societal attitudes about acceptability in pursuing treatment for the condition.

The 73 individuals with an ADHD diagnoses in this study were found to have less education and be slightly younger than were the veterans who did not have an ADHD diagnosis. This finding is not unexpected, as individuals with ADHD are known to struggle in school and often drop out of high school and pursue alternative means of getting an equivalency degree or certification.²¹ Early departure from high school can be followed by earlier enlistment in the military. Prior studies by Krauss and colleagues found similar findings in an ADHD study of military recruits (ie, they were less likely to have education beyond a high school degree).⁷

ADHD and TBI

Given problems with attention, impulsivity, and high levels of aggressive behaviors associated with ADHD, individuals with ADHD have been found to be at higher risk for accidental injuries, including TBI, than are individuals without ADHD.^21,22 Thus, soldiers with ADHD may be at greater risk for TBI during their time in the military. In the current sample, although veterans with ADHD showed a trend toward having more TBIs prior to joining the military relative to non-ADHD veterans, the veterans with ADHD had a similar rate of TBIs during their time in the military relative to non-ADHD veterans.

Although individuals with ADHD are reported to have a higher prevalence of mental health issues than does the general public, this was not evident in the current sample.²¹ Veterans with ADHD in this study did not have a disproportionate prevalence of PTSD, depression, anxiety, or substance abuse.

There was a nonsignificant trend for more individuals with an ADHD diagnosis compared with those without the diagnosis to report experiencing pain during the 30 days prior to their evaluation in the PC. Although not statistically significant, this finding would not be unexpected, in that individuals with ADHD are known to show less tolerance for frustration relative to that of the general population.²¹ In the current study, reports of pain in the ADHD group correlated with reports of being irritable and easily annoyed (r = .27, P = .024), but no correlation was observed with reports of poor frustration tolerance (r = .04, P = .74). Still, of note, > 90% of the OEF/OIF/OND veterans in this study, regardless of their ADHD diagnosis, reported pain symptoms of some type. The high prevalence of pain symptoms in this sample is consistent with a previous study that found pain to be one of the most common problems in polytrauma patients.¹⁰

Related: Civilian Stress Compounds Service-Related Stress

Not surprisingly, as shown in Table 2, veterans with ADHD compared with those without the diagnosis reported more problems with attention and concentration. The report of more attentional problems is seemingly not accounted for by group differences in reports of pain in general, headaches, sleep disturbance, or memory problems.

Study Strengths

A large sample of veterans constituted this study, and the data were gathered in consecutive referrals to the CJZVAMC PC over a 5-year period. Also, information on a number of comorbidities were captured simultaneously with the polytrauma and ADHD diagnoses, allowing much greater ability to investigate the interaction of multiple comorbidities as well as lingering reports of symptoms following discharge from active military service.

In these authors’ experience, veterans with ADHD benefit substantially from structured treatment interventions that are focused on developing compensatory skills for their problems with attention and impulsivity. Individuals with ADHD typically have a greater need for assistance with planning and organizing, making decisions, problem solving, and regulating their attention and affect. Individuals with ADHD may benefit from treatment strategies focused on ADHD behaviors in conjunction with traditional treatment strategies frequently used in the PC. These strategies include increased case management, medication trials, education regarding ADHD, vocational assistance, and consideration of both the school and work accommodations.

Studies have shown that treatments with stimulants improve functioning and reduce depression and substance use.²¹ In this study, < 5% of individuals with ADHD were taking stimulants at the time they were initially assessed in the PC, whereas the majority were taking stimulants after being referred for ADHD evaluation. Thus, identification of veterans with ADHD has clinical relevance in understanding the specific needs that guide development of individualized treatment plans to promote successful community reintegration.

Limitations

One limitation of the study is the lack of available medical records of historical ADHD diagnoses prior to military service. Also, although DSM-IV criteria for ADHD were operational in the psychodiagnostic clinics for these subjects, because the polytrauma study team did not conduct the evaluations in this sample, uniform diagnostic standards may not have been consistently applied when establishing the ADHD diagnosis. There was a 93% agreement between the 2 methods of diagnosis (ie, report of developmental diagnosis or positive adult evaluation), suggesting that diagnostic precision for ADHD in this study was reasonably accurate.

Community reintegration of individuals with ADHD will likely be challenging, as these individuals often have struggled with functioning in their communities prior to their military service.

Another significant limitation of this study, apart from establishing medical and psychiatric status at the time of the initial referral to the PC, is the omission of functional outcome assessments regarding success of polytrauma treatment initiatives or ultimate community reintegration of successful psychosocial participation or academic and vocational achievements. Future longitudinal outcome studies are needed to determine whether ADHD has a significant impact on clinical outcomes. Of interest, pain was an overwhelmingly common factor (> 90%) for the military population studied at this site. Some degree of disturbance in attentional capacities is common in patients with chronic pain, which may aggravate ADHD symptoms and vice versa. Further investigations are needed to determine the potential functional impact of pain, including use of pain and psychotropic medications, on ADHD symptoms and the combined effect of these symptoms on overall outcome from rehabilitation and reintegration efforts.

Although these findings suggest that polytrauma veterans with ADHD do not have more psychiatric or physical comorbidities than do veterans without ADHD, it is premature to conclude that community reintegration can be optimally managed in the same way for both groups. Community reintegration of individuals with ADHD will likely be challenging, as these individuals often have struggled with functioning in their communities prior to their military service.

Studies of adult ADHD in the U.S. and in other countries have found that it is often associated with substantial impairment in managing the demands of functioning as an adult in society.⁴ Although some theorists have speculated that symptoms of ADHD may have been evolutionarily adaptive to survival in select environments (eg, predatory hunting environments), there is no clear evidence to support such adaptive benefits of the symptom in modern combat environments.^23,24 Symptoms of ADHD are typically maladaptive to soldiers transitioning to civilian lives.

Conclusions

This investigation described the demographic and clinical characteristics of OEF/OIF/OND veterans referred for evaluation of TBI to the CJZVAMC PC during 5 years of operation from 2008 through 2012. The aim was to increase provider awareness of possible important variables that may influence recovery and community reintegration. This study may help to form the foundation for future lines of research into variables such as ADHD that may influence outcomes of rehabilitation and reintegration interventions.

To better understand the treatment needs of young veterans returning home from the wars in Iraq and Afghanistan, this study sought to identify the prevalence rate of ADHD, a condition known to complicate community adjustment. In this study, there was a 10.6% prevalence of ADHD among the 690 OEF/OIF/OND combat veterans seen over the 5-year period in the CJZVAMC PC, which is substantially higher than prevalence estimates in the U.S. general population but similar to estimates in previous military samples.

Compared with veterans who did not have ADHD, veterans with ADHD were younger, less well educated, and reported more problems with attention and concentration but did not have a greater incidence of military TBI or mental health comorbidities. The high prevalence of ADHD in this group argues for greater awareness of this clinical variable and development of intervention programs tailored to the specific skill deficiencies found in the condition, which can be included as part of the comprehensive treatment interventions.

Veterans with ADHD treated in the PC seem to benefit from structured treatment plans and education to promote self-awareness and veteran-centered self-management for effective symptom reduction and coping strategies. Development of effective integrated treatment options with a focus on educational and vocational resources and assistance could facilitate successful community reintegration. Future studies are needed to further assess outcomes of community reintegration, including academic and occupational outcomes, in this population.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Stenosing tenosynovitis, or trigger finger, is a pathology commonly referred to the plastic and hand surgery service of the North Florida/South Georgia Veterans Health System (NFSGVHS). Patients usually present to their primary care provider with symptoms of the finger being temporarily locked or stuck in the flexed position. This can be a painful problem due to the size mismatch between the flexor tendon and the pulley under which it glides.

Patients are typically referred to surgery after failing ≥ 1 attempt at nonoperative management. The surgery is relatively quick and straightforward; however, postoperative complications can lead to an unexpected costly and lengthy recovery. The objective of this study was to identify potential risk factors that can predispose patients to postoperative complications so that those risk factors may be better anticipated and modified, if possible.

Methods

A retrospective chart review of trigger finger release surgery was performed on-site at the Malcom Randall VAMC in Gainesville, Florida, from January 2005 to December 2010 to identify risk factors associated with postoperative complications. The study was approved by both the NFSGVHS Internal Review Board and the University of Florida Institutional Review Board. Patients who underwent surgery exclusively for ≥ 1 trigger fingers by the plastic surgery service were included in the study.

The surgery involves making an incision over the affected A1 pulley in the hand (Figure 1) and sharply releasing it (Figure 2) under direct vision. Potential risk factors for postoperative complications were recorded. These risk factors included smoking status, diabetic status, type of incision, and number of digits released during the surgical procedure.

Results

Ninety-eight digits (on 81 hands) were identified as meeting inclusion criteria. Surgeries were performed using a longitudinal (43), transverse (48), oblique (5), or Brunner (2) incision. There were 10 complications: cellulitis (3), pyogenic flexor tenosynovitis (3), scar adhesion (1), delayed healing (2), and incomplete release (1). The overall complication rate was 10.2%. The authors compared risk factors with complications, using the chi square test and a determining of P < .05.

Related: Making the Case for Minimally Invasive Surgery

There was no link found between overall postoperative complications and diabetic status, incision type, or smoking status. There was a statistically significant link between diabetic patients and the incidence of postoperative infection (P = .002) and between 2 digits operated on during the same surgery and postoperative infection (P = .027)

Discussion

The routine practice of the NFSGVHS hand clinic is to offer a steroid injection as the initial treatment for trigger finger. Health care providers (HCPs) allow no more than 3 injections to the same digit to avoid the rare but potentially serious complication of a tendon rupture.¹ Due to the large NFSGVHS catchment area, wait time for elective trigger finger surgery is several months. This 3-injection plan has been well received by patients and referring providers due to these wait times. However, a recent article by Kerrigan and Stanwix concluded that the most cost-efficient treatment strategy is 2 steroid injections before surgery.²

More often than not, trigger finger release is a short, outpatient surgery with a quick recovery. To minimize the risk of stiffness and scar adhesions, the NFSGVHS practice is to refer all postoperative hand cases for ≥ 1 hand therapy appointment on the same day as their first postoperative visit.

Cost Estimates

When complications occur, they can be costly to patients due to both time spent away from home and work and additional expenses. When the current procedural terminology (CPT) codes are run through the VistA integrated billing system, based on the VHA Chief Business Office Reasonable Charges, a complication can more than double the charges associated with A1 pulley surgery.

A flexor sheath incision and drainage (I+D) (CPT 26020) charges $8,935.35 (facility charge, $6,911.95 plus professional fee, $2,023.40), compared with open trigger finger release (CPT 26055) at $8,365.66 (facility charge, $6,911.95 plus professional fee, $1,453.71). According to a conversation with the finance service officer at NFSGVHS (2/11/2014), the anesthesia bill ($490.56/15 min), anticipated level 3 emergency department visits (facility charge, $889.22 plus professional fee $493.40), and inpatient stays (daily floor bed $786.19) can make an infectious complication costly.

Trigger finger can also be released percutaneously. This is a reasonable option that avoids the operating room, but NFSGVHS surgeons prefer the open surgery due to concerns for tendon and nerve injury that can result from a blind sweep of the needle.^3,4 

Related: Prevention of Venous Thromboembolism After Total Joint Replacement

Existing studies found complications for trigger finger release ranging from 1% to 31%.^5,6 Wound complications and joint stiffness are known complications.^5-7 In this study, 60% of the complications were infections, and 80% of the complications were wound complications. Six of 8 patients with wound-healing complications received perioperative antibiotics. Three patients returned to the operating room for an I+D of the flexor sheath. The results showed a statistically significant link between > 1 digit treated at the same surgery and postoperative complications (P = .027). A PubMed search revealed no existing hand literature with this association.

Risk Factors

Diabetes, tobacco use, type of incision, and number of digits treated were assessed as risk factors for complications after trigger finger surgery. Nicotine is widely accepted as increasing the risk for wound complications.⁸ Almost 20% of the U.S. population smokes, compared with 22% of the VA population and 32% of active-duty military personnel.⁹ One in 4 veterans has been diagnosed with diabetes, a well-known predisposing factor in delayed wound healing and infection.^10,11 No prior studies were found comparing type of incision or multiple digits treated as complications risk factors.

There is also a well-known association between trigger finger and diabetes. Chronic hyperglycemia results in the accumulation of collagen within tendon sheaths due to impairment of collagen breakdown. Patients with diabetes tend to present with multiple digit involvement and respond less favorably to steroid injections compared with patients without diabetes.¹² Wound healing is also impaired in patients with diabetes. All 6 wound infections in this study were in patients with diabetes. Proposed etiologies for wound-healing complications include pathologic angiogenesis, impaired fibroblast proliferation and migration, impaired circulation, decreased oxygenation, and a defective immune response to the injured site.¹³

Trigger finger may develop in multiple digits. Once surgery has been planned for 1 digit, patients may request surgery on another digit on the same hand that has not had an attempt at nonoperative intervention. The NFSGVHS plastic surgeons have raised the threshold to offer multiple surgical procedures on the same hand at the same operative visit to minimize recovery time and number of visits, particularly when patients are travelling long distances. This may be less convenient; however, the overall cost to the patient and the health care system in the event of a complication is significant. Plastic surgery providers also run an alcohol prep pad over the incision site to prevent inoculation of the flexor sheath during suture removal.

Current recommendations to ameliorate the postoperative risks to the patient and costs to the system include endorsing a more conservative approach to treating trigger finger than was previously practiced at NFSGVHS. The known, less favorable response of patients with diabetes to steroid injections plus their elevated risk of postoperative infection create a catch-22 for the treatment plan. Given the low risk of a single steroid injection to the flexor sheath, this procedure is still recommended as a first-line treatment.

Related: Experience Tells in Hip Arthroplasty

During the 5-year study there was a lower threshold for surgical management and for treatment of multiple digits during the same surgery than the one currently practiced, with an overall consensus of the hospital’s HCPs. The authors recommend that all patients start with a steroid injection before committing to surgery. Patients with diabetes are informed that the injection will cause a temporary rise in their blood glucose.¹⁴ If they are resistant to the injection, high-dose oral nonsteroidal anti-inflammatory drugs and/or proximal interphalangeal joint splinting is ordered.

Verification of A_1C values showing better chronic management of blood sugar is a procedure HCPs from the NFSGVHS will begin to follow. Preoperative A_1C values between 6.5% and 8% in patients known to have diabetes has been recommended.¹⁵ A_1C values > 7% have been found to be an independent risk factor for stenosing tenosynovitis.¹⁶ The total number of trigger finger surgeries may drop with the benefit of improved utilization of resources.

Conclusion

The authors found a statistically significant association between postoperative infection and 2 patient populations: patients with diabetes (P = .002) and patients having > 1 digit released during the same surgery (P = .027). This outcome suggests using caution when offering A1 pulley release in select patient populations.

Acknowledgement
Justine Pierson, BS, research coordinator at University of Florida, for statistical analysis. Funding is through salary.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Stenosing tenosynovitis, or trigger finger, is a pathology commonly referred to the plastic and hand surgery service of the North Florida/South Georgia Veterans Health System (NFSGVHS). Patients usually present to their primary care provider with symptoms of the finger being temporarily locked or stuck in the flexed position. This can be a painful problem due to the size mismatch between the flexor tendon and the pulley under which it glides.

Patients are typically referred to surgery after failing ≥ 1 attempt at nonoperative management. The surgery is relatively quick and straightforward; however, postoperative complications can lead to an unexpected costly and lengthy recovery. The objective of this study was to identify potential risk factors that can predispose patients to postoperative complications so that those risk factors may be better anticipated and modified, if possible.

Methods

A retrospective chart review of trigger finger release surgery was performed on-site at the Malcom Randall VAMC in Gainesville, Florida, from January 2005 to December 2010 to identify risk factors associated with postoperative complications. The study was approved by both the NFSGVHS Internal Review Board and the University of Florida Institutional Review Board. Patients who underwent surgery exclusively for ≥ 1 trigger fingers by the plastic surgery service were included in the study.

The surgery involves making an incision over the affected A1 pulley in the hand (Figure 1) and sharply releasing it (Figure 2) under direct vision. Potential risk factors for postoperative complications were recorded. These risk factors included smoking status, diabetic status, type of incision, and number of digits released during the surgical procedure.

Results

Ninety-eight digits (on 81 hands) were identified as meeting inclusion criteria. Surgeries were performed using a longitudinal (43), transverse (48), oblique (5), or Brunner (2) incision. There were 10 complications: cellulitis (3), pyogenic flexor tenosynovitis (3), scar adhesion (1), delayed healing (2), and incomplete release (1). The overall complication rate was 10.2%. The authors compared risk factors with complications, using the chi square test and a determining of P < .05.

Related: Making the Case for Minimally Invasive Surgery

There was no link found between overall postoperative complications and diabetic status, incision type, or smoking status. There was a statistically significant link between diabetic patients and the incidence of postoperative infection (P = .002) and between 2 digits operated on during the same surgery and postoperative infection (P = .027)

Discussion

The routine practice of the NFSGVHS hand clinic is to offer a steroid injection as the initial treatment for trigger finger. Health care providers (HCPs) allow no more than 3 injections to the same digit to avoid the rare but potentially serious complication of a tendon rupture.¹ Due to the large NFSGVHS catchment area, wait time for elective trigger finger surgery is several months. This 3-injection plan has been well received by patients and referring providers due to these wait times. However, a recent article by Kerrigan and Stanwix concluded that the most cost-efficient treatment strategy is 2 steroid injections before surgery.²

More often than not, trigger finger release is a short, outpatient surgery with a quick recovery. To minimize the risk of stiffness and scar adhesions, the NFSGVHS practice is to refer all postoperative hand cases for ≥ 1 hand therapy appointment on the same day as their first postoperative visit.

Cost Estimates

When complications occur, they can be costly to patients due to both time spent away from home and work and additional expenses. When the current procedural terminology (CPT) codes are run through the VistA integrated billing system, based on the VHA Chief Business Office Reasonable Charges, a complication can more than double the charges associated with A1 pulley surgery.

A flexor sheath incision and drainage (I+D) (CPT 26020) charges $8,935.35 (facility charge, $6,911.95 plus professional fee, $2,023.40), compared with open trigger finger release (CPT 26055) at $8,365.66 (facility charge, $6,911.95 plus professional fee, $1,453.71). According to a conversation with the finance service officer at NFSGVHS (2/11/2014), the anesthesia bill ($490.56/15 min), anticipated level 3 emergency department visits (facility charge, $889.22 plus professional fee $493.40), and inpatient stays (daily floor bed $786.19) can make an infectious complication costly.

Trigger finger can also be released percutaneously. This is a reasonable option that avoids the operating room, but NFSGVHS surgeons prefer the open surgery due to concerns for tendon and nerve injury that can result from a blind sweep of the needle.^3,4 

Related: Prevention of Venous Thromboembolism After Total Joint Replacement

Existing studies found complications for trigger finger release ranging from 1% to 31%.^5,6 Wound complications and joint stiffness are known complications.^5-7 In this study, 60% of the complications were infections, and 80% of the complications were wound complications. Six of 8 patients with wound-healing complications received perioperative antibiotics. Three patients returned to the operating room for an I+D of the flexor sheath. The results showed a statistically significant link between > 1 digit treated at the same surgery and postoperative complications (P = .027). A PubMed search revealed no existing hand literature with this association.

Risk Factors

Diabetes, tobacco use, type of incision, and number of digits treated were assessed as risk factors for complications after trigger finger surgery. Nicotine is widely accepted as increasing the risk for wound complications.⁸ Almost 20% of the U.S. population smokes, compared with 22% of the VA population and 32% of active-duty military personnel.⁹ One in 4 veterans has been diagnosed with diabetes, a well-known predisposing factor in delayed wound healing and infection.^10,11 No prior studies were found comparing type of incision or multiple digits treated as complications risk factors.

There is also a well-known association between trigger finger and diabetes. Chronic hyperglycemia results in the accumulation of collagen within tendon sheaths due to impairment of collagen breakdown. Patients with diabetes tend to present with multiple digit involvement and respond less favorably to steroid injections compared with patients without diabetes.¹² Wound healing is also impaired in patients with diabetes. All 6 wound infections in this study were in patients with diabetes. Proposed etiologies for wound-healing complications include pathologic angiogenesis, impaired fibroblast proliferation and migration, impaired circulation, decreased oxygenation, and a defective immune response to the injured site.¹³

Trigger finger may develop in multiple digits. Once surgery has been planned for 1 digit, patients may request surgery on another digit on the same hand that has not had an attempt at nonoperative intervention. The NFSGVHS plastic surgeons have raised the threshold to offer multiple surgical procedures on the same hand at the same operative visit to minimize recovery time and number of visits, particularly when patients are travelling long distances. This may be less convenient; however, the overall cost to the patient and the health care system in the event of a complication is significant. Plastic surgery providers also run an alcohol prep pad over the incision site to prevent inoculation of the flexor sheath during suture removal.

Current recommendations to ameliorate the postoperative risks to the patient and costs to the system include endorsing a more conservative approach to treating trigger finger than was previously practiced at NFSGVHS. The known, less favorable response of patients with diabetes to steroid injections plus their elevated risk of postoperative infection create a catch-22 for the treatment plan. Given the low risk of a single steroid injection to the flexor sheath, this procedure is still recommended as a first-line treatment.

Related: Experience Tells in Hip Arthroplasty

During the 5-year study there was a lower threshold for surgical management and for treatment of multiple digits during the same surgery than the one currently practiced, with an overall consensus of the hospital’s HCPs. The authors recommend that all patients start with a steroid injection before committing to surgery. Patients with diabetes are informed that the injection will cause a temporary rise in their blood glucose.¹⁴ If they are resistant to the injection, high-dose oral nonsteroidal anti-inflammatory drugs and/or proximal interphalangeal joint splinting is ordered.

Verification of A_1C values showing better chronic management of blood sugar is a procedure HCPs from the NFSGVHS will begin to follow. Preoperative A_1C values between 6.5% and 8% in patients known to have diabetes has been recommended.¹⁵ A_1C values > 7% have been found to be an independent risk factor for stenosing tenosynovitis.¹⁶ The total number of trigger finger surgeries may drop with the benefit of improved utilization of resources.

Conclusion

The authors found a statistically significant association between postoperative infection and 2 patient populations: patients with diabetes (P = .002) and patients having > 1 digit released during the same surgery (P = .027). This outcome suggests using caution when offering A1 pulley release in select patient populations.

Acknowledgement
Justine Pierson, BS, research coordinator at University of Florida, for statistical analysis. Funding is through salary.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Stenosing tenosynovitis, or trigger finger, is a pathology commonly referred to the plastic and hand surgery service of the North Florida/South Georgia Veterans Health System (NFSGVHS). Patients usually present to their primary care provider with symptoms of the finger being temporarily locked or stuck in the flexed position. This can be a painful problem due to the size mismatch between the flexor tendon and the pulley under which it glides.

Patients are typically referred to surgery after failing ≥ 1 attempt at nonoperative management. The surgery is relatively quick and straightforward; however, postoperative complications can lead to an unexpected costly and lengthy recovery. The objective of this study was to identify potential risk factors that can predispose patients to postoperative complications so that those risk factors may be better anticipated and modified, if possible.

Methods

A retrospective chart review of trigger finger release surgery was performed on-site at the Malcom Randall VAMC in Gainesville, Florida, from January 2005 to December 2010 to identify risk factors associated with postoperative complications. The study was approved by both the NFSGVHS Internal Review Board and the University of Florida Institutional Review Board. Patients who underwent surgery exclusively for ≥ 1 trigger fingers by the plastic surgery service were included in the study.

The surgery involves making an incision over the affected A1 pulley in the hand (Figure 1) and sharply releasing it (Figure 2) under direct vision. Potential risk factors for postoperative complications were recorded. These risk factors included smoking status, diabetic status, type of incision, and number of digits released during the surgical procedure.

Results

Ninety-eight digits (on 81 hands) were identified as meeting inclusion criteria. Surgeries were performed using a longitudinal (43), transverse (48), oblique (5), or Brunner (2) incision. There were 10 complications: cellulitis (3), pyogenic flexor tenosynovitis (3), scar adhesion (1), delayed healing (2), and incomplete release (1). The overall complication rate was 10.2%. The authors compared risk factors with complications, using the chi square test and a determining of P < .05.

Related: Making the Case for Minimally Invasive Surgery

There was no link found between overall postoperative complications and diabetic status, incision type, or smoking status. There was a statistically significant link between diabetic patients and the incidence of postoperative infection (P = .002) and between 2 digits operated on during the same surgery and postoperative infection (P = .027)

Discussion

The routine practice of the NFSGVHS hand clinic is to offer a steroid injection as the initial treatment for trigger finger. Health care providers (HCPs) allow no more than 3 injections to the same digit to avoid the rare but potentially serious complication of a tendon rupture.¹ Due to the large NFSGVHS catchment area, wait time for elective trigger finger surgery is several months. This 3-injection plan has been well received by patients and referring providers due to these wait times. However, a recent article by Kerrigan and Stanwix concluded that the most cost-efficient treatment strategy is 2 steroid injections before surgery.²

More often than not, trigger finger release is a short, outpatient surgery with a quick recovery. To minimize the risk of stiffness and scar adhesions, the NFSGVHS practice is to refer all postoperative hand cases for ≥ 1 hand therapy appointment on the same day as their first postoperative visit.

Cost Estimates

When complications occur, they can be costly to patients due to both time spent away from home and work and additional expenses. When the current procedural terminology (CPT) codes are run through the VistA integrated billing system, based on the VHA Chief Business Office Reasonable Charges, a complication can more than double the charges associated with A1 pulley surgery.

A flexor sheath incision and drainage (I+D) (CPT 26020) charges $8,935.35 (facility charge, $6,911.95 plus professional fee, $2,023.40), compared with open trigger finger release (CPT 26055) at $8,365.66 (facility charge, $6,911.95 plus professional fee, $1,453.71). According to a conversation with the finance service officer at NFSGVHS (2/11/2014), the anesthesia bill ($490.56/15 min), anticipated level 3 emergency department visits (facility charge, $889.22 plus professional fee $493.40), and inpatient stays (daily floor bed $786.19) can make an infectious complication costly.

Trigger finger can also be released percutaneously. This is a reasonable option that avoids the operating room, but NFSGVHS surgeons prefer the open surgery due to concerns for tendon and nerve injury that can result from a blind sweep of the needle.^3,4 

Related: Prevention of Venous Thromboembolism After Total Joint Replacement

Existing studies found complications for trigger finger release ranging from 1% to 31%.^5,6 Wound complications and joint stiffness are known complications.^5-7 In this study, 60% of the complications were infections, and 80% of the complications were wound complications. Six of 8 patients with wound-healing complications received perioperative antibiotics. Three patients returned to the operating room for an I+D of the flexor sheath. The results showed a statistically significant link between > 1 digit treated at the same surgery and postoperative complications (P = .027). A PubMed search revealed no existing hand literature with this association.

Risk Factors

Diabetes, tobacco use, type of incision, and number of digits treated were assessed as risk factors for complications after trigger finger surgery. Nicotine is widely accepted as increasing the risk for wound complications.⁸ Almost 20% of the U.S. population smokes, compared with 22% of the VA population and 32% of active-duty military personnel.⁹ One in 4 veterans has been diagnosed with diabetes, a well-known predisposing factor in delayed wound healing and infection.^10,11 No prior studies were found comparing type of incision or multiple digits treated as complications risk factors.

There is also a well-known association between trigger finger and diabetes. Chronic hyperglycemia results in the accumulation of collagen within tendon sheaths due to impairment of collagen breakdown. Patients with diabetes tend to present with multiple digit involvement and respond less favorably to steroid injections compared with patients without diabetes.¹² Wound healing is also impaired in patients with diabetes. All 6 wound infections in this study were in patients with diabetes. Proposed etiologies for wound-healing complications include pathologic angiogenesis, impaired fibroblast proliferation and migration, impaired circulation, decreased oxygenation, and a defective immune response to the injured site.¹³

Trigger finger may develop in multiple digits. Once surgery has been planned for 1 digit, patients may request surgery on another digit on the same hand that has not had an attempt at nonoperative intervention. The NFSGVHS plastic surgeons have raised the threshold to offer multiple surgical procedures on the same hand at the same operative visit to minimize recovery time and number of visits, particularly when patients are travelling long distances. This may be less convenient; however, the overall cost to the patient and the health care system in the event of a complication is significant. Plastic surgery providers also run an alcohol prep pad over the incision site to prevent inoculation of the flexor sheath during suture removal.

Current recommendations to ameliorate the postoperative risks to the patient and costs to the system include endorsing a more conservative approach to treating trigger finger than was previously practiced at NFSGVHS. The known, less favorable response of patients with diabetes to steroid injections plus their elevated risk of postoperative infection create a catch-22 for the treatment plan. Given the low risk of a single steroid injection to the flexor sheath, this procedure is still recommended as a first-line treatment.

Related: Experience Tells in Hip Arthroplasty

During the 5-year study there was a lower threshold for surgical management and for treatment of multiple digits during the same surgery than the one currently practiced, with an overall consensus of the hospital’s HCPs. The authors recommend that all patients start with a steroid injection before committing to surgery. Patients with diabetes are informed that the injection will cause a temporary rise in their blood glucose.¹⁴ If they are resistant to the injection, high-dose oral nonsteroidal anti-inflammatory drugs and/or proximal interphalangeal joint splinting is ordered.

Verification of A_1C values showing better chronic management of blood sugar is a procedure HCPs from the NFSGVHS will begin to follow. Preoperative A_1C values between 6.5% and 8% in patients known to have diabetes has been recommended.¹⁵ A_1C values > 7% have been found to be an independent risk factor for stenosing tenosynovitis.¹⁶ The total number of trigger finger surgeries may drop with the benefit of improved utilization of resources.

Conclusion

The authors found a statistically significant association between postoperative infection and 2 patient populations: patients with diabetes (P = .002) and patients having > 1 digit released during the same surgery (P = .027). This outcome suggests using caution when offering A1 pulley release in select patient populations.

Acknowledgement
Justine Pierson, BS, research coordinator at University of Florida, for statistical analysis. Funding is through salary.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Compared with monoarticular arthritis, polyarticular arthritis may yield an initially narrower differential diagnosis that focuses on systemic inflammatory conditions, such as rheumatoid arthritis (RA). Approximately 15% to 30% of septic arthritis is polyarticular, of which about 45% is associated with underlying RA.^1,2 Regardless of the number of joints involved, septic (infectious) arthritis is a valid consideration given the morbidity and mortality.

In a retrospective study in the United Kingdom (UK) between 1982 and 1991, the morbidity and mortality of septic arthritis was 31.6% and 11.5%, respectively, and 16% of the study population had RA.³ A review of the literature by Dubost and colleagues found that polyarticular septic arthritis (PASA) has a mortality of 31% to 42% compared with 4% to 8% for monoarticular septic arthritis, and RA was present in 67% of the PASA fatalities.¹

Related: The Golden Era of Treatment in Rheumatology

Rheumatoid arthritis and its treatment predispose patients to septic arthritis. Septic arthritis in the UK general population is 0.42 per 100 patient-years for patients with RA on antitumor necrosis factor therapy.^3,4 In a retrospective study in the U.S., the incidence of septic arthritis was 0.40 per 100 patient-years for patients with RA compared with 0.02 per 100 patient-years for patients without RA.⁵

Other complications of RA include infectious tenosynovitis and tendon rupture. The incidence and prevalence of infectious tenosynovitis and tendon rupture in RA are not firmly established in the literature.

We present a patient with RA and psoriasis who responded initially to acute management for RA but subsequently was diagnosed with culture-negative polyarticular arthritis and infectious tenosynovitis associated with beta hemolytic group G Streptococcus (GGS), a part of Streptococcus milleri (S. milleri). During surgery, he was also found to have bilateral extensor pollicus longus (EPL) tendon rupture. Given the possible morbidity, the authors believe this patient may be of interest to the medical community.

Case Presentation

A 69-year-old African American male presented with 3 to 4 days of swelling and pain of bilateral wrists, bilateral hands, and the left ankle with subjective, but resolved, fevers and chills. His medical history was significant for seropositive erosive RA, psoriasis, hypertension, hyperlipidemia, alcohol abuse, chronic tobacco use, osteoporosis, and glaucoma. He did not have diabetes, reported no IV drug abuse, and except for the immunosuppressive effects of his medications, was not otherwise immunocompromised.

For 2 years in the outpatient setting, the rheumatology clinic had been managing the patient’s rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (CCP) antibody positive erosive RA with etanercept 25 mg subcutaneously twice a week. The RA affected his hands, wrists, shoulders, and ankles bilaterally but was successfully controlled. The dermatology clinic was managing the patient’s psoriasis with calcipotriene cream 0.005% twice a week and clobetasol ointment 0.05% twice a week. Psoriatic plaques were noted on bilateral elbows, bilateral dorsal hands, and bilateral dorsal feet.

Initial Evaluation

At evaluation, the patient’s vital signs revealed a temperature of 36.3°C (97.3°F), pulse of 102 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 99% on room air, and blood pressure of 102/70 mm Hg. He was found to have edema, tenderness, and erythema of the wrists bilaterally and left metacarpophalangeal joints (MCPs) and edematous right MCPs and left medial ankle.

The patient had been nonadherent with etanercept for 5 monthsand restarted taking the medication only 2 weeks before presentation. He had noticed worsening arthritis for at least 1 month. His last RA flare was approximately 1 year before presentation. Additional symptoms included 4 days of nausea, nonbloody and nonbilious emesis, left lower quadrant pain, and diarrhea without melena or hematochezia.

Initial laboratory studies found 3.2 k/μL white blood cells (WBCs) with a differential of 11.9% lymphocytes, 4.2% monocytes, 83.3% neutrophils, 0.5% eosinophils, and 0.1% basophils; 165 k/μL platelets; 96 mm/h erythrocyte sedimentation rate (ESR); and 45 mg/dL C-reactive protein. The patient was diagnosed with viral gastroenteritis and RA flare and was admitted for inpatient management secondary to limited ability to care for himself.

Related: Infliximab-Induced Complications

The patient was started on prednisone 40 mg orally once a day (for 5 days) for empiric treatment of an RA flare and continued on etanercept. The inpatient rheumatology service was consulted. Further evaluation later that day found involvement of the proximal interphalangeal joints and elbows and tenderness of the tendons of the dorsal hand bilaterally. Over the next 2 days, the patient remained afebrile and WBCs were within normal limits. Edema, erythema, and tenderness of the involved joints somewhat improved, but tenderness along the tendons of the dorsal hand worsened, which concerned the managing teams for infectious tenosynovitis.

By day 4, the patient was afebrile and had a leukocytosis of 12.9 k/μLwith neutrophils 86.7%, but improvement of erythema, pain, and range of motion of involved joints and no tenderness to palpation of tendons was noted. The inpatient orthopedic surgery service evaluated the patient and did not find sufficient evidence necessitating surgical intervention.

Worsening Condition

On day 6, arthrocentesis of the left wrist was performed secondary to worsening of erythema and edema. The patient experienced new edema of the left shoulder and leukocytosis continued to trend upward (15.7 k/μL on day 6). Purulent aspirate (1.5 mL) was obtained from the fluctuance and tenosynovium of the left wrist. Empiric vancomycin 1 g IV twice daily and ceftriaxone 2 g IV daily were started and continued for 3 days. By this point in his hospital course, the patient had received 1 dose of etanercept. Prednisone and etanercept were previously discontinued because of the discovered infection. Blood cultures were drawn and had no growth (Table). Gastroenterology studies were limited to stool cultures and did not include colonoscopy. Leukocytosis began trending down.

On day 8, antibiotics were tailored to penicillin G 4 million units IV every 4 hours following growth of GGS from the sample of the left wrist. Subsequently, synovial fluid (3 mL) from the left shoulder was obtained following initiation of antibiotic therapy and had no growth. Magnetic resonance imaging (MRI) found tenosynovitis of the left ankle and right wrist.

On day 9, transthoracic echocardiography was performed and found no evidence of infectious endocarditis. Later that night, the patient was taken to surgery for incision and drainage/debridement of bilateral wrists and left ankle, synovectomy of right wrist, and aspiration of right shoulder. Findings included abscess in the left wrist and inflammatory synovitis and bilateral EPL tendon rupture consistent with RA. Pus from the left ankle had few gram-positive cocci in chains with no growth, and the specimens from both wrists grew GGS. Aspirate from the left ankle was an opaque yellow fluid with 14,900/mm³ WBC, 30,000/mm³ red blood cells (RBC), 97% neutrophils, 1% macrophages, 2% lymphocytes, and 0% monocytes. Aspirate from the right shoulder was an opaque bloody fluid with 10,100/mm³ WBC, 40,000/mm³ RBC, 95% neutrophils, 2% macrophages, 1% lymphocytes, and 1% monocytes. On day 10, sulfasalazine 500 mg twice a day was initiated for RA.

Following surgery and continued antibiotics, the patient’s leukocytosis resolved, and improvement was seen in all joints with decreased edema, erythema, and pain and increased range of motion. Postoperative recovery was complicated by ileus, urinary retention, and fungal (Candida albicans) urinary tract infection, all of which resolved without significant complications. The inpatient rheumatology service restarted prednisone at a lower dose of 20 mg. The patient became afebrile and sufficiently stable for transfer to a lower level of care with continued physical therapy and IV antibiotics for another 3 weeks.

Discussion

The patient had 2 underlying systemic inflammatory conditions: RA and psoriasis. The underlying chronic arthritis was likely caused by RA, not psoriatic arthritis (PsA). The patient met the 2010 American College of Rheumatology criteria but failed to meet the classification criteria for PsA.^6,7 However, the clinical features of RA and PsA overlap. Rheumatoid factor and CCP can be positive laboratory findings in both RA and PsA.^8-14 Tenosynovitis is found in about half of RA patients and PsA patients (P > .05).¹⁵ In its evaluation of the patient, the inpatient rheumatology service suspected that the patient may have had RA with components of PsA.

Rheumatoid arthritis complicates the diagnosis of septic arthritis. In a study by Nolla and colleagues, a mean of 7.3 days (range 3 to 18 days) elapsed before a diagnosis of septic arthritis was made in 10 patients with RA on corticosteroids.² Consideration of risk factors such as increasing age, male sex, tobacco use, extra-articular manifestations of RA, positive RF, rheumatoid nodules, poor functional capacity, high ESR, leukopenia, comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes), and the use of corticosteroids may expedite the diagnosis of infections in patients with RA.¹⁶ In this case, the patient had some of these risk factors: age, male sex, alcoholism, chronic tobacco use, positive RF, high ESR, and leukopenia (at presentation).

Related: Trend Toward Concomitant Supplements and Medications

The history of medication nonadherence of etanercept with progressively worsening arthritis and early clinical improvement (reduction in erythema, edema, and pain and temporary loss of signs of tenosynovitis on examination) while on prednisone suggested that the patient had a RA flare. The prednisone likely alleviated the inflammatory process but created an immunosuppressed state that allowed GGS to invade and possibly disseminate. Alternately, the patient may have been infected before presentation. The lack of a definitive time line for his case prevented the authors from forming conclusions about a possible causal relationship between the infection and medications. The subjective fevers before admission were nonspecific and could have been caused by RA, presumed gastroenteritis, or other undiagnosed infectious processes. The observed leukocytosis may have been initially corticosteroid-induced.¹⁷

Septic Arthritis

The suspicion of septic arthritis and infectious tenosynovitis substantially increased on day 6 with worsening symptoms, involvement of additional joints, and spiking fevers. Group G Streptococcus was obtained from the aspirate of the left wrist and from the surgical specimens from the bilateral wrists. The clinical presentation, MRI imaging studies, and surgical and nonsurgical specimens supported a diagnosis of GGS tenosynovitis. However, there was no clear evidence (ie, positive culture with identified organism) of septic arthritis, likely secondary to early septic arthritis and initiation of antibiotics before joint aspirations. The aspirate from the left ankle was yellow and opaque, but the culture was negative.

The pathogenic organism in the patient was GGS. Group G Streptococcus is normal flora of the oral cavity, gastrointestinal (GI) tract, upper respiratory tract, genital tract, and skin, which were all possible sources of seeding.¹⁸ Streptococcal species account for about 20% of septic arthritis, and GGS arthritis accounts for 4% to 19% of streptococcal arthritis.^19-22 From a review of the literature, 2 cases of GGS tenosynovitis have been published.^23,24 However, in an ultrasound study and MRI study, 49% and 43%, respectively, of patients with RA had tenosynovitis of the tendons of the hands.^15,25

GGS Demographics

About three-quarters (71%) of patients with GGS arthritis are male.¹⁹ The analysis of the literature by Bronze and colleagues found that chronic joint disease and alcoholism are present in 34% and 14% of patients with GGS arthritis, respectively. One-quarter (23% from Dubost and colleagues) to one-third (32% from Schattner and colleagues) of patients with GGS arthritis have RA.^19,26

Fever is present in less than half (43%) of patients with GGS arthritis.¹⁹ Positive synovial fluid is expected in 90% of patients.¹⁹ Leukocytosis and elevated ESR need not be present.^27,28 The arthritis is polyarticular in one-quarter of patients (24% from Bronze and colleagues and 26% from Dubost and colleagues).^19,26

Positive blood cultures can be expected in one-fourth (26%) of patients with GGS arthritis.¹⁹ The patient’s blood cultures were negative. Blood cultures drawn before initiation of antibiotics yielded no growth, so if the spread was hematogenous, the bacteremia was transient or intermittent. Before and after initiation of antibiotics, specimens from the shoulders did not grow colonies, whereas specimens from the wrists did. If the shoulders were truly infected, these findings and the notably later involvement of the shoulders suggest that the shoulders may have been seeded later in the hospital course.

Trenkner and colleagues proposed that GI abnormalities provide a portal of entry for GGS, which is under the umbrella of S. milleri.²⁹S. milleri is associated with abscess formation, usually of the GI tract.^30-32 In the study patient, the possible gastroenteritis may have provided such a portal of entry and subsequent seeding to the joints, and an abscess was found in the left wrist.

Tendon Rupture

Additionally, bilateral EPL tendon rupture likely occurred as a consequence of the inflammatory process from RA and infectious tenosynovitis in the patient. According to Zheng and colleagues, tenosynovitis is an inflammatory process of the synovial tendon sheath that may result in degeneration and rupture of the tendons and may contribute to bone erosions, development of joint deformities, and loss of functional capacity.³³ In a histologic study of a ruptured EPL tendon from a patient with RA, Harris observed a chronic inflammatory cellular reaction.³⁴ Harris also described a male with RA with unconfirmed bilateral EPL rupture.³⁴ Björkman and colleague identified previous injury, RA, and local or systemic steroids as important etiologic factors for EPL tendon rupture.³⁵

As in the case of this patient, the utilization of both medical and surgical therapy is not uncommon for treating GGS infection. Antibiotic therapy typically consists of penicillin (74%).²⁶ Surgical intervention is necessary in 16% to 37% of patients.^19,26 This patient required both penicillin and incision and drainage/debridement before significant clinical improvement was noted. Prognosis of GGS arthritis is favorable with 5% mortality.²⁶

Conclusion

Septic arthritis and infectious tenosynovitis are readily treatable with low mortality if promptly identified. Identification can be masked by other medical conditions, such as RA and psoriasis, and their associated immunosuppressive treatment. Bilateral EPL tendon rupture may be a complication of RA, particularly with an underlying septic arthritis and infectious tenosynovitis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Compared with monoarticular arthritis, polyarticular arthritis may yield an initially narrower differential diagnosis that focuses on systemic inflammatory conditions, such as rheumatoid arthritis (RA). Approximately 15% to 30% of septic arthritis is polyarticular, of which about 45% is associated with underlying RA.^1,2 Regardless of the number of joints involved, septic (infectious) arthritis is a valid consideration given the morbidity and mortality.

In a retrospective study in the United Kingdom (UK) between 1982 and 1991, the morbidity and mortality of septic arthritis was 31.6% and 11.5%, respectively, and 16% of the study population had RA.³ A review of the literature by Dubost and colleagues found that polyarticular septic arthritis (PASA) has a mortality of 31% to 42% compared with 4% to 8% for monoarticular septic arthritis, and RA was present in 67% of the PASA fatalities.¹

Related: The Golden Era of Treatment in Rheumatology

Rheumatoid arthritis and its treatment predispose patients to septic arthritis. Septic arthritis in the UK general population is 0.42 per 100 patient-years for patients with RA on antitumor necrosis factor therapy.^3,4 In a retrospective study in the U.S., the incidence of septic arthritis was 0.40 per 100 patient-years for patients with RA compared with 0.02 per 100 patient-years for patients without RA.⁵

Other complications of RA include infectious tenosynovitis and tendon rupture. The incidence and prevalence of infectious tenosynovitis and tendon rupture in RA are not firmly established in the literature.

We present a patient with RA and psoriasis who responded initially to acute management for RA but subsequently was diagnosed with culture-negative polyarticular arthritis and infectious tenosynovitis associated with beta hemolytic group G Streptococcus (GGS), a part of Streptococcus milleri (S. milleri). During surgery, he was also found to have bilateral extensor pollicus longus (EPL) tendon rupture. Given the possible morbidity, the authors believe this patient may be of interest to the medical community.

Case Presentation

A 69-year-old African American male presented with 3 to 4 days of swelling and pain of bilateral wrists, bilateral hands, and the left ankle with subjective, but resolved, fevers and chills. His medical history was significant for seropositive erosive RA, psoriasis, hypertension, hyperlipidemia, alcohol abuse, chronic tobacco use, osteoporosis, and glaucoma. He did not have diabetes, reported no IV drug abuse, and except for the immunosuppressive effects of his medications, was not otherwise immunocompromised.

For 2 years in the outpatient setting, the rheumatology clinic had been managing the patient’s rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (CCP) antibody positive erosive RA with etanercept 25 mg subcutaneously twice a week. The RA affected his hands, wrists, shoulders, and ankles bilaterally but was successfully controlled. The dermatology clinic was managing the patient’s psoriasis with calcipotriene cream 0.005% twice a week and clobetasol ointment 0.05% twice a week. Psoriatic plaques were noted on bilateral elbows, bilateral dorsal hands, and bilateral dorsal feet.

Initial Evaluation

At evaluation, the patient’s vital signs revealed a temperature of 36.3°C (97.3°F), pulse of 102 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 99% on room air, and blood pressure of 102/70 mm Hg. He was found to have edema, tenderness, and erythema of the wrists bilaterally and left metacarpophalangeal joints (MCPs) and edematous right MCPs and left medial ankle.

The patient had been nonadherent with etanercept for 5 monthsand restarted taking the medication only 2 weeks before presentation. He had noticed worsening arthritis for at least 1 month. His last RA flare was approximately 1 year before presentation. Additional symptoms included 4 days of nausea, nonbloody and nonbilious emesis, left lower quadrant pain, and diarrhea without melena or hematochezia.

Initial laboratory studies found 3.2 k/μL white blood cells (WBCs) with a differential of 11.9% lymphocytes, 4.2% monocytes, 83.3% neutrophils, 0.5% eosinophils, and 0.1% basophils; 165 k/μL platelets; 96 mm/h erythrocyte sedimentation rate (ESR); and 45 mg/dL C-reactive protein. The patient was diagnosed with viral gastroenteritis and RA flare and was admitted for inpatient management secondary to limited ability to care for himself.

Related: Infliximab-Induced Complications

The patient was started on prednisone 40 mg orally once a day (for 5 days) for empiric treatment of an RA flare and continued on etanercept. The inpatient rheumatology service was consulted. Further evaluation later that day found involvement of the proximal interphalangeal joints and elbows and tenderness of the tendons of the dorsal hand bilaterally. Over the next 2 days, the patient remained afebrile and WBCs were within normal limits. Edema, erythema, and tenderness of the involved joints somewhat improved, but tenderness along the tendons of the dorsal hand worsened, which concerned the managing teams for infectious tenosynovitis.

By day 4, the patient was afebrile and had a leukocytosis of 12.9 k/μLwith neutrophils 86.7%, but improvement of erythema, pain, and range of motion of involved joints and no tenderness to palpation of tendons was noted. The inpatient orthopedic surgery service evaluated the patient and did not find sufficient evidence necessitating surgical intervention.

Worsening Condition

On day 6, arthrocentesis of the left wrist was performed secondary to worsening of erythema and edema. The patient experienced new edema of the left shoulder and leukocytosis continued to trend upward (15.7 k/μL on day 6). Purulent aspirate (1.5 mL) was obtained from the fluctuance and tenosynovium of the left wrist. Empiric vancomycin 1 g IV twice daily and ceftriaxone 2 g IV daily were started and continued for 3 days. By this point in his hospital course, the patient had received 1 dose of etanercept. Prednisone and etanercept were previously discontinued because of the discovered infection. Blood cultures were drawn and had no growth (Table). Gastroenterology studies were limited to stool cultures and did not include colonoscopy. Leukocytosis began trending down.

On day 8, antibiotics were tailored to penicillin G 4 million units IV every 4 hours following growth of GGS from the sample of the left wrist. Subsequently, synovial fluid (3 mL) from the left shoulder was obtained following initiation of antibiotic therapy and had no growth. Magnetic resonance imaging (MRI) found tenosynovitis of the left ankle and right wrist.

On day 9, transthoracic echocardiography was performed and found no evidence of infectious endocarditis. Later that night, the patient was taken to surgery for incision and drainage/debridement of bilateral wrists and left ankle, synovectomy of right wrist, and aspiration of right shoulder. Findings included abscess in the left wrist and inflammatory synovitis and bilateral EPL tendon rupture consistent with RA. Pus from the left ankle had few gram-positive cocci in chains with no growth, and the specimens from both wrists grew GGS. Aspirate from the left ankle was an opaque yellow fluid with 14,900/mm³ WBC, 30,000/mm³ red blood cells (RBC), 97% neutrophils, 1% macrophages, 2% lymphocytes, and 0% monocytes. Aspirate from the right shoulder was an opaque bloody fluid with 10,100/mm³ WBC, 40,000/mm³ RBC, 95% neutrophils, 2% macrophages, 1% lymphocytes, and 1% monocytes. On day 10, sulfasalazine 500 mg twice a day was initiated for RA.

Following surgery and continued antibiotics, the patient’s leukocytosis resolved, and improvement was seen in all joints with decreased edema, erythema, and pain and increased range of motion. Postoperative recovery was complicated by ileus, urinary retention, and fungal (Candida albicans) urinary tract infection, all of which resolved without significant complications. The inpatient rheumatology service restarted prednisone at a lower dose of 20 mg. The patient became afebrile and sufficiently stable for transfer to a lower level of care with continued physical therapy and IV antibiotics for another 3 weeks.

Discussion

The patient had 2 underlying systemic inflammatory conditions: RA and psoriasis. The underlying chronic arthritis was likely caused by RA, not psoriatic arthritis (PsA). The patient met the 2010 American College of Rheumatology criteria but failed to meet the classification criteria for PsA.^6,7 However, the clinical features of RA and PsA overlap. Rheumatoid factor and CCP can be positive laboratory findings in both RA and PsA.^8-14 Tenosynovitis is found in about half of RA patients and PsA patients (P > .05).¹⁵ In its evaluation of the patient, the inpatient rheumatology service suspected that the patient may have had RA with components of PsA.

Rheumatoid arthritis complicates the diagnosis of septic arthritis. In a study by Nolla and colleagues, a mean of 7.3 days (range 3 to 18 days) elapsed before a diagnosis of septic arthritis was made in 10 patients with RA on corticosteroids.² Consideration of risk factors such as increasing age, male sex, tobacco use, extra-articular manifestations of RA, positive RF, rheumatoid nodules, poor functional capacity, high ESR, leukopenia, comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes), and the use of corticosteroids may expedite the diagnosis of infections in patients with RA.¹⁶ In this case, the patient had some of these risk factors: age, male sex, alcoholism, chronic tobacco use, positive RF, high ESR, and leukopenia (at presentation).

Related: Trend Toward Concomitant Supplements and Medications

The history of medication nonadherence of etanercept with progressively worsening arthritis and early clinical improvement (reduction in erythema, edema, and pain and temporary loss of signs of tenosynovitis on examination) while on prednisone suggested that the patient had a RA flare. The prednisone likely alleviated the inflammatory process but created an immunosuppressed state that allowed GGS to invade and possibly disseminate. Alternately, the patient may have been infected before presentation. The lack of a definitive time line for his case prevented the authors from forming conclusions about a possible causal relationship between the infection and medications. The subjective fevers before admission were nonspecific and could have been caused by RA, presumed gastroenteritis, or other undiagnosed infectious processes. The observed leukocytosis may have been initially corticosteroid-induced.¹⁷

Septic Arthritis

The suspicion of septic arthritis and infectious tenosynovitis substantially increased on day 6 with worsening symptoms, involvement of additional joints, and spiking fevers. Group G Streptococcus was obtained from the aspirate of the left wrist and from the surgical specimens from the bilateral wrists. The clinical presentation, MRI imaging studies, and surgical and nonsurgical specimens supported a diagnosis of GGS tenosynovitis. However, there was no clear evidence (ie, positive culture with identified organism) of septic arthritis, likely secondary to early septic arthritis and initiation of antibiotics before joint aspirations. The aspirate from the left ankle was yellow and opaque, but the culture was negative.

The pathogenic organism in the patient was GGS. Group G Streptococcus is normal flora of the oral cavity, gastrointestinal (GI) tract, upper respiratory tract, genital tract, and skin, which were all possible sources of seeding.¹⁸ Streptococcal species account for about 20% of septic arthritis, and GGS arthritis accounts for 4% to 19% of streptococcal arthritis.^19-22 From a review of the literature, 2 cases of GGS tenosynovitis have been published.^23,24 However, in an ultrasound study and MRI study, 49% and 43%, respectively, of patients with RA had tenosynovitis of the tendons of the hands.^15,25

GGS Demographics

About three-quarters (71%) of patients with GGS arthritis are male.¹⁹ The analysis of the literature by Bronze and colleagues found that chronic joint disease and alcoholism are present in 34% and 14% of patients with GGS arthritis, respectively. One-quarter (23% from Dubost and colleagues) to one-third (32% from Schattner and colleagues) of patients with GGS arthritis have RA.^19,26

Fever is present in less than half (43%) of patients with GGS arthritis.¹⁹ Positive synovial fluid is expected in 90% of patients.¹⁹ Leukocytosis and elevated ESR need not be present.^27,28 The arthritis is polyarticular in one-quarter of patients (24% from Bronze and colleagues and 26% from Dubost and colleagues).^19,26

Positive blood cultures can be expected in one-fourth (26%) of patients with GGS arthritis.¹⁹ The patient’s blood cultures were negative. Blood cultures drawn before initiation of antibiotics yielded no growth, so if the spread was hematogenous, the bacteremia was transient or intermittent. Before and after initiation of antibiotics, specimens from the shoulders did not grow colonies, whereas specimens from the wrists did. If the shoulders were truly infected, these findings and the notably later involvement of the shoulders suggest that the shoulders may have been seeded later in the hospital course.

Trenkner and colleagues proposed that GI abnormalities provide a portal of entry for GGS, which is under the umbrella of S. milleri.²⁹S. milleri is associated with abscess formation, usually of the GI tract.^30-32 In the study patient, the possible gastroenteritis may have provided such a portal of entry and subsequent seeding to the joints, and an abscess was found in the left wrist.

Tendon Rupture

Additionally, bilateral EPL tendon rupture likely occurred as a consequence of the inflammatory process from RA and infectious tenosynovitis in the patient. According to Zheng and colleagues, tenosynovitis is an inflammatory process of the synovial tendon sheath that may result in degeneration and rupture of the tendons and may contribute to bone erosions, development of joint deformities, and loss of functional capacity.³³ In a histologic study of a ruptured EPL tendon from a patient with RA, Harris observed a chronic inflammatory cellular reaction.³⁴ Harris also described a male with RA with unconfirmed bilateral EPL rupture.³⁴ Björkman and colleague identified previous injury, RA, and local or systemic steroids as important etiologic factors for EPL tendon rupture.³⁵

As in the case of this patient, the utilization of both medical and surgical therapy is not uncommon for treating GGS infection. Antibiotic therapy typically consists of penicillin (74%).²⁶ Surgical intervention is necessary in 16% to 37% of patients.^19,26 This patient required both penicillin and incision and drainage/debridement before significant clinical improvement was noted. Prognosis of GGS arthritis is favorable with 5% mortality.²⁶

Conclusion

Septic arthritis and infectious tenosynovitis are readily treatable with low mortality if promptly identified. Identification can be masked by other medical conditions, such as RA and psoriasis, and their associated immunosuppressive treatment. Bilateral EPL tendon rupture may be a complication of RA, particularly with an underlying septic arthritis and infectious tenosynovitis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Compared with monoarticular arthritis, polyarticular arthritis may yield an initially narrower differential diagnosis that focuses on systemic inflammatory conditions, such as rheumatoid arthritis (RA). Approximately 15% to 30% of septic arthritis is polyarticular, of which about 45% is associated with underlying RA.^1,2 Regardless of the number of joints involved, septic (infectious) arthritis is a valid consideration given the morbidity and mortality.

In a retrospective study in the United Kingdom (UK) between 1982 and 1991, the morbidity and mortality of septic arthritis was 31.6% and 11.5%, respectively, and 16% of the study population had RA.³ A review of the literature by Dubost and colleagues found that polyarticular septic arthritis (PASA) has a mortality of 31% to 42% compared with 4% to 8% for monoarticular septic arthritis, and RA was present in 67% of the PASA fatalities.¹

Related: The Golden Era of Treatment in Rheumatology

Rheumatoid arthritis and its treatment predispose patients to septic arthritis. Septic arthritis in the UK general population is 0.42 per 100 patient-years for patients with RA on antitumor necrosis factor therapy.^3,4 In a retrospective study in the U.S., the incidence of septic arthritis was 0.40 per 100 patient-years for patients with RA compared with 0.02 per 100 patient-years for patients without RA.⁵

Other complications of RA include infectious tenosynovitis and tendon rupture. The incidence and prevalence of infectious tenosynovitis and tendon rupture in RA are not firmly established in the literature.

We present a patient with RA and psoriasis who responded initially to acute management for RA but subsequently was diagnosed with culture-negative polyarticular arthritis and infectious tenosynovitis associated with beta hemolytic group G Streptococcus (GGS), a part of Streptococcus milleri (S. milleri). During surgery, he was also found to have bilateral extensor pollicus longus (EPL) tendon rupture. Given the possible morbidity, the authors believe this patient may be of interest to the medical community.

Case Presentation

A 69-year-old African American male presented with 3 to 4 days of swelling and pain of bilateral wrists, bilateral hands, and the left ankle with subjective, but resolved, fevers and chills. His medical history was significant for seropositive erosive RA, psoriasis, hypertension, hyperlipidemia, alcohol abuse, chronic tobacco use, osteoporosis, and glaucoma. He did not have diabetes, reported no IV drug abuse, and except for the immunosuppressive effects of his medications, was not otherwise immunocompromised.

For 2 years in the outpatient setting, the rheumatology clinic had been managing the patient’s rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (CCP) antibody positive erosive RA with etanercept 25 mg subcutaneously twice a week. The RA affected his hands, wrists, shoulders, and ankles bilaterally but was successfully controlled. The dermatology clinic was managing the patient’s psoriasis with calcipotriene cream 0.005% twice a week and clobetasol ointment 0.05% twice a week. Psoriatic plaques were noted on bilateral elbows, bilateral dorsal hands, and bilateral dorsal feet.

Initial Evaluation

At evaluation, the patient’s vital signs revealed a temperature of 36.3°C (97.3°F), pulse of 102 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 99% on room air, and blood pressure of 102/70 mm Hg. He was found to have edema, tenderness, and erythema of the wrists bilaterally and left metacarpophalangeal joints (MCPs) and edematous right MCPs and left medial ankle.

The patient had been nonadherent with etanercept for 5 monthsand restarted taking the medication only 2 weeks before presentation. He had noticed worsening arthritis for at least 1 month. His last RA flare was approximately 1 year before presentation. Additional symptoms included 4 days of nausea, nonbloody and nonbilious emesis, left lower quadrant pain, and diarrhea without melena or hematochezia.

Initial laboratory studies found 3.2 k/μL white blood cells (WBCs) with a differential of 11.9% lymphocytes, 4.2% monocytes, 83.3% neutrophils, 0.5% eosinophils, and 0.1% basophils; 165 k/μL platelets; 96 mm/h erythrocyte sedimentation rate (ESR); and 45 mg/dL C-reactive protein. The patient was diagnosed with viral gastroenteritis and RA flare and was admitted for inpatient management secondary to limited ability to care for himself.

Related: Infliximab-Induced Complications

The patient was started on prednisone 40 mg orally once a day (for 5 days) for empiric treatment of an RA flare and continued on etanercept. The inpatient rheumatology service was consulted. Further evaluation later that day found involvement of the proximal interphalangeal joints and elbows and tenderness of the tendons of the dorsal hand bilaterally. Over the next 2 days, the patient remained afebrile and WBCs were within normal limits. Edema, erythema, and tenderness of the involved joints somewhat improved, but tenderness along the tendons of the dorsal hand worsened, which concerned the managing teams for infectious tenosynovitis.

By day 4, the patient was afebrile and had a leukocytosis of 12.9 k/μLwith neutrophils 86.7%, but improvement of erythema, pain, and range of motion of involved joints and no tenderness to palpation of tendons was noted. The inpatient orthopedic surgery service evaluated the patient and did not find sufficient evidence necessitating surgical intervention.

Worsening Condition

On day 6, arthrocentesis of the left wrist was performed secondary to worsening of erythema and edema. The patient experienced new edema of the left shoulder and leukocytosis continued to trend upward (15.7 k/μL on day 6). Purulent aspirate (1.5 mL) was obtained from the fluctuance and tenosynovium of the left wrist. Empiric vancomycin 1 g IV twice daily and ceftriaxone 2 g IV daily were started and continued for 3 days. By this point in his hospital course, the patient had received 1 dose of etanercept. Prednisone and etanercept were previously discontinued because of the discovered infection. Blood cultures were drawn and had no growth (Table). Gastroenterology studies were limited to stool cultures and did not include colonoscopy. Leukocytosis began trending down.

On day 8, antibiotics were tailored to penicillin G 4 million units IV every 4 hours following growth of GGS from the sample of the left wrist. Subsequently, synovial fluid (3 mL) from the left shoulder was obtained following initiation of antibiotic therapy and had no growth. Magnetic resonance imaging (MRI) found tenosynovitis of the left ankle and right wrist.

On day 9, transthoracic echocardiography was performed and found no evidence of infectious endocarditis. Later that night, the patient was taken to surgery for incision and drainage/debridement of bilateral wrists and left ankle, synovectomy of right wrist, and aspiration of right shoulder. Findings included abscess in the left wrist and inflammatory synovitis and bilateral EPL tendon rupture consistent with RA. Pus from the left ankle had few gram-positive cocci in chains with no growth, and the specimens from both wrists grew GGS. Aspirate from the left ankle was an opaque yellow fluid with 14,900/mm³ WBC, 30,000/mm³ red blood cells (RBC), 97% neutrophils, 1% macrophages, 2% lymphocytes, and 0% monocytes. Aspirate from the right shoulder was an opaque bloody fluid with 10,100/mm³ WBC, 40,000/mm³ RBC, 95% neutrophils, 2% macrophages, 1% lymphocytes, and 1% monocytes. On day 10, sulfasalazine 500 mg twice a day was initiated for RA.

Following surgery and continued antibiotics, the patient’s leukocytosis resolved, and improvement was seen in all joints with decreased edema, erythema, and pain and increased range of motion. Postoperative recovery was complicated by ileus, urinary retention, and fungal (Candida albicans) urinary tract infection, all of which resolved without significant complications. The inpatient rheumatology service restarted prednisone at a lower dose of 20 mg. The patient became afebrile and sufficiently stable for transfer to a lower level of care with continued physical therapy and IV antibiotics for another 3 weeks.

Discussion

The patient had 2 underlying systemic inflammatory conditions: RA and psoriasis. The underlying chronic arthritis was likely caused by RA, not psoriatic arthritis (PsA). The patient met the 2010 American College of Rheumatology criteria but failed to meet the classification criteria for PsA.^6,7 However, the clinical features of RA and PsA overlap. Rheumatoid factor and CCP can be positive laboratory findings in both RA and PsA.^8-14 Tenosynovitis is found in about half of RA patients and PsA patients (P > .05).¹⁵ In its evaluation of the patient, the inpatient rheumatology service suspected that the patient may have had RA with components of PsA.

Rheumatoid arthritis complicates the diagnosis of septic arthritis. In a study by Nolla and colleagues, a mean of 7.3 days (range 3 to 18 days) elapsed before a diagnosis of septic arthritis was made in 10 patients with RA on corticosteroids.² Consideration of risk factors such as increasing age, male sex, tobacco use, extra-articular manifestations of RA, positive RF, rheumatoid nodules, poor functional capacity, high ESR, leukopenia, comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes), and the use of corticosteroids may expedite the diagnosis of infections in patients with RA.¹⁶ In this case, the patient had some of these risk factors: age, male sex, alcoholism, chronic tobacco use, positive RF, high ESR, and leukopenia (at presentation).

Related: Trend Toward Concomitant Supplements and Medications

The history of medication nonadherence of etanercept with progressively worsening arthritis and early clinical improvement (reduction in erythema, edema, and pain and temporary loss of signs of tenosynovitis on examination) while on prednisone suggested that the patient had a RA flare. The prednisone likely alleviated the inflammatory process but created an immunosuppressed state that allowed GGS to invade and possibly disseminate. Alternately, the patient may have been infected before presentation. The lack of a definitive time line for his case prevented the authors from forming conclusions about a possible causal relationship between the infection and medications. The subjective fevers before admission were nonspecific and could have been caused by RA, presumed gastroenteritis, or other undiagnosed infectious processes. The observed leukocytosis may have been initially corticosteroid-induced.¹⁷

Septic Arthritis

The suspicion of septic arthritis and infectious tenosynovitis substantially increased on day 6 with worsening symptoms, involvement of additional joints, and spiking fevers. Group G Streptococcus was obtained from the aspirate of the left wrist and from the surgical specimens from the bilateral wrists. The clinical presentation, MRI imaging studies, and surgical and nonsurgical specimens supported a diagnosis of GGS tenosynovitis. However, there was no clear evidence (ie, positive culture with identified organism) of septic arthritis, likely secondary to early septic arthritis and initiation of antibiotics before joint aspirations. The aspirate from the left ankle was yellow and opaque, but the culture was negative.

The pathogenic organism in the patient was GGS. Group G Streptococcus is normal flora of the oral cavity, gastrointestinal (GI) tract, upper respiratory tract, genital tract, and skin, which were all possible sources of seeding.¹⁸ Streptococcal species account for about 20% of septic arthritis, and GGS arthritis accounts for 4% to 19% of streptococcal arthritis.^19-22 From a review of the literature, 2 cases of GGS tenosynovitis have been published.^23,24 However, in an ultrasound study and MRI study, 49% and 43%, respectively, of patients with RA had tenosynovitis of the tendons of the hands.^15,25

GGS Demographics

About three-quarters (71%) of patients with GGS arthritis are male.¹⁹ The analysis of the literature by Bronze and colleagues found that chronic joint disease and alcoholism are present in 34% and 14% of patients with GGS arthritis, respectively. One-quarter (23% from Dubost and colleagues) to one-third (32% from Schattner and colleagues) of patients with GGS arthritis have RA.^19,26

Fever is present in less than half (43%) of patients with GGS arthritis.¹⁹ Positive synovial fluid is expected in 90% of patients.¹⁹ Leukocytosis and elevated ESR need not be present.^27,28 The arthritis is polyarticular in one-quarter of patients (24% from Bronze and colleagues and 26% from Dubost and colleagues).^19,26

Positive blood cultures can be expected in one-fourth (26%) of patients with GGS arthritis.¹⁹ The patient’s blood cultures were negative. Blood cultures drawn before initiation of antibiotics yielded no growth, so if the spread was hematogenous, the bacteremia was transient or intermittent. Before and after initiation of antibiotics, specimens from the shoulders did not grow colonies, whereas specimens from the wrists did. If the shoulders were truly infected, these findings and the notably later involvement of the shoulders suggest that the shoulders may have been seeded later in the hospital course.

Trenkner and colleagues proposed that GI abnormalities provide a portal of entry for GGS, which is under the umbrella of S. milleri.²⁹S. milleri is associated with abscess formation, usually of the GI tract.^30-32 In the study patient, the possible gastroenteritis may have provided such a portal of entry and subsequent seeding to the joints, and an abscess was found in the left wrist.

Tendon Rupture

Additionally, bilateral EPL tendon rupture likely occurred as a consequence of the inflammatory process from RA and infectious tenosynovitis in the patient. According to Zheng and colleagues, tenosynovitis is an inflammatory process of the synovial tendon sheath that may result in degeneration and rupture of the tendons and may contribute to bone erosions, development of joint deformities, and loss of functional capacity.³³ In a histologic study of a ruptured EPL tendon from a patient with RA, Harris observed a chronic inflammatory cellular reaction.³⁴ Harris also described a male with RA with unconfirmed bilateral EPL rupture.³⁴ Björkman and colleague identified previous injury, RA, and local or systemic steroids as important etiologic factors for EPL tendon rupture.³⁵

As in the case of this patient, the utilization of both medical and surgical therapy is not uncommon for treating GGS infection. Antibiotic therapy typically consists of penicillin (74%).²⁶ Surgical intervention is necessary in 16% to 37% of patients.^19,26 This patient required both penicillin and incision and drainage/debridement before significant clinical improvement was noted. Prognosis of GGS arthritis is favorable with 5% mortality.²⁶

Conclusion

Septic arthritis and infectious tenosynovitis are readily treatable with low mortality if promptly identified. Identification can be masked by other medical conditions, such as RA and psoriasis, and their associated immunosuppressive treatment. Bilateral EPL tendon rupture may be a complication of RA, particularly with an underlying septic arthritis and infectious tenosynovitis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Estimates of the annual incidence of sudden cardiac death (SCD) vary from 180,000 to  456,000.¹ About 80% to 85% of the cases of SCD are due to a ventricular arrhythmia.² One type of ventricular arrhythmia, torsades de pointes (TdP), is caused by a prolongation of the QT interval. Because the QT interval is dependent on heart rate, clinicians use the corrected QT (QTc) interval, which has been adjusted for heart rate. The HHS recommends using a gender-independent threshold of 450 msec to define QTc prolongation when conducting research.³ Additionally, a QTc interval > 500 msec is associated with an increased risk for TdP.⁴ Female gender, hypokalemia, hypomagnesemia, and medical conditions such as congenital long QT syndrome, heart failure, and left ventricular hypertrophy can predispose a person to QTc prolongation.⁵

Methadone is a synthetic opioid used for chronic pain management or for opioid or heroin addiction. In 2006, the FDA issued a public health advisory, which was followed by the addition of a black box warning to the labeling of methadone regarding cardiac abnormalities that caused serious adverse effects, including QT prolongation, TdP, and death.⁶ Additional recommendations to evaluate the pharmacokinetic and pharmacodynamic drug interactions were also added to the labeling.

Related: Reducing Opioid Use for Chronic Pain

Several prospective studies, cross-sectional studies, and retrospective reviews have reported QTc prolongation with methadone.^7-14 Many cases of QTc prolongation and TdP have been in patients receiving methadone in large doses (> 100 mg/d); however, incidences have also occurred in those receiving typical doses of methadone for addiction treatment.^8,15,16 Multiple studies have demonstrated that methadone-induced QTc prolongation is dose-dependent.^8,17-20 In an observational study of 90 subjects who were undergoing methadone maintenance treatment, the subjects taking < 60 mg/d of methadone had a 7.7 msec prolongation of the QTc interval, which was significantly less QTc prolongation than in those receiving 60 mg/d to 109 mg/d (15.6 msec, P < .001) and 110 mg/d to 150 mg/d (17.4 msec, P = .001).²¹

However, in the current literature there are few studies evaluating the QTc prolonging effects of methadone when used in lower doses for pain, such as those used at the Southern Arizona VA Health Care System (SAVAHCS).⁸ Given the increased risk of cardiac arrhythmias, it is important to understand the effects of methadone on the QTc interval in a veteran patient population using methadone at lower doses for pain. Understanding this risk can help clinicians develop strategies and protocols for the safe use of methadone.

The purpose of this study was to evaluate the effect of methadone on the QTc interval among patients at SAVAHCS. The primary objective was to determine whether methadone prolongs the QTc interval when used for pain. Secondary outcomes included evaluations of the (1) QTc interval when stratified by the QTc interval obtained while prescribed methadone; (2) effects of low, medium, and high doses of methadone on the QTc interval; (3) effects of the concurrent use of QTc prolonging medications on the QTc interval; and (4) effects of the concurrent use of strong inhibitors of methadone clearance on the QTc interval. It was hypothesized that methadone, when used for pain, causes a significant prolongation of the QTc interval, and methadone-induced QTc prolongation is dose-dependent. It was also hypothesized that the QTc interval will be more prolonged when methadone is used concurrently with other medications with a known or conditional risk of TdP or with medications that are strong inhibitors of methadone clearance.

Methods

Full Institutional Review Board approval was obtained prior to initiating this retrospective pre-post study. This study used the electronic medical records (EMRs) of SAVAHCS from July 1, 2004, to July 31, 2012, to compare the QTc interval of patients on stable doses of methadone with the baseline QTc interval. Patients included were aged 18 to 87 years and dispensed a new prescription for methadone between January 1, 2006, and July 31, 2010. Patients must have been adherent to methadone as defined by a medication possession ratio of ≥ 0.8. Patients without a baseline electrocardiogram (ECG) within the 18 months prior to starting methadone, without at least 1 follow-up ECG 7 days to 2 years after the initial prescription, who had a diagnosis of heart failure, or used an implanted cardiac defibrillator or pacemaker as indicated by ICD-9 codes were excluded.

Information collected from the EMR included demographics (age and gender), the QTc interval before starting methadone (pre-QTc), the first QTc interval recorded while prescribed methadone (post-QTc) at a stable dose (defined as ≥ 7 days without a dose change), methadone total daily dose at the time of the post-QTc, concurrent QTc prolonging medications used at the time of each ECG, time elapsed between pre-QTc and post-QTc, time elapsed between the pre-QTc and initiation of methadone, and time elapsed between starting methadone and the post-QTc. All ECGs were recorded using a 12-lead ECG by the MAC 5500 Resting ECG Analysis System (GE Healthcare), which automatically calculates the QTc interval.

For the primary outcome, the mean pre-QTc and post-QTc were compared. These QTc intervals were further analyzed as secondary outcomes. The mean pre-QTc and post-QTc were compared when stratified by post-QTc of < 450 msec, 450 msec to 499 msec, and ≥ 500 msec. To analyze the dose effect of methadone, the mean pre-QTc and post-QTc were compared when stratified by methadone total daily dose: low (≤ 15 mg/d), medium (16-30 mg/d), and high (> 30 mg/d). Dose ranges were based on typical SAVAHCS prescriptions.

An additional secondary outcome was to determine the effect of the concurrent use of QTc prolonging medications on the QTc interval. The medications the subject was taking at the time of each ECG were reviewed to determine whether any of the medications were listed as Drugs with a risk of Torsades de Pointes or Drugs with a conditional risk of Torsades de Pointes on the CredibleMeds website.^22,23 Drugs with a conditional risk of TdP are defined as drugs in which there is evidence that the drug prolongs the QTc interval and has a risk of TdP but only under certain conditions, such as high doses or drug interactions. The mean pre-QTc with and without concurrent use of QTc prolonging medications was compared with the mean post-QTc with QTc prolonging medications in addition to methadone.

Because methadone is extensively metabolized by cytochrome P450 3A4 (CYP3A4), another outcome was to determine the effect of the concurrent use of strong CYP3A4 inhibitors on the QTc interval. The medications the subject was taking at the time of each ECG were reviewed to determine whether any of the medications were listed as strong CYP3A4 inhibitors in The Pharmacist’s Letter/The Prescriber’s Letter.²⁴ The mean pre-QTc with and without the concurrent use of strong CYP3A4 inhibitors was compared with the mean post-QTc with strong CYP3A4 inhibitors in addition to methadone.

Related: Pharmacist-Managed Collaborative Practice for Chronic Stable Angina

The primary and secondary outcomes were compared using a paired t test and descriptive statistics; demographics were analyzed using descriptive statistics. Based on the findings of a previous study, a minimum of 8 patients were needed to meet a power of 0.8 with an alpha 0.05 and a medium effect size when comparing the mean pre-QTc and post-QTc for the primary outcome.²⁵

Results

Of 893 EMRs reviewed, 93 met inclusion criteria (Figure 1). The main reason for exclusion was lack of pre-QTc and/or post-QTc (n = 544). The mean age was 58 years (± 10 years), 92% were male, and the mean daily methadone dose at the time of the post-QTc was 29 mg (5 mg-160 mg) (Table 1). Thirty patients were prescribed ≥ 1 QTc prolonging medication at the time of the pre-QTc, 40 patients were prescribed ≥ 1 QTc prolonging medication at the time of the post-QTc, and 0 patients were prescribed a strong CYP3A4 inhibitor at the time of either QTc. There was an average of 151 days (0-554 days) between the pre-QTc and methadone initiation, 161 days (8-664 days) between methadone initiation and the post-QTc, and 312 days (10-1,003 days) between the pre-QTc and post-QTc.

For the primary outcome, there was no significant increase in the QTc interval when comparing the pre-QTc and post-QTc (432 ± 26 msec vs 436 ± 28 msec, P = .221) (Figure 2). When stratified by post QTc, the group of patients with a post-QTc < 450 msec (n = 66) and the group with a post-QTc of ≥ 500 msec (n = 2) had no significant increase in the QTc interval (427 ± 26 msec vs 422 ± 16 msec and 422 ± 18 msec vs 533 ± 21 msec, respectively; P > .05) (Table 2). For the group of patients with a post-QTc of 450 msec to 499 msec (n = 25), methadone significantly prolonged the QTc interval (447 ± 21 msec vs 465 ± 12 msec, P < .001).

When stratified by methadone daily dose of ≤ 15 mg (n = 45), 16 mg to 30 mg (n = 27), and > 30 mg (n = 21), methadone did not significantly prolong the QTc interval in any group (428 ± 29 msec vs 430 ± 25 msec, 436 ± 16 msec vs 439 ± 21 msec, 437 ± 29 msec vs 446 ± 39 msec, respectively; P > .05) (Table 3). For the group of patients using ≥ 1 QTc prolonging medication at the time of the post-QTc and no QTc prolonging medications at the time of the pre-QTc, the addition of methadone did not significantly increase the QTc interval when compared with the pre-QTc (n = 15; 425 ± 23 msec vs 437 ± 31 msec, respectively; P > .05) (Table 4). For the group of patients prescribed ≥ 1 QTc prolonging medication at the pre-QTc and post-QTc, methadone did not significantly prolong the QTc interval (n = 25; 437 ± 32 msec vs 441 ± 33 msec, respectively; P > .05) (Table 5). No subjects were using strong CYP3A4 inhibitors; therefore, the effect of strong CYP3A4 inhibitors could not be assessed.