Brian F. Mandell, MD, PhD

New laboratory tests seem to go through a life cycle. At first, some are used mainly by subspecialists, who became aware of them through early clinical trials or studies presented at specialty meetings. The general medical community adopts their use after noting that they are being ordered by consultants or were used in important published studies.

Sometimes, a new test is significantly better than the older ones, and clinical pathologists and subspecialists encourage us to use it. Sometimes, a new test may represent a breakthrough in the understanding of the pathophysiology of a disease, and its use is promoted by clinicians with special interest in that disease. Testing for serum troponin, as discussed by Sebastian et al in this issue of the Journal, is an example primarily of the first situation, while testing for antineutrophil cytoplasmic antibodies (ANCA) and immunoglobulin G4 are two of many examples of the second.

Once a test comes into widespread use, its accuracy and reproducibility can be problematic. The assay itself may have inherent weaknesses, or techniques may not be standardized among different laboratories; think about diagnosis of the antiphospholipid antibody syndrome. Standardization of laboratory techniques can often be achieved. For troponin, this remains a problem, though small, for patients whose serum is tested in different laboratories or for clinicians trying to directly compare different clinical trial results; but it doesn’t affect clinical decision-making when longitudinally following a specific patient through a single hospitalization.

In its mature years, as a useful novel test becomes widely used, it may alter how we view the management and pathophysiology of a disease. For example, in the days when postoperative myocardial infarction (MI) was diagnosed by electrocardiographic changes and then by elevations in creatine kinase (CK) and alterations in the ratio of  aspartate aminotransferase (AST) to alanine aminotransferase (ALT), the peak in MI incidence was thought to occur several days after surgery. With the advent of CK isoenzymes and then cardiac myocyte-derived troponin, it became apparent that perioperative myocardial injury occurs more in a time frame of hours after surgery. Laboratory data dovetailed with pathologic and angiographic data indicating that the mechanism of MI in the perioperative setting for many patients is different than in “native” MI. As newer, highly sensitive troponin assays are introduced, they may further our understanding of mechanisms of cardiac myocyte membrane injury and tissue necrosis, and may further clarify (or blur) the distinction between the two.

Often, a widely used test is ordered in clinical situations that were not specifically evaluated during initial studies of the test and early use by specialists. Case reports of unexpected results then appear in the literature. Intrinsic test performance may occasionally be influenced in unanticipated ways (eg, rheumatoid factor can affect test results of some troponin and cryptococcal antigen assays), but more frequently it is the definition of “normal” and interpretation of the test results in specific clinical conditions that are affected. For example, troponin levels are higher in patients with chronic kidney disease and severe sepsis. These elevations may be explained by decreased renal clearance of detected fragments of troponin but may also reflect subclinical myocardial injury related to circulating cytokines or other factors. Elevation of troponins in patients with these and other conditions has correlated with poorer outcomes. Thus, in some settings, elevated circulating troponin has greater prognostic than diagnostic significance.

Recognizing imperfect test specificity (false-positive results) is critical when using a test in complex clinical situations. This can be especially challenging when using indirect serologic tests: consider the many reasons for “false-positive” antinuclear antibody, ANCA, and rheumatoid factor test results. But it can also be a challenge when trying to use a targeted test like troponin to distinguish between MI, sepsis, and pulmonary embolism as the cause of acute hypotension.

Many routinely ordered tests require more nuanced interpretation than simply checking the value against the defined laboratory “normal.” These nuances may be well known to those who order the test often or to specialists, but not to all. Familiarity with tests can also result in a subliminal assumption that we fully understand their characteristics and can lead to misinterpretation of results. There are forgotten critical concepts about tests that are ordered extremely commonly: eg, AST and ALT do not come only from the liver and do not reflect “liver function.” Liver biopsy is unlikely to provide the explanation for a myositis patient’s sense of weakness, even if the aminotransferase levels are elevated in the several-hundred range.

A CALL FOR MANUSCRIPTS

I invite you to draw on your personal experience and the literature and submit short manuscripts that address the nuanced interpretation, limitations, and cost of specific laboratory tests. As with all submissions, these will undergo peer review for content accuracy, as well as relevancy and utility for our core readership before being considered for publication.

New laboratory tests seem to go through a life cycle. At first, some are used mainly by subspecialists, who became aware of them through early clinical trials or studies presented at specialty meetings. The general medical community adopts their use after noting that they are being ordered by consultants or were used in important published studies.

Sometimes, a new test is significantly better than the older ones, and clinical pathologists and subspecialists encourage us to use it. Sometimes, a new test may represent a breakthrough in the understanding of the pathophysiology of a disease, and its use is promoted by clinicians with special interest in that disease. Testing for serum troponin, as discussed by Sebastian et al in this issue of the Journal, is an example primarily of the first situation, while testing for antineutrophil cytoplasmic antibodies (ANCA) and immunoglobulin G4 are two of many examples of the second.

Once a test comes into widespread use, its accuracy and reproducibility can be problematic. The assay itself may have inherent weaknesses, or techniques may not be standardized among different laboratories; think about diagnosis of the antiphospholipid antibody syndrome. Standardization of laboratory techniques can often be achieved. For troponin, this remains a problem, though small, for patients whose serum is tested in different laboratories or for clinicians trying to directly compare different clinical trial results; but it doesn’t affect clinical decision-making when longitudinally following a specific patient through a single hospitalization.

In its mature years, as a useful novel test becomes widely used, it may alter how we view the management and pathophysiology of a disease. For example, in the days when postoperative myocardial infarction (MI) was diagnosed by electrocardiographic changes and then by elevations in creatine kinase (CK) and alterations in the ratio of  aspartate aminotransferase (AST) to alanine aminotransferase (ALT), the peak in MI incidence was thought to occur several days after surgery. With the advent of CK isoenzymes and then cardiac myocyte-derived troponin, it became apparent that perioperative myocardial injury occurs more in a time frame of hours after surgery. Laboratory data dovetailed with pathologic and angiographic data indicating that the mechanism of MI in the perioperative setting for many patients is different than in “native” MI. As newer, highly sensitive troponin assays are introduced, they may further our understanding of mechanisms of cardiac myocyte membrane injury and tissue necrosis, and may further clarify (or blur) the distinction between the two.

Often, a widely used test is ordered in clinical situations that were not specifically evaluated during initial studies of the test and early use by specialists. Case reports of unexpected results then appear in the literature. Intrinsic test performance may occasionally be influenced in unanticipated ways (eg, rheumatoid factor can affect test results of some troponin and cryptococcal antigen assays), but more frequently it is the definition of “normal” and interpretation of the test results in specific clinical conditions that are affected. For example, troponin levels are higher in patients with chronic kidney disease and severe sepsis. These elevations may be explained by decreased renal clearance of detected fragments of troponin but may also reflect subclinical myocardial injury related to circulating cytokines or other factors. Elevation of troponins in patients with these and other conditions has correlated with poorer outcomes. Thus, in some settings, elevated circulating troponin has greater prognostic than diagnostic significance.

Recognizing imperfect test specificity (false-positive results) is critical when using a test in complex clinical situations. This can be especially challenging when using indirect serologic tests: consider the many reasons for “false-positive” antinuclear antibody, ANCA, and rheumatoid factor test results. But it can also be a challenge when trying to use a targeted test like troponin to distinguish between MI, sepsis, and pulmonary embolism as the cause of acute hypotension.

Many routinely ordered tests require more nuanced interpretation than simply checking the value against the defined laboratory “normal.” These nuances may be well known to those who order the test often or to specialists, but not to all. Familiarity with tests can also result in a subliminal assumption that we fully understand their characteristics and can lead to misinterpretation of results. There are forgotten critical concepts about tests that are ordered extremely commonly: eg, AST and ALT do not come only from the liver and do not reflect “liver function.” Liver biopsy is unlikely to provide the explanation for a myositis patient’s sense of weakness, even if the aminotransferase levels are elevated in the several-hundred range.

A CALL FOR MANUSCRIPTS

I invite you to draw on your personal experience and the literature and submit short manuscripts that address the nuanced interpretation, limitations, and cost of specific laboratory tests. As with all submissions, these will undergo peer review for content accuracy, as well as relevancy and utility for our core readership before being considered for publication.

New laboratory tests seem to go through a life cycle. At first, some are used mainly by subspecialists, who became aware of them through early clinical trials or studies presented at specialty meetings. The general medical community adopts their use after noting that they are being ordered by consultants or were used in important published studies.

Sometimes, a new test is significantly better than the older ones, and clinical pathologists and subspecialists encourage us to use it. Sometimes, a new test may represent a breakthrough in the understanding of the pathophysiology of a disease, and its use is promoted by clinicians with special interest in that disease. Testing for serum troponin, as discussed by Sebastian et al in this issue of the Journal, is an example primarily of the first situation, while testing for antineutrophil cytoplasmic antibodies (ANCA) and immunoglobulin G4 are two of many examples of the second.

Once a test comes into widespread use, its accuracy and reproducibility can be problematic. The assay itself may have inherent weaknesses, or techniques may not be standardized among different laboratories; think about diagnosis of the antiphospholipid antibody syndrome. Standardization of laboratory techniques can often be achieved. For troponin, this remains a problem, though small, for patients whose serum is tested in different laboratories or for clinicians trying to directly compare different clinical trial results; but it doesn’t affect clinical decision-making when longitudinally following a specific patient through a single hospitalization.

In its mature years, as a useful novel test becomes widely used, it may alter how we view the management and pathophysiology of a disease. For example, in the days when postoperative myocardial infarction (MI) was diagnosed by electrocardiographic changes and then by elevations in creatine kinase (CK) and alterations in the ratio of  aspartate aminotransferase (AST) to alanine aminotransferase (ALT), the peak in MI incidence was thought to occur several days after surgery. With the advent of CK isoenzymes and then cardiac myocyte-derived troponin, it became apparent that perioperative myocardial injury occurs more in a time frame of hours after surgery. Laboratory data dovetailed with pathologic and angiographic data indicating that the mechanism of MI in the perioperative setting for many patients is different than in “native” MI. As newer, highly sensitive troponin assays are introduced, they may further our understanding of mechanisms of cardiac myocyte membrane injury and tissue necrosis, and may further clarify (or blur) the distinction between the two.

Often, a widely used test is ordered in clinical situations that were not specifically evaluated during initial studies of the test and early use by specialists. Case reports of unexpected results then appear in the literature. Intrinsic test performance may occasionally be influenced in unanticipated ways (eg, rheumatoid factor can affect test results of some troponin and cryptococcal antigen assays), but more frequently it is the definition of “normal” and interpretation of the test results in specific clinical conditions that are affected. For example, troponin levels are higher in patients with chronic kidney disease and severe sepsis. These elevations may be explained by decreased renal clearance of detected fragments of troponin but may also reflect subclinical myocardial injury related to circulating cytokines or other factors. Elevation of troponins in patients with these and other conditions has correlated with poorer outcomes. Thus, in some settings, elevated circulating troponin has greater prognostic than diagnostic significance.

Recognizing imperfect test specificity (false-positive results) is critical when using a test in complex clinical situations. This can be especially challenging when using indirect serologic tests: consider the many reasons for “false-positive” antinuclear antibody, ANCA, and rheumatoid factor test results. But it can also be a challenge when trying to use a targeted test like troponin to distinguish between MI, sepsis, and pulmonary embolism as the cause of acute hypotension.

Many routinely ordered tests require more nuanced interpretation than simply checking the value against the defined laboratory “normal.” These nuances may be well known to those who order the test often or to specialists, but not to all. Familiarity with tests can also result in a subliminal assumption that we fully understand their characteristics and can lead to misinterpretation of results. There are forgotten critical concepts about tests that are ordered extremely commonly: eg, AST and ALT do not come only from the liver and do not reflect “liver function.” Liver biopsy is unlikely to provide the explanation for a myositis patient’s sense of weakness, even if the aminotransferase levels are elevated in the several-hundred range.

A CALL FOR MANUSCRIPTS

I invite you to draw on your personal experience and the literature and submit short manuscripts that address the nuanced interpretation, limitations, and cost of specific laboratory tests. As with all submissions, these will undergo peer review for content accuracy, as well as relevancy and utility for our core readership before being considered for publication.

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

It is difficult to provide enough information for informed consent and to ensure that the patient and his or her family fully understand what we are saying. Patients often come in with their own preferences and biases based on anecdote, dinner conversations, or the Internet. The physician must push hard to dispel a patient’s bias with the facts, while recognizing that we too regularly present “facts” and recommendations colored by our own biases based on anecdotal experience, professional ritual, and intellectual hubris.

Two articles in this issue of the Journal, one by Dr. Michael Rothberg¹ and the other by Dr. Umesh Khot,² examine percutaneous coronary intervention (PCI) in patients with stable chronic angina. Both discuss the findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³ and how to use these findings in helping patients decide whether to undergo PCI.

Rothberg and Khot agree that in the COURAGE trial, PCI effectively if not completely reduced angina but did not decrease the likelihood of death or subsequent myocardial infarction (MI). Patients were excluded from the study if they had a likelihood of left main disease, heart failure, or severe angina. All underwent catheterization, and all were given optimal medical therapy. Thus, the trial results do not directly relate to every patient with stable angina.

While the patient may find it confusing that angina and the risk of MI are not reduced in parallel, since both are due to atherosclerosis, their dynamic pathophysiology is different. The COURAGE results are the mirror image of those in some early studies of aspirin in coronary disease, in which aspirin reduced the incidence of MI but did not significantly affect angina.

In view of the COURAGE results, Rothberg seems surprised that PCI continues to be frequently used in patients with stable angina. He points out that according to some surveys,⁴ not all cardiologists have embraced these (and other similar study) results. But as Khot notes, the use of PCI in stable angina has decreased. More interesting to me were the results of an online study conducted by Rothberg and colleagues in which participants were provided different background information about PCI.⁵ Even if given explicit information that PCI did not prevent MI, a fair number still said they would choose it and still believed it would prevent this outcome. Bias clearly influences what patients read and hear, and they bring these biases into the shared decision-making process.

While some patients may not fully understand PCI’s risks and putative benefits, others may choose it because of their personal knowledge of others’ experience or perhaps because the “softer” benefits demonstrated in COURAGE and other trials are important to them. As outlined by Khot, patients who underwent PCI had more rapid relief of angina symptoms, possibly experienced greater relief of symptoms even if incomplete, and needed less medication. More patients needed urgent revascularization in the medical group than in the PCI group. Rothberg appropriately notes that this did not “equate to a reduction in the rate of MI,” but to some patients (eg, international travelers, caregivers) this higher possibility of needing an urgent procedure may be enough to make them want the initial elective procedure. While patients should be told that many of the patients in the medical therapy group in COURAGE crossed over to get PCI (16% at 1 year, and about 1/3 after a median of 4.6 years of follow-up), a patient for whom avoiding invasive procedures is the highest priority will likely “hear” that he or she has a 2/3 likelihood of not needing PCI without being at increased risk of death or MI with medical therapy.

As Rothberg points out, “providing information alone is not enough.” The patient needs to recognize, verbalize, and perhaps rank his or her own biases, fears, and desires. Equally important, we need to recognize our own biases and not let them overshadow the patient’s concerns.

I urge you to read both articles, not only because they offer excellent critiques of the COURAGE results and what they mean in practice, but also because they should make us reflect on how often and well we engage in shared decision-making with our patients. Reading these made me realize that I need to better understand my patients’ concerns. Discussing my interpretation of clinical study results, no matter how sophisticated or correct, and then offering a recommendation without fully understanding the patient’s treatment goals is not shared decision-making. The seemingly “wrong” decision may be right for the patient.

It is difficult to provide enough information for informed consent and to ensure that the patient and his or her family fully understand what we are saying. Patients often come in with their own preferences and biases based on anecdote, dinner conversations, or the Internet. The physician must push hard to dispel a patient’s bias with the facts, while recognizing that we too regularly present “facts” and recommendations colored by our own biases based on anecdotal experience, professional ritual, and intellectual hubris.

Two articles in this issue of the Journal, one by Dr. Michael Rothberg¹ and the other by Dr. Umesh Khot,² examine percutaneous coronary intervention (PCI) in patients with stable chronic angina. Both discuss the findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³ and how to use these findings in helping patients decide whether to undergo PCI.

Rothberg and Khot agree that in the COURAGE trial, PCI effectively if not completely reduced angina but did not decrease the likelihood of death or subsequent myocardial infarction (MI). Patients were excluded from the study if they had a likelihood of left main disease, heart failure, or severe angina. All underwent catheterization, and all were given optimal medical therapy. Thus, the trial results do not directly relate to every patient with stable angina.

While the patient may find it confusing that angina and the risk of MI are not reduced in parallel, since both are due to atherosclerosis, their dynamic pathophysiology is different. The COURAGE results are the mirror image of those in some early studies of aspirin in coronary disease, in which aspirin reduced the incidence of MI but did not significantly affect angina.

In view of the COURAGE results, Rothberg seems surprised that PCI continues to be frequently used in patients with stable angina. He points out that according to some surveys,⁴ not all cardiologists have embraced these (and other similar study) results. But as Khot notes, the use of PCI in stable angina has decreased. More interesting to me were the results of an online study conducted by Rothberg and colleagues in which participants were provided different background information about PCI.⁵ Even if given explicit information that PCI did not prevent MI, a fair number still said they would choose it and still believed it would prevent this outcome. Bias clearly influences what patients read and hear, and they bring these biases into the shared decision-making process.

While some patients may not fully understand PCI’s risks and putative benefits, others may choose it because of their personal knowledge of others’ experience or perhaps because the “softer” benefits demonstrated in COURAGE and other trials are important to them. As outlined by Khot, patients who underwent PCI had more rapid relief of angina symptoms, possibly experienced greater relief of symptoms even if incomplete, and needed less medication. More patients needed urgent revascularization in the medical group than in the PCI group. Rothberg appropriately notes that this did not “equate to a reduction in the rate of MI,” but to some patients (eg, international travelers, caregivers) this higher possibility of needing an urgent procedure may be enough to make them want the initial elective procedure. While patients should be told that many of the patients in the medical therapy group in COURAGE crossed over to get PCI (16% at 1 year, and about 1/3 after a median of 4.6 years of follow-up), a patient for whom avoiding invasive procedures is the highest priority will likely “hear” that he or she has a 2/3 likelihood of not needing PCI without being at increased risk of death or MI with medical therapy.

As Rothberg points out, “providing information alone is not enough.” The patient needs to recognize, verbalize, and perhaps rank his or her own biases, fears, and desires. Equally important, we need to recognize our own biases and not let them overshadow the patient’s concerns.

I urge you to read both articles, not only because they offer excellent critiques of the COURAGE results and what they mean in practice, but also because they should make us reflect on how often and well we engage in shared decision-making with our patients. Reading these made me realize that I need to better understand my patients’ concerns. Discussing my interpretation of clinical study results, no matter how sophisticated or correct, and then offering a recommendation without fully understanding the patient’s treatment goals is not shared decision-making. The seemingly “wrong” decision may be right for the patient.

It is difficult to provide enough information for informed consent and to ensure that the patient and his or her family fully understand what we are saying. Patients often come in with their own preferences and biases based on anecdote, dinner conversations, or the Internet. The physician must push hard to dispel a patient’s bias with the facts, while recognizing that we too regularly present “facts” and recommendations colored by our own biases based on anecdotal experience, professional ritual, and intellectual hubris.

Two articles in this issue of the Journal, one by Dr. Michael Rothberg¹ and the other by Dr. Umesh Khot,² examine percutaneous coronary intervention (PCI) in patients with stable chronic angina. Both discuss the findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³ and how to use these findings in helping patients decide whether to undergo PCI.

Rothberg and Khot agree that in the COURAGE trial, PCI effectively if not completely reduced angina but did not decrease the likelihood of death or subsequent myocardial infarction (MI). Patients were excluded from the study if they had a likelihood of left main disease, heart failure, or severe angina. All underwent catheterization, and all were given optimal medical therapy. Thus, the trial results do not directly relate to every patient with stable angina.

While the patient may find it confusing that angina and the risk of MI are not reduced in parallel, since both are due to atherosclerosis, their dynamic pathophysiology is different. The COURAGE results are the mirror image of those in some early studies of aspirin in coronary disease, in which aspirin reduced the incidence of MI but did not significantly affect angina.

In view of the COURAGE results, Rothberg seems surprised that PCI continues to be frequently used in patients with stable angina. He points out that according to some surveys,⁴ not all cardiologists have embraced these (and other similar study) results. But as Khot notes, the use of PCI in stable angina has decreased. More interesting to me were the results of an online study conducted by Rothberg and colleagues in which participants were provided different background information about PCI.⁵ Even if given explicit information that PCI did not prevent MI, a fair number still said they would choose it and still believed it would prevent this outcome. Bias clearly influences what patients read and hear, and they bring these biases into the shared decision-making process.

While some patients may not fully understand PCI’s risks and putative benefits, others may choose it because of their personal knowledge of others’ experience or perhaps because the “softer” benefits demonstrated in COURAGE and other trials are important to them. As outlined by Khot, patients who underwent PCI had more rapid relief of angina symptoms, possibly experienced greater relief of symptoms even if incomplete, and needed less medication. More patients needed urgent revascularization in the medical group than in the PCI group. Rothberg appropriately notes that this did not “equate to a reduction in the rate of MI,” but to some patients (eg, international travelers, caregivers) this higher possibility of needing an urgent procedure may be enough to make them want the initial elective procedure. While patients should be told that many of the patients in the medical therapy group in COURAGE crossed over to get PCI (16% at 1 year, and about 1/3 after a median of 4.6 years of follow-up), a patient for whom avoiding invasive procedures is the highest priority will likely “hear” that he or she has a 2/3 likelihood of not needing PCI without being at increased risk of death or MI with medical therapy.

As Rothberg points out, “providing information alone is not enough.” The patient needs to recognize, verbalize, and perhaps rank his or her own biases, fears, and desires. Equally important, we need to recognize our own biases and not let them overshadow the patient’s concerns.

I urge you to read both articles, not only because they offer excellent critiques of the COURAGE results and what they mean in practice, but also because they should make us reflect on how often and well we engage in shared decision-making with our patients. Reading these made me realize that I need to better understand my patients’ concerns. Discussing my interpretation of clinical study results, no matter how sophisticated or correct, and then offering a recommendation without fully understanding the patient’s treatment goals is not shared decision-making. The seemingly “wrong” decision may be right for the patient.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

For many patients, Raynaud symptoms are mild enough to not even mention to their primary care provider, and conversely, there is little reason for most clinicians to routinely inquire about such symptoms. So it may surprise some readers to read about the nuances of diagnosis and treatment discussed by Shapiro and Wigley in this issue of the Journal.

To a rheumatologist, Raynaud phenomenon, particularly of recent onset in an adult, raises the specter of an underlying systemic inflammatory disease. The phenomenon is not linked to a specific diagnosis; it is associated with lupus, rheumatoid arthritis, cryoglobulinemia, inflammatory myopathy, Sjögren syndrome, and, in its severe form, with the scleroderma syndromes. We focus on differentiating between these rheumatic disorders once we have discarded nonrheumatic causes such as atherosclerotic arterial disease, carcinoma, embolism, Buerger disease, medications, smoking, or thrombosis.

But rheumatologists are toward the bottom of the diagnostic funnel—we see these patients when an underlying disease is already suspected. The real challenge is for the primary care providers who first recognize the digital vasospasm on examination or are told of the symptoms by their patient. These clinicians need to know which initial reflexive actions are warranted and which can wait, for, as noted by Shapiro and Wigley, there are several options.

The first action is to try to determine the timeline, although Raynaud disease often has an insidious onset or the patient doesn’t recall the onset. New and sudden onset likely has a stronger association with an underlying disease. A focused physical examination should look for digital stigmata of ischemic damage; the presence of digital ulcers or healed digital pits indicates a possible vascular occlusive component in addition to the vascular spasm. This strongly suggests scleroderma or Buerger disease, as tissue damage doesn’t occur in (primary) Raynaud disease or generally even with Raynaud phenomenon associated with lupus or other rheumatic disorders. Sclerodactyly should be looked for: diffuse finger puffiness, skin-tightening, or early signs such as loss of the usual finger skin creases. Telangiectasia (not vascular spiders or cherry angiomata) should be searched for, particularly on the palms, face, and inner lips, as these vascular lesions are common in patients with limited scleroderma. Careful auscultation for basilar lung crackles should be done. Distal pulses should all be assessed, and bruits in the neck, abdomen and inguinal areas should be carefully sought.

Patients should be questioned about any symptom-associated reduction in exercise tolerance and particularly about trouble swallowing, “heartburn,” and symptoms of reflux. Although patients with Raynaud disease may have demonstrable esophageal dysmotility, the presence of significant, new, or worsened symptoms raises the concern of scleroderma. Patients should be asked about symptoms of malabsorption. Specific questioning should be directed at eliciting a history of joint stiffness and especially muscle weakness. The latter can be approached by inquiring about new or progressive difficulty in specific tasks such as walking up steps, brushing hair, and arising from low chairs or the toilet. Distinguishing muscle weakness from general fatigue is not always easy, but it is important.

Shapiro and Wigley discuss the extremely useful evaluation of nailfold capillaries, which can be done with a standard magnifier or ophthalmoscope. This is very valuable to help predict the development or current presence of a systemic rheumatic disease. But this is not a technique that most clinicians are familiar with. A potentially useful surrogate or adjunctive test, especially in the setting of new-onset Raynaud, is the antinuclear antibody (ANA) test; I prefer the immunofluorescent assay. While a positive test alone (with Raynaud) does not define the presence of any rheumatic disease, several older studies suggest that patients with a new onset of Raynaud phenomenon and a positive ANA test are more likely to develop a systemic autoimmune disorder than if the test is negative. Those who do so (and this is far from all) are most likely to have the disease manifest within a few years. Hence, if the ANA test is positive but the history, physical examination, and limited laboratory testing (complete blood cell count with differential, complete metabolic panel, creatine kinase, and urinalysis) are normal, it is reasonable to reexamine the patient in 3 months and then every 6 months for 2 to 3 years, repeating the focused history and physical examination. It is also reasonable at some point to refer these patients to a rheumatologist.

Since Raynaud phenomenon is common, and the associated severe rheumatic disorders associated with it are rare, it is easy to not recognize Raynaud phenomenon as a clue to the onset of a potentially severe systemic disease. Yet with a few simple questions, a focused examination, and minimal laboratory testing, patients who are more likely to harbor a systemic disease can usually be treated symptomatically if necessary, and appropriately triaged to observation or for subspecialty referral.

For many patients, Raynaud symptoms are mild enough to not even mention to their primary care provider, and conversely, there is little reason for most clinicians to routinely inquire about such symptoms. So it may surprise some readers to read about the nuances of diagnosis and treatment discussed by Shapiro and Wigley in this issue of the Journal.

To a rheumatologist, Raynaud phenomenon, particularly of recent onset in an adult, raises the specter of an underlying systemic inflammatory disease. The phenomenon is not linked to a specific diagnosis; it is associated with lupus, rheumatoid arthritis, cryoglobulinemia, inflammatory myopathy, Sjögren syndrome, and, in its severe form, with the scleroderma syndromes. We focus on differentiating between these rheumatic disorders once we have discarded nonrheumatic causes such as atherosclerotic arterial disease, carcinoma, embolism, Buerger disease, medications, smoking, or thrombosis.

But rheumatologists are toward the bottom of the diagnostic funnel—we see these patients when an underlying disease is already suspected. The real challenge is for the primary care providers who first recognize the digital vasospasm on examination or are told of the symptoms by their patient. These clinicians need to know which initial reflexive actions are warranted and which can wait, for, as noted by Shapiro and Wigley, there are several options.

The first action is to try to determine the timeline, although Raynaud disease often has an insidious onset or the patient doesn’t recall the onset. New and sudden onset likely has a stronger association with an underlying disease. A focused physical examination should look for digital stigmata of ischemic damage; the presence of digital ulcers or healed digital pits indicates a possible vascular occlusive component in addition to the vascular spasm. This strongly suggests scleroderma or Buerger disease, as tissue damage doesn’t occur in (primary) Raynaud disease or generally even with Raynaud phenomenon associated with lupus or other rheumatic disorders. Sclerodactyly should be looked for: diffuse finger puffiness, skin-tightening, or early signs such as loss of the usual finger skin creases. Telangiectasia (not vascular spiders or cherry angiomata) should be searched for, particularly on the palms, face, and inner lips, as these vascular lesions are common in patients with limited scleroderma. Careful auscultation for basilar lung crackles should be done. Distal pulses should all be assessed, and bruits in the neck, abdomen and inguinal areas should be carefully sought.

Patients should be questioned about any symptom-associated reduction in exercise tolerance and particularly about trouble swallowing, “heartburn,” and symptoms of reflux. Although patients with Raynaud disease may have demonstrable esophageal dysmotility, the presence of significant, new, or worsened symptoms raises the concern of scleroderma. Patients should be asked about symptoms of malabsorption. Specific questioning should be directed at eliciting a history of joint stiffness and especially muscle weakness. The latter can be approached by inquiring about new or progressive difficulty in specific tasks such as walking up steps, brushing hair, and arising from low chairs or the toilet. Distinguishing muscle weakness from general fatigue is not always easy, but it is important.

Shapiro and Wigley discuss the extremely useful evaluation of nailfold capillaries, which can be done with a standard magnifier or ophthalmoscope. This is very valuable to help predict the development or current presence of a systemic rheumatic disease. But this is not a technique that most clinicians are familiar with. A potentially useful surrogate or adjunctive test, especially in the setting of new-onset Raynaud, is the antinuclear antibody (ANA) test; I prefer the immunofluorescent assay. While a positive test alone (with Raynaud) does not define the presence of any rheumatic disease, several older studies suggest that patients with a new onset of Raynaud phenomenon and a positive ANA test are more likely to develop a systemic autoimmune disorder than if the test is negative. Those who do so (and this is far from all) are most likely to have the disease manifest within a few years. Hence, if the ANA test is positive but the history, physical examination, and limited laboratory testing (complete blood cell count with differential, complete metabolic panel, creatine kinase, and urinalysis) are normal, it is reasonable to reexamine the patient in 3 months and then every 6 months for 2 to 3 years, repeating the focused history and physical examination. It is also reasonable at some point to refer these patients to a rheumatologist.

Since Raynaud phenomenon is common, and the associated severe rheumatic disorders associated with it are rare, it is easy to not recognize Raynaud phenomenon as a clue to the onset of a potentially severe systemic disease. Yet with a few simple questions, a focused examination, and minimal laboratory testing, patients who are more likely to harbor a systemic disease can usually be treated symptomatically if necessary, and appropriately triaged to observation or for subspecialty referral.

For many patients, Raynaud symptoms are mild enough to not even mention to their primary care provider, and conversely, there is little reason for most clinicians to routinely inquire about such symptoms. So it may surprise some readers to read about the nuances of diagnosis and treatment discussed by Shapiro and Wigley in this issue of the Journal.

To a rheumatologist, Raynaud phenomenon, particularly of recent onset in an adult, raises the specter of an underlying systemic inflammatory disease. The phenomenon is not linked to a specific diagnosis; it is associated with lupus, rheumatoid arthritis, cryoglobulinemia, inflammatory myopathy, Sjögren syndrome, and, in its severe form, with the scleroderma syndromes. We focus on differentiating between these rheumatic disorders once we have discarded nonrheumatic causes such as atherosclerotic arterial disease, carcinoma, embolism, Buerger disease, medications, smoking, or thrombosis.

But rheumatologists are toward the bottom of the diagnostic funnel—we see these patients when an underlying disease is already suspected. The real challenge is for the primary care providers who first recognize the digital vasospasm on examination or are told of the symptoms by their patient. These clinicians need to know which initial reflexive actions are warranted and which can wait, for, as noted by Shapiro and Wigley, there are several options.

The first action is to try to determine the timeline, although Raynaud disease often has an insidious onset or the patient doesn’t recall the onset. New and sudden onset likely has a stronger association with an underlying disease. A focused physical examination should look for digital stigmata of ischemic damage; the presence of digital ulcers or healed digital pits indicates a possible vascular occlusive component in addition to the vascular spasm. This strongly suggests scleroderma or Buerger disease, as tissue damage doesn’t occur in (primary) Raynaud disease or generally even with Raynaud phenomenon associated with lupus or other rheumatic disorders. Sclerodactyly should be looked for: diffuse finger puffiness, skin-tightening, or early signs such as loss of the usual finger skin creases. Telangiectasia (not vascular spiders or cherry angiomata) should be searched for, particularly on the palms, face, and inner lips, as these vascular lesions are common in patients with limited scleroderma. Careful auscultation for basilar lung crackles should be done. Distal pulses should all be assessed, and bruits in the neck, abdomen and inguinal areas should be carefully sought.

Patients should be questioned about any symptom-associated reduction in exercise tolerance and particularly about trouble swallowing, “heartburn,” and symptoms of reflux. Although patients with Raynaud disease may have demonstrable esophageal dysmotility, the presence of significant, new, or worsened symptoms raises the concern of scleroderma. Patients should be asked about symptoms of malabsorption. Specific questioning should be directed at eliciting a history of joint stiffness and especially muscle weakness. The latter can be approached by inquiring about new or progressive difficulty in specific tasks such as walking up steps, brushing hair, and arising from low chairs or the toilet. Distinguishing muscle weakness from general fatigue is not always easy, but it is important.

Shapiro and Wigley discuss the extremely useful evaluation of nailfold capillaries, which can be done with a standard magnifier or ophthalmoscope. This is very valuable to help predict the development or current presence of a systemic rheumatic disease. But this is not a technique that most clinicians are familiar with. A potentially useful surrogate or adjunctive test, especially in the setting of new-onset Raynaud, is the antinuclear antibody (ANA) test; I prefer the immunofluorescent assay. While a positive test alone (with Raynaud) does not define the presence of any rheumatic disease, several older studies suggest that patients with a new onset of Raynaud phenomenon and a positive ANA test are more likely to develop a systemic autoimmune disorder than if the test is negative. Those who do so (and this is far from all) are most likely to have the disease manifest within a few years. Hence, if the ANA test is positive but the history, physical examination, and limited laboratory testing (complete blood cell count with differential, complete metabolic panel, creatine kinase, and urinalysis) are normal, it is reasonable to reexamine the patient in 3 months and then every 6 months for 2 to 3 years, repeating the focused history and physical examination. It is also reasonable at some point to refer these patients to a rheumatologist.

Since Raynaud phenomenon is common, and the associated severe rheumatic disorders associated with it are rare, it is easy to not recognize Raynaud phenomenon as a clue to the onset of a potentially severe systemic disease. Yet with a few simple questions, a focused examination, and minimal laboratory testing, patients who are more likely to harbor a systemic disease can usually be treated symptomatically if necessary, and appropriately triaged to observation or for subspecialty referral.

What common message do a 64-year-old woman with postoperative cognitive changes and an 83-year-old man with red palms have for us as physicians? As I read their clinical scenarios and the editorial by Westendorp, I was struck by the value and significance of informed clinical observation, an activity that I fear is going the way of the music CD and handwritten letters.

As I read the descriptions of these patients I was reminded of the internal satisfaction that I feel when I pick up a clinical or historical finding that directs me to a specific diagnosis and therapeutic recommendation. Sherlock Holmes I am not. Those satisfying pickups are infrequent, and I have no idea how many clues I have missed. I do know that most come from taking the time to perform a methodical physical examination, directed and informed by the patient’s recounted history. Some, like red palms or anisocoria, may be readily apparent and diagnostically useful—if the observer recognizes their potential significance. The 2 patients described in this issue of the Journal highlight the value of both observation and the knowledge and experience to place what we observe into a clinical context. Watson (the computer) can provide data regarding the potential significance of a physical finding, but only if someone first detects its existence.

Once it is recognized (or pointed out), we can all pull out our smartphones and Google “palmar erythema and disease,” and on our screen up pops liver disease, pregnancy, and assorted other conditions, including malignancies. But how many of us in our clinic, as opposed to the artificial scenario of reading it in the Journal or attending a clinicopathologic conference, will spontaneously recognize palmar erythema as a potentially relevant clinical finding?

For many physicians, the sense of professional satisfaction in making these observations is diminished. The professional joy gleaned from these moments has been diluted. We are in jeopardy of losing the passion for the professional work that we do as well as the intellectual and emotional satisfaction that accompanies a nuanced professional job well done, while focusing instead on our contracted jobs, frequently evaluated by our ability to meet commercial needs. The absence of emotional and intellectual satisfaction that should come from these collected moments of patient interaction and reflection undoubtedly contributes to the rising rate of physician burnout.

There are so many pressures on us in the office. Did I record that my new patient with known rheumatoid arthritis (who has had a recent MI and pneumonia and who has tried several biologic therapies without success and is in need of a creative change in her medication) has a cousin with hypothyroidism so I could include family history in my electronic medical record note and thus bill at a “desired” level of complexity? Did I use the appropriate catchphrase stating that over 50% of my time was spent in education of the patient (after collecting and reading for 30 minutes the stack of prior records, preparing to do battle with her insurance company to get the next therapy approved for coverage)?

There is little wonder that an observation of red palms gets missed or, if it is noted, that the Google search is never actually done. And when we do recognize the finding and its clinical significance, we often don’t take a moment to reflect and bask in the glow of a job well done, the satisfaction of successfully applying both our knowledge and experience to help resolve a clinical problem.

As Westendorp points out, bedside observation is still relevant. And I will add that there still should be joy in the intellectual pursuit of the job well done as well as the patient well managed. It takes more than a smartphone to know when and how to look at the palms and the eyes before typing in a Google search or consulting the digital (not the doctor) Watson. Those are skills to be proud of.

What common message do a 64-year-old woman with postoperative cognitive changes and an 83-year-old man with red palms have for us as physicians? As I read their clinical scenarios and the editorial by Westendorp, I was struck by the value and significance of informed clinical observation, an activity that I fear is going the way of the music CD and handwritten letters.

As I read the descriptions of these patients I was reminded of the internal satisfaction that I feel when I pick up a clinical or historical finding that directs me to a specific diagnosis and therapeutic recommendation. Sherlock Holmes I am not. Those satisfying pickups are infrequent, and I have no idea how many clues I have missed. I do know that most come from taking the time to perform a methodical physical examination, directed and informed by the patient’s recounted history. Some, like red palms or anisocoria, may be readily apparent and diagnostically useful—if the observer recognizes their potential significance. The 2 patients described in this issue of the Journal highlight the value of both observation and the knowledge and experience to place what we observe into a clinical context. Watson (the computer) can provide data regarding the potential significance of a physical finding, but only if someone first detects its existence.

Once it is recognized (or pointed out), we can all pull out our smartphones and Google “palmar erythema and disease,” and on our screen up pops liver disease, pregnancy, and assorted other conditions, including malignancies. But how many of us in our clinic, as opposed to the artificial scenario of reading it in the Journal or attending a clinicopathologic conference, will spontaneously recognize palmar erythema as a potentially relevant clinical finding?

For many physicians, the sense of professional satisfaction in making these observations is diminished. The professional joy gleaned from these moments has been diluted. We are in jeopardy of losing the passion for the professional work that we do as well as the intellectual and emotional satisfaction that accompanies a nuanced professional job well done, while focusing instead on our contracted jobs, frequently evaluated by our ability to meet commercial needs. The absence of emotional and intellectual satisfaction that should come from these collected moments of patient interaction and reflection undoubtedly contributes to the rising rate of physician burnout.

There are so many pressures on us in the office. Did I record that my new patient with known rheumatoid arthritis (who has had a recent MI and pneumonia and who has tried several biologic therapies without success and is in need of a creative change in her medication) has a cousin with hypothyroidism so I could include family history in my electronic medical record note and thus bill at a “desired” level of complexity? Did I use the appropriate catchphrase stating that over 50% of my time was spent in education of the patient (after collecting and reading for 30 minutes the stack of prior records, preparing to do battle with her insurance company to get the next therapy approved for coverage)?

There is little wonder that an observation of red palms gets missed or, if it is noted, that the Google search is never actually done. And when we do recognize the finding and its clinical significance, we often don’t take a moment to reflect and bask in the glow of a job well done, the satisfaction of successfully applying both our knowledge and experience to help resolve a clinical problem.

As Westendorp points out, bedside observation is still relevant. And I will add that there still should be joy in the intellectual pursuit of the job well done as well as the patient well managed. It takes more than a smartphone to know when and how to look at the palms and the eyes before typing in a Google search or consulting the digital (not the doctor) Watson. Those are skills to be proud of.

What common message do a 64-year-old woman with postoperative cognitive changes and an 83-year-old man with red palms have for us as physicians? As I read their clinical scenarios and the editorial by Westendorp, I was struck by the value and significance of informed clinical observation, an activity that I fear is going the way of the music CD and handwritten letters.

As I read the descriptions of these patients I was reminded of the internal satisfaction that I feel when I pick up a clinical or historical finding that directs me to a specific diagnosis and therapeutic recommendation. Sherlock Holmes I am not. Those satisfying pickups are infrequent, and I have no idea how many clues I have missed. I do know that most come from taking the time to perform a methodical physical examination, directed and informed by the patient’s recounted history. Some, like red palms or anisocoria, may be readily apparent and diagnostically useful—if the observer recognizes their potential significance. The 2 patients described in this issue of the Journal highlight the value of both observation and the knowledge and experience to place what we observe into a clinical context. Watson (the computer) can provide data regarding the potential significance of a physical finding, but only if someone first detects its existence.

Once it is recognized (or pointed out), we can all pull out our smartphones and Google “palmar erythema and disease,” and on our screen up pops liver disease, pregnancy, and assorted other conditions, including malignancies. But how many of us in our clinic, as opposed to the artificial scenario of reading it in the Journal or attending a clinicopathologic conference, will spontaneously recognize palmar erythema as a potentially relevant clinical finding?

For many physicians, the sense of professional satisfaction in making these observations is diminished. The professional joy gleaned from these moments has been diluted. We are in jeopardy of losing the passion for the professional work that we do as well as the intellectual and emotional satisfaction that accompanies a nuanced professional job well done, while focusing instead on our contracted jobs, frequently evaluated by our ability to meet commercial needs. The absence of emotional and intellectual satisfaction that should come from these collected moments of patient interaction and reflection undoubtedly contributes to the rising rate of physician burnout.

There are so many pressures on us in the office. Did I record that my new patient with known rheumatoid arthritis (who has had a recent MI and pneumonia and who has tried several biologic therapies without success and is in need of a creative change in her medication) has a cousin with hypothyroidism so I could include family history in my electronic medical record note and thus bill at a “desired” level of complexity? Did I use the appropriate catchphrase stating that over 50% of my time was spent in education of the patient (after collecting and reading for 30 minutes the stack of prior records, preparing to do battle with her insurance company to get the next therapy approved for coverage)?

There is little wonder that an observation of red palms gets missed or, if it is noted, that the Google search is never actually done. And when we do recognize the finding and its clinical significance, we often don’t take a moment to reflect and bask in the glow of a job well done, the satisfaction of successfully applying both our knowledge and experience to help resolve a clinical problem.

As Westendorp points out, bedside observation is still relevant. And I will add that there still should be joy in the intellectual pursuit of the job well done as well as the patient well managed. It takes more than a smartphone to know when and how to look at the palms and the eyes before typing in a Google search or consulting the digital (not the doctor) Watson. Those are skills to be proud of.

We well recall, back in the day, getting our “bell rung” from some form of sports-related head contact. If we could count the coach’s fingers clearly, run fast and straight, and know the plays, we could happily go back into the game. There was little additional thought given to short-term or lasting effects. I recall hearing tales from my grandfather, a boxing enthusiast, of retired punch-drunk fighters working as bouncers and greeters at sports-focused restaurants and clubs. I certainly didn’t draw any link to a few episodes of personally feeling spacey or dizzy after playing football.

But now, as parents, we are all highly tuned in to the issue of wrongly minimized “minor” head contact and concussion in our children playing sports. There is a growing research-based understanding of the mechanisms of concussion, which remains a clinical syndrome diagnosed on the basis of symptoms and sometimes subtle objective findings that occur in the appropriate environmental context. Intracranial brain impact sets the stage for locally spreading firing of neurons outside their usual pattern. This can result in a diffuse jamming of some normal electrochemical pathways of cognitive function, as well as create additional mismatch between neuronal metabolic needs and the local blood flow providing oxygen and nutrients. This disruption in autoregulation of blood flow sets the stage for enhanced brain sensitivity to any second injurious event, even a minimal one. Hence the aggressive implementation of enforced rest and recovery time for athletes and others with concussion.

It is critical to realize that the patient may not have had a loss of consciousness. Equally important is to consider the need for imaging and protection of patients who are not recovering as expected in 7 to 10 days, as well as for initial imaging of those with severe head impact or baseline neurologic disease, the aged, and those on anticoagulation.

We well recall, back in the day, getting our “bell rung” from some form of sports-related head contact. If we could count the coach’s fingers clearly, run fast and straight, and know the plays, we could happily go back into the game. There was little additional thought given to short-term or lasting effects. I recall hearing tales from my grandfather, a boxing enthusiast, of retired punch-drunk fighters working as bouncers and greeters at sports-focused restaurants and clubs. I certainly didn’t draw any link to a few episodes of personally feeling spacey or dizzy after playing football.

But now, as parents, we are all highly tuned in to the issue of wrongly minimized “minor” head contact and concussion in our children playing sports. There is a growing research-based understanding of the mechanisms of concussion, which remains a clinical syndrome diagnosed on the basis of symptoms and sometimes subtle objective findings that occur in the appropriate environmental context. Intracranial brain impact sets the stage for locally spreading firing of neurons outside their usual pattern. This can result in a diffuse jamming of some normal electrochemical pathways of cognitive function, as well as create additional mismatch between neuronal metabolic needs and the local blood flow providing oxygen and nutrients. This disruption in autoregulation of blood flow sets the stage for enhanced brain sensitivity to any second injurious event, even a minimal one. Hence the aggressive implementation of enforced rest and recovery time for athletes and others with concussion.

It is critical to realize that the patient may not have had a loss of consciousness. Equally important is to consider the need for imaging and protection of patients who are not recovering as expected in 7 to 10 days, as well as for initial imaging of those with severe head impact or baseline neurologic disease, the aged, and those on anticoagulation.

Some topics we review in the Journal are as relevant and interesting to us as “people” as they are to us in our professional roles. Concussion, discussed by Stillman at al in this issue, is one of these.

We well recall, back in the day, getting our “bell rung” from some form of sports-related head contact. If we could count the coach’s fingers clearly, run fast and straight, and know the plays, we could happily go back into the game. There was little additional thought given to short-term or lasting effects. I recall hearing tales from my grandfather, a boxing enthusiast, of retired punch-drunk fighters working as bouncers and greeters at sports-focused restaurants and clubs. I certainly didn’t draw any link to a few episodes of personally feeling spacey or dizzy after playing football.

But now, as parents, we are all highly tuned in to the issue of wrongly minimized “minor” head contact and concussion in our children playing sports. There is a growing research-based understanding of the mechanisms of concussion, which remains a clinical syndrome diagnosed on the basis of symptoms and sometimes subtle objective findings that occur in the appropriate environmental context. Intracranial brain impact sets the stage for locally spreading firing of neurons outside their usual pattern. This can result in a diffuse jamming of some normal electrochemical pathways of cognitive function, as well as create additional mismatch between neuronal metabolic needs and the local blood flow providing oxygen and nutrients. This disruption in autoregulation of blood flow sets the stage for enhanced brain sensitivity to any second injurious event, even a minimal one. Hence the aggressive implementation of enforced rest and recovery time for athletes and others with concussion.

It is critical to realize that the patient may not have had a loss of consciousness. Equally important is to consider the need for imaging and protection of patients who are not recovering as expected in 7 to 10 days, as well as for initial imaging of those with severe head impact or baseline neurologic disease, the aged, and those on anticoagulation.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.