Brian F. Mandell, MD, PhD

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

Medical screening consists of trying to detect an occult disease at a point in its course—earlier than if diagnosed by clinical manifestations—when treatment offers a meaningful benefit to the patient. If the cost is acceptable, one would think that most care providers and patients would embrace the concept. So why are there such heated controversies surrounding screening for breast, prostate, and lung cancer?

The answer to that question is interpretive and philosophical and depends in part on the frame of reference. Are we looking at screening from the perspective of the health care system or from the perspective of the individual patient who is contemplating being screened?

The US Preventive Services Task Force (USPSTF), whose guidelines on screening are reviewed by Dr. Craig Nielsen in this issue of the Journal, went to great lengths to generate evidence-based guidelines based on rigorously conducted trials. They did not consider observational information or the emotional contextual biases of individual patients. Since their guidelines carry great weight, they have a big impact, sometimes including effects on insurance reimbursement for certain screening tests.

As with all “evidence-based” decisions, when applying guidelines or trial data in the clinic, we weigh the effect of our recommendations on individual patients, not on populations. Is a test worthwhile if it offers a 1 in 250 (or fill in your own number) chance of prolonging a specific patient’s life but is expensive and uncomfortable and poses the possible stress of a false-positive result that will warrant more testing? Which is actually more stressful: undergoing additional testing (with expense and discomfort) or not knowing whether you have a potentially lethal tumor? What is a reasonable cost to the patient and to a financially failing health system in attempting to delay the end of life to some time in the future when the patient may well be frail and perhaps even incapacitated?

People may differ in how they answer these questions, some of which may not even be answerable. The USPSTF guidelines, I believe, offer solid scaffolding for informed discussion. But we and our patients should use the offered evidence-based guidelines, and perhaps assume some costs, within a personalized context. Guidelines are only guidelines.

Medical screening consists of trying to detect an occult disease at a point in its course—earlier than if diagnosed by clinical manifestations—when treatment offers a meaningful benefit to the patient. If the cost is acceptable, one would think that most care providers and patients would embrace the concept. So why are there such heated controversies surrounding screening for breast, prostate, and lung cancer?

The answer to that question is interpretive and philosophical and depends in part on the frame of reference. Are we looking at screening from the perspective of the health care system or from the perspective of the individual patient who is contemplating being screened?

The US Preventive Services Task Force (USPSTF), whose guidelines on screening are reviewed by Dr. Craig Nielsen in this issue of the Journal, went to great lengths to generate evidence-based guidelines based on rigorously conducted trials. They did not consider observational information or the emotional contextual biases of individual patients. Since their guidelines carry great weight, they have a big impact, sometimes including effects on insurance reimbursement for certain screening tests.

As with all “evidence-based” decisions, when applying guidelines or trial data in the clinic, we weigh the effect of our recommendations on individual patients, not on populations. Is a test worthwhile if it offers a 1 in 250 (or fill in your own number) chance of prolonging a specific patient’s life but is expensive and uncomfortable and poses the possible stress of a false-positive result that will warrant more testing? Which is actually more stressful: undergoing additional testing (with expense and discomfort) or not knowing whether you have a potentially lethal tumor? What is a reasonable cost to the patient and to a financially failing health system in attempting to delay the end of life to some time in the future when the patient may well be frail and perhaps even incapacitated?

People may differ in how they answer these questions, some of which may not even be answerable. The USPSTF guidelines, I believe, offer solid scaffolding for informed discussion. But we and our patients should use the offered evidence-based guidelines, and perhaps assume some costs, within a personalized context. Guidelines are only guidelines.

Medical screening consists of trying to detect an occult disease at a point in its course—earlier than if diagnosed by clinical manifestations—when treatment offers a meaningful benefit to the patient. If the cost is acceptable, one would think that most care providers and patients would embrace the concept. So why are there such heated controversies surrounding screening for breast, prostate, and lung cancer?

The answer to that question is interpretive and philosophical and depends in part on the frame of reference. Are we looking at screening from the perspective of the health care system or from the perspective of the individual patient who is contemplating being screened?

The US Preventive Services Task Force (USPSTF), whose guidelines on screening are reviewed by Dr. Craig Nielsen in this issue of the Journal, went to great lengths to generate evidence-based guidelines based on rigorously conducted trials. They did not consider observational information or the emotional contextual biases of individual patients. Since their guidelines carry great weight, they have a big impact, sometimes including effects on insurance reimbursement for certain screening tests.

As with all “evidence-based” decisions, when applying guidelines or trial data in the clinic, we weigh the effect of our recommendations on individual patients, not on populations. Is a test worthwhile if it offers a 1 in 250 (or fill in your own number) chance of prolonging a specific patient’s life but is expensive and uncomfortable and poses the possible stress of a false-positive result that will warrant more testing? Which is actually more stressful: undergoing additional testing (with expense and discomfort) or not knowing whether you have a potentially lethal tumor? What is a reasonable cost to the patient and to a financially failing health system in attempting to delay the end of life to some time in the future when the patient may well be frail and perhaps even incapacitated?

People may differ in how they answer these questions, some of which may not even be answerable. The USPSTF guidelines, I believe, offer solid scaffolding for informed discussion. But we and our patients should use the offered evidence-based guidelines, and perhaps assume some costs, within a personalized context. Guidelines are only guidelines.

The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

Dr. Braun is an iconic figure in Cleveland Clinic medicine. He is the consummate internist, nephrologist, and transplantation physician, but he is also a critical thinker. He strives to understand (and explain) what underpins our clinical observations and therapeutic decisions. He asks the “why” questions. As he ticked through the manifestations of PKD and the diagnostic dilemmas that arise in taking care of these patients, and then transitioned into explaining the interesting though incomplete current molecular understanding of this relatively prevalent genetic disorder, I heard many of the same questions I had asked myself 30 years ago. But this time I was getting some answers.

How can one be certain a cyst is infected? How do these cysts form and expand without apparent communication with the tubular lumens? (Intracystic bleeding and infection may not be reflected in the urinalysis, although the organism isolated from infected cysts is frequently Escherichia coli.) If renal cysts are formed from tubular epithelial cells that are preprogrammed to self-organize into lumen-like structures, how does the same genetic defect predispose to cyst formation in organs such as the liver, or to aneurysms in blood vessels in the brain? Why does the disease take so long to express itself, and why is its expression so variable?

The patient did well during his hospital stay 30 years ago. As I recall, he had staphylococcal bacteremia with an infected cyst. We discussed the clinical scenario but had no suggestions as to how to prevent the growth of what we now know are about 60 subclinical cysts for every one that we recognize. And we certainly didn’t discuss the idea that the disease process may be partially driven by dysfunctional nonmotile cilia that should respond to urine flow by appropriately directing regeneration and proliferation of renal tubular cells.

I love getting answers to questions that I didn’t know enough to ask.

Dr. Braun is an iconic figure in Cleveland Clinic medicine. He is the consummate internist, nephrologist, and transplantation physician, but he is also a critical thinker. He strives to understand (and explain) what underpins our clinical observations and therapeutic decisions. He asks the “why” questions. As he ticked through the manifestations of PKD and the diagnostic dilemmas that arise in taking care of these patients, and then transitioned into explaining the interesting though incomplete current molecular understanding of this relatively prevalent genetic disorder, I heard many of the same questions I had asked myself 30 years ago. But this time I was getting some answers.

How can one be certain a cyst is infected? How do these cysts form and expand without apparent communication with the tubular lumens? (Intracystic bleeding and infection may not be reflected in the urinalysis, although the organism isolated from infected cysts is frequently Escherichia coli.) If renal cysts are formed from tubular epithelial cells that are preprogrammed to self-organize into lumen-like structures, how does the same genetic defect predispose to cyst formation in organs such as the liver, or to aneurysms in blood vessels in the brain? Why does the disease take so long to express itself, and why is its expression so variable?

The patient did well during his hospital stay 30 years ago. As I recall, he had staphylococcal bacteremia with an infected cyst. We discussed the clinical scenario but had no suggestions as to how to prevent the growth of what we now know are about 60 subclinical cysts for every one that we recognize. And we certainly didn’t discuss the idea that the disease process may be partially driven by dysfunctional nonmotile cilia that should respond to urine flow by appropriately directing regeneration and proliferation of renal tubular cells.

I love getting answers to questions that I didn’t know enough to ask.

Dr. Braun is an iconic figure in Cleveland Clinic medicine. He is the consummate internist, nephrologist, and transplantation physician, but he is also a critical thinker. He strives to understand (and explain) what underpins our clinical observations and therapeutic decisions. He asks the “why” questions. As he ticked through the manifestations of PKD and the diagnostic dilemmas that arise in taking care of these patients, and then transitioned into explaining the interesting though incomplete current molecular understanding of this relatively prevalent genetic disorder, I heard many of the same questions I had asked myself 30 years ago. But this time I was getting some answers.

How can one be certain a cyst is infected? How do these cysts form and expand without apparent communication with the tubular lumens? (Intracystic bleeding and infection may not be reflected in the urinalysis, although the organism isolated from infected cysts is frequently Escherichia coli.) If renal cysts are formed from tubular epithelial cells that are preprogrammed to self-organize into lumen-like structures, how does the same genetic defect predispose to cyst formation in organs such as the liver, or to aneurysms in blood vessels in the brain? Why does the disease take so long to express itself, and why is its expression so variable?

The patient did well during his hospital stay 30 years ago. As I recall, he had staphylococcal bacteremia with an infected cyst. We discussed the clinical scenario but had no suggestions as to how to prevent the growth of what we now know are about 60 subclinical cysts for every one that we recognize. And we certainly didn’t discuss the idea that the disease process may be partially driven by dysfunctional nonmotile cilia that should respond to urine flow by appropriately directing regeneration and proliferation of renal tubular cells.

I love getting answers to questions that I didn’t know enough to ask.

We have all seen cartoons of an unhappy wife awake in bed next to her loudly snoring husband. Casual conversations with friends, particularly female ones, indicate that this is an accurate representation of a common scenario. As I have started to probe more diligently for evidence of obstructive sleep apnea (OSA) in my patients, not just in those who complain of “fatigue” (more patients use this term with me than “sleepiness”), I see a lot of shaking of heads from the wives of men who deny that they snore or have disrupted sleep. I am not implying that this is solely a male disease. Far from it. But as in other medical scenarios, the Y chromosome seems somehow linked to denial or lack of awareness of symptoms. In any event, I was not a bit surprised to read in the review by Dr. Mehra in this issue of the Journal that 17% of adults may have OSA.

As awareness of OSA has grown and testing for it has become easier, multiple reports have documented associated comorbidities: hypertension, restless leg syndrome, gout, and neurocognitive deficits. Home devices to treat OSA have significantly improved. Technological advances have led to the development of small, quiet, smart pumps that provide continuous positive airway pressure (CPAP) via nasal or relatively comfortable full-face masks. Compliance and patient acceptance of CPAP have improved, although patient education and a bit of cajoling in the office are still necessary—less so if the bedroom partner is also present for this discussion.

Perhaps surprising is a growing pool of data showing that CPAP’s benefits extend to more than just reducing sleepiness. It can reduce nocturia, restless leg syndrome, arrhythmias including atrial fibrillation, gastric reflux, and fatal and nonfatal cardiovascular events. Snoring and thus probably sleep-partner satisfaction are also improved.

Several physiologic mechanisms may explain the benefits of CPAP, including reducing hypoxic episodes (explaining its effect on atrial fibrillation), altered atrial natriuretic factor levels (thus reducing nocturia), and changing intrathoracic pressure (thus reducing gastric reflux). It will be interesting to see if there are long-term effects of successfully applied CPAP on neurocognition and progression of neurodegenerative diseases.

While high-decibel snoring and snorting are not present in all patients with OSA, it is quite clear now that they represent far more than an annoyance. We should be vigilant about looking for OSA and strongly encourage a trial of CPAP in appropriately diagnosed patients.

We have all seen cartoons of an unhappy wife awake in bed next to her loudly snoring husband. Casual conversations with friends, particularly female ones, indicate that this is an accurate representation of a common scenario. As I have started to probe more diligently for evidence of obstructive sleep apnea (OSA) in my patients, not just in those who complain of “fatigue” (more patients use this term with me than “sleepiness”), I see a lot of shaking of heads from the wives of men who deny that they snore or have disrupted sleep. I am not implying that this is solely a male disease. Far from it. But as in other medical scenarios, the Y chromosome seems somehow linked to denial or lack of awareness of symptoms. In any event, I was not a bit surprised to read in the review by Dr. Mehra in this issue of the Journal that 17% of adults may have OSA.

As awareness of OSA has grown and testing for it has become easier, multiple reports have documented associated comorbidities: hypertension, restless leg syndrome, gout, and neurocognitive deficits. Home devices to treat OSA have significantly improved. Technological advances have led to the development of small, quiet, smart pumps that provide continuous positive airway pressure (CPAP) via nasal or relatively comfortable full-face masks. Compliance and patient acceptance of CPAP have improved, although patient education and a bit of cajoling in the office are still necessary—less so if the bedroom partner is also present for this discussion.

Perhaps surprising is a growing pool of data showing that CPAP’s benefits extend to more than just reducing sleepiness. It can reduce nocturia, restless leg syndrome, arrhythmias including atrial fibrillation, gastric reflux, and fatal and nonfatal cardiovascular events. Snoring and thus probably sleep-partner satisfaction are also improved.

Several physiologic mechanisms may explain the benefits of CPAP, including reducing hypoxic episodes (explaining its effect on atrial fibrillation), altered atrial natriuretic factor levels (thus reducing nocturia), and changing intrathoracic pressure (thus reducing gastric reflux). It will be interesting to see if there are long-term effects of successfully applied CPAP on neurocognition and progression of neurodegenerative diseases.

While high-decibel snoring and snorting are not present in all patients with OSA, it is quite clear now that they represent far more than an annoyance. We should be vigilant about looking for OSA and strongly encourage a trial of CPAP in appropriately diagnosed patients.

We have all seen cartoons of an unhappy wife awake in bed next to her loudly snoring husband. Casual conversations with friends, particularly female ones, indicate that this is an accurate representation of a common scenario. As I have started to probe more diligently for evidence of obstructive sleep apnea (OSA) in my patients, not just in those who complain of “fatigue” (more patients use this term with me than “sleepiness”), I see a lot of shaking of heads from the wives of men who deny that they snore or have disrupted sleep. I am not implying that this is solely a male disease. Far from it. But as in other medical scenarios, the Y chromosome seems somehow linked to denial or lack of awareness of symptoms. In any event, I was not a bit surprised to read in the review by Dr. Mehra in this issue of the Journal that 17% of adults may have OSA.

As awareness of OSA has grown and testing for it has become easier, multiple reports have documented associated comorbidities: hypertension, restless leg syndrome, gout, and neurocognitive deficits. Home devices to treat OSA have significantly improved. Technological advances have led to the development of small, quiet, smart pumps that provide continuous positive airway pressure (CPAP) via nasal or relatively comfortable full-face masks. Compliance and patient acceptance of CPAP have improved, although patient education and a bit of cajoling in the office are still necessary—less so if the bedroom partner is also present for this discussion.

Perhaps surprising is a growing pool of data showing that CPAP’s benefits extend to more than just reducing sleepiness. It can reduce nocturia, restless leg syndrome, arrhythmias including atrial fibrillation, gastric reflux, and fatal and nonfatal cardiovascular events. Snoring and thus probably sleep-partner satisfaction are also improved.

Several physiologic mechanisms may explain the benefits of CPAP, including reducing hypoxic episodes (explaining its effect on atrial fibrillation), altered atrial natriuretic factor levels (thus reducing nocturia), and changing intrathoracic pressure (thus reducing gastric reflux). It will be interesting to see if there are long-term effects of successfully applied CPAP on neurocognition and progression of neurodegenerative diseases.

While high-decibel snoring and snorting are not present in all patients with OSA, it is quite clear now that they represent far more than an annoyance. We should be vigilant about looking for OSA and strongly encourage a trial of CPAP in appropriately diagnosed patients.

It’s simple. It’s obvious. None of us would like to be known as someone who orders diagnostic tests in a careless or stupid manner. And none of us order that way—just ask us! Yet, when critically evaluated, someone is ordering slews of unnecessary or inappropriate tests. In my own hospital we saved about $100,000 last year by putting “hard stops” on duplicated blood tests that were ordered too frequently to be of clinical value. This is an obvious and easily enacted intervention, but it is just the tip of the testing iceberg.

As technology advances, our testing practices must change. For example, the ventilation-perfusion nuclear scan is now seldom the test of choice when evaluating a patient with possible pulmonary embolism. However, it still has a role for experienced clinicians evaluating selected patients who have unexplained dyspnea or pulmonary hypertension. There is value in knowing the old as well as new testing modalities.

We like to think we practice evidence-based diagnostic testing. We talk about the gold-standard value of randomized controlled trials and using published data on pretest and posttest diagnostic likelihoods to assist us in choosing the appropriate test. However, the individual patient in front of us may have comorbidities that would have excluded her from the randomized trials. Who knows if my diagnostic acumen in determining the pretest likelihood of disease is better or worse than that of the clinicians who published the paper on the utility of that test? Sometimes choosing a test is not so simple.

Much of my clinical decision-making occurs in a gray zone of uncertainty. Rarely will a single test provide an indisputable diagnosis. So, I may bristle when someone, often for cost reasons, questions the necessity of a diagnostic test that I have ordered to help me understand a clinical problem in a specific patient.

Nevertheless, as Dr. Patrick Alguire points out in an editorial, the frequent use of sophisticated and expensive testing in the United States has not resulted in better clinical outcomes. And as Drs. Alraies and Buitrago et al discuss in letters to the editor, even relatively simple and minimally invasive tests can result in dire, unexpected outcomes. The choice of test matters to individual patients and to the health care system as a whole.

I do not minimize the financial impact of inappropriate testing, but in the clinic I am a doctor, not a businessman. I am far more swayed by clinical arguments than financial ones when making decisions for the patient on the examining table in front of me. Despite the general examples I provided above as to why regulated, cookbook approaches to test-ordering may lead to suboptimal care and physician and patient dissatisfaction (albeit while decreasing costs), sometimes ordering certain tests in certain circumstances just doesn’t make sense. Yet, there are many questionable test and scenario pairings that are ingrained in common practice. Some we learned during our training but have become less useful in light of new knowledge, some we may have adopted because of anecdotal experiences, and some are “demanded” by our patients. It is these that we hope to help expunge from routine clinical care.

In this issue of the Journal  we are initiating a new series within our 1-Minute Consults, called Smart Testing. We are joining the efforts of the American College of Physicians (ACP) in educating physicians about reasons to avoid ordering frequently misused tests—tests that may add more harm, cost, or both than clinical utility to the care of our patients. The ACP also has an educational initiative called “High Value Care” that can be accessed (at no cost) at http://hvc.acponline.org/index.html. We at the Journal are very pleased to be working with physicians at the ACP to offer you this peer-reviewed series of patient vignettes that will focus, in an evidence-based and common-sense way, on the clinical value of selected tests in specific scenarios. Next month we will also be presenting a commentary on the impact that “defensive medicine” plays in test ordering and malpractice case decisions.

The tests and scenarios to be presented are chosen in clinician group discussions. Some of the tests have also been identified by specialty societies as providing limited value to patients. In selecting the topics, we pick common scenarios, realizing that there can often (always?) be some situational nuance that negates the accompanying discussion. We are not expecting to throw light on those nuanced zones of uncertainty, but we do hope to change test-ordering behaviors in situations in which there is a smart—and a not-so-smart—way to pursue a diagnosis.

It’s simple. It’s obvious. None of us would like to be known as someone who orders diagnostic tests in a careless or stupid manner. And none of us order that way—just ask us! Yet, when critically evaluated, someone is ordering slews of unnecessary or inappropriate tests. In my own hospital we saved about $100,000 last year by putting “hard stops” on duplicated blood tests that were ordered too frequently to be of clinical value. This is an obvious and easily enacted intervention, but it is just the tip of the testing iceberg.

As technology advances, our testing practices must change. For example, the ventilation-perfusion nuclear scan is now seldom the test of choice when evaluating a patient with possible pulmonary embolism. However, it still has a role for experienced clinicians evaluating selected patients who have unexplained dyspnea or pulmonary hypertension. There is value in knowing the old as well as new testing modalities.

We like to think we practice evidence-based diagnostic testing. We talk about the gold-standard value of randomized controlled trials and using published data on pretest and posttest diagnostic likelihoods to assist us in choosing the appropriate test. However, the individual patient in front of us may have comorbidities that would have excluded her from the randomized trials. Who knows if my diagnostic acumen in determining the pretest likelihood of disease is better or worse than that of the clinicians who published the paper on the utility of that test? Sometimes choosing a test is not so simple.

Much of my clinical decision-making occurs in a gray zone of uncertainty. Rarely will a single test provide an indisputable diagnosis. So, I may bristle when someone, often for cost reasons, questions the necessity of a diagnostic test that I have ordered to help me understand a clinical problem in a specific patient.

Nevertheless, as Dr. Patrick Alguire points out in an editorial, the frequent use of sophisticated and expensive testing in the United States has not resulted in better clinical outcomes. And as Drs. Alraies and Buitrago et al discuss in letters to the editor, even relatively simple and minimally invasive tests can result in dire, unexpected outcomes. The choice of test matters to individual patients and to the health care system as a whole.

I do not minimize the financial impact of inappropriate testing, but in the clinic I am a doctor, not a businessman. I am far more swayed by clinical arguments than financial ones when making decisions for the patient on the examining table in front of me. Despite the general examples I provided above as to why regulated, cookbook approaches to test-ordering may lead to suboptimal care and physician and patient dissatisfaction (albeit while decreasing costs), sometimes ordering certain tests in certain circumstances just doesn’t make sense. Yet, there are many questionable test and scenario pairings that are ingrained in common practice. Some we learned during our training but have become less useful in light of new knowledge, some we may have adopted because of anecdotal experiences, and some are “demanded” by our patients. It is these that we hope to help expunge from routine clinical care.

In this issue of the Journal  we are initiating a new series within our 1-Minute Consults, called Smart Testing. We are joining the efforts of the American College of Physicians (ACP) in educating physicians about reasons to avoid ordering frequently misused tests—tests that may add more harm, cost, or both than clinical utility to the care of our patients. The ACP also has an educational initiative called “High Value Care” that can be accessed (at no cost) at http://hvc.acponline.org/index.html. We at the Journal are very pleased to be working with physicians at the ACP to offer you this peer-reviewed series of patient vignettes that will focus, in an evidence-based and common-sense way, on the clinical value of selected tests in specific scenarios. Next month we will also be presenting a commentary on the impact that “defensive medicine” plays in test ordering and malpractice case decisions.

The tests and scenarios to be presented are chosen in clinician group discussions. Some of the tests have also been identified by specialty societies as providing limited value to patients. In selecting the topics, we pick common scenarios, realizing that there can often (always?) be some situational nuance that negates the accompanying discussion. We are not expecting to throw light on those nuanced zones of uncertainty, but we do hope to change test-ordering behaviors in situations in which there is a smart—and a not-so-smart—way to pursue a diagnosis.

It’s simple. It’s obvious. None of us would like to be known as someone who orders diagnostic tests in a careless or stupid manner. And none of us order that way—just ask us! Yet, when critically evaluated, someone is ordering slews of unnecessary or inappropriate tests. In my own hospital we saved about $100,000 last year by putting “hard stops” on duplicated blood tests that were ordered too frequently to be of clinical value. This is an obvious and easily enacted intervention, but it is just the tip of the testing iceberg.

As technology advances, our testing practices must change. For example, the ventilation-perfusion nuclear scan is now seldom the test of choice when evaluating a patient with possible pulmonary embolism. However, it still has a role for experienced clinicians evaluating selected patients who have unexplained dyspnea or pulmonary hypertension. There is value in knowing the old as well as new testing modalities.

We like to think we practice evidence-based diagnostic testing. We talk about the gold-standard value of randomized controlled trials and using published data on pretest and posttest diagnostic likelihoods to assist us in choosing the appropriate test. However, the individual patient in front of us may have comorbidities that would have excluded her from the randomized trials. Who knows if my diagnostic acumen in determining the pretest likelihood of disease is better or worse than that of the clinicians who published the paper on the utility of that test? Sometimes choosing a test is not so simple.

Much of my clinical decision-making occurs in a gray zone of uncertainty. Rarely will a single test provide an indisputable diagnosis. So, I may bristle when someone, often for cost reasons, questions the necessity of a diagnostic test that I have ordered to help me understand a clinical problem in a specific patient.

Nevertheless, as Dr. Patrick Alguire points out in an editorial, the frequent use of sophisticated and expensive testing in the United States has not resulted in better clinical outcomes. And as Drs. Alraies and Buitrago et al discuss in letters to the editor, even relatively simple and minimally invasive tests can result in dire, unexpected outcomes. The choice of test matters to individual patients and to the health care system as a whole.

I do not minimize the financial impact of inappropriate testing, but in the clinic I am a doctor, not a businessman. I am far more swayed by clinical arguments than financial ones when making decisions for the patient on the examining table in front of me. Despite the general examples I provided above as to why regulated, cookbook approaches to test-ordering may lead to suboptimal care and physician and patient dissatisfaction (albeit while decreasing costs), sometimes ordering certain tests in certain circumstances just doesn’t make sense. Yet, there are many questionable test and scenario pairings that are ingrained in common practice. Some we learned during our training but have become less useful in light of new knowledge, some we may have adopted because of anecdotal experiences, and some are “demanded” by our patients. It is these that we hope to help expunge from routine clinical care.

In this issue of the Journal  we are initiating a new series within our 1-Minute Consults, called Smart Testing. We are joining the efforts of the American College of Physicians (ACP) in educating physicians about reasons to avoid ordering frequently misused tests—tests that may add more harm, cost, or both than clinical utility to the care of our patients. The ACP also has an educational initiative called “High Value Care” that can be accessed (at no cost) at http://hvc.acponline.org/index.html. We at the Journal are very pleased to be working with physicians at the ACP to offer you this peer-reviewed series of patient vignettes that will focus, in an evidence-based and common-sense way, on the clinical value of selected tests in specific scenarios. Next month we will also be presenting a commentary on the impact that “defensive medicine” plays in test ordering and malpractice case decisions.

The tests and scenarios to be presented are chosen in clinician group discussions. Some of the tests have also been identified by specialty societies as providing limited value to patients. In selecting the topics, we pick common scenarios, realizing that there can often (always?) be some situational nuance that negates the accompanying discussion. We are not expecting to throw light on those nuanced zones of uncertainty, but we do hope to change test-ordering behaviors in situations in which there is a smart—and a not-so-smart—way to pursue a diagnosis.

Some common diseases outside of my specialty areas of interest have, over time, blended into the background of daily practice. When patients have clearly inadequately controlled disease I refer them back to their internist or relevant subspecialist. Otherwise I find myself accepting the clinical status quo, providing stopgap care when necessary, utilizing my present knowledge of the disease process. But if I am not aware of any paradigm shifts in management, I tend to just peruse the published studies of new drug therapies as they appear in major journals, and not necessarily incorporate new therapies into my practice.

Chronic obstructive pulmonary disease (COPD) is one of those diseases, and the update by Hatipoğlu and Aboussouan in this issue of the Journal provided the opportunity to review some important things I have missed and to take note of the therapeutic principles that haven’t changed that much.

The incidence of COPD seems to be increasing. Cigarette smoking remains the major reversible cause, but one-fourth of current COPD patients have never smoked.

Patients who have early COPD may not be asked about or may not volunteer complaints specific to COPD. Lung examinations are insensitive, and chest radiography, if done, rarely identifies patients with early disease, so it is no surprise that COPD is underdiagnosed. While for many patients it is unclear whether the natural progression of lung damage can be dramatically altered by early diagnosis, other than by stopping smoking, that may not be the case for subsets of patients such as those with alpha-1 antitrypsin deficiency. But COPD generally has to be suspected in order to prompt appropriate screening for it.

COPD is still diagnosed by spirometry, with findings demonstrating incompletely reversible airway obstruction. The forced expiratory volume in 1 second (FEV₁), a spirometric measure required to make the diagnosis, has been a useful surrogate marker of drug efficacy, but it is far from the ideal measure of disease progression and risk of death. Patients who have frequent exacerbations requiring hospitalization tend to have a tumultuous clinical course. The best predictor of future exacerbations is the patient’s history of exacerbations. Reducing the exacerbation rate improves the quality of life but may not translate to a benefit in terms of the mortality risk.

A lower risk of death is most consistently attained by helping patients stop smoking and, if they have sustained hypoxemia, giving them supplemental oxygen. The former intervention is the population game-changer—yet the US Centers for Disease Control and Prevention reports that 18% of American adults still smoke cigarettes, a number that dropped only slightly between 2005 and 2012. Americans with less education and less income more frequently smoke cigarettes, and it is estimated that one in 13 Americans currently 17 years or younger will die prematurely from the effects of cigarette smoking.

As for newer therapies, many that are applicable to most patients with COPD represent a fine-tuning of drug therapies we have been using for decades. Thus, it is not surprising that no dramatic increase in survival rates has been achieved. The advantage of several of the newer therapies in terms of FEV₁ or exacerbation rate is statistically significant but relatively modest in terms of clinical impact. Their clinical promise (including specific antibiotics in low doses), revealed in recent studies, may be dependent upon using them in the most appropriate patients. Reducing the exacerbation rate is a significant advantage, but I would also like to know which drugs or drug combinations are most likely to permit major reductions in patients’ corticosteroid requirements. Hopefully, these data will come from real-world comparative efficacy studies.

Reading the article by Hatipoğlu and Aboussouan, I was reminded that utilizing our pulmonary colleagues’ expertise is of particular value in individualizing therapy for our patients with COPD—using newer drugs and combinations when most appropriate, not just because they are readily available. As physicians who are not pulmonary specialists, we need to be vigilant in recognizing the treatable comorbidities that contribute to dyspnea and poor outcome in patients with COPD, such as obstructive sleep apnea, congestive heart failure, obesity, and thromboembolism.

But to make the largest impact on the mortality rate, we need to continue to engage in and expand the ongoing war against cigarette use.

Some common diseases outside of my specialty areas of interest have, over time, blended into the background of daily practice. When patients have clearly inadequately controlled disease I refer them back to their internist or relevant subspecialist. Otherwise I find myself accepting the clinical status quo, providing stopgap care when necessary, utilizing my present knowledge of the disease process. But if I am not aware of any paradigm shifts in management, I tend to just peruse the published studies of new drug therapies as they appear in major journals, and not necessarily incorporate new therapies into my practice.

Chronic obstructive pulmonary disease (COPD) is one of those diseases, and the update by Hatipoğlu and Aboussouan in this issue of the Journal provided the opportunity to review some important things I have missed and to take note of the therapeutic principles that haven’t changed that much.

The incidence of COPD seems to be increasing. Cigarette smoking remains the major reversible cause, but one-fourth of current COPD patients have never smoked.

Patients who have early COPD may not be asked about or may not volunteer complaints specific to COPD. Lung examinations are insensitive, and chest radiography, if done, rarely identifies patients with early disease, so it is no surprise that COPD is underdiagnosed. While for many patients it is unclear whether the natural progression of lung damage can be dramatically altered by early diagnosis, other than by stopping smoking, that may not be the case for subsets of patients such as those with alpha-1 antitrypsin deficiency. But COPD generally has to be suspected in order to prompt appropriate screening for it.

COPD is still diagnosed by spirometry, with findings demonstrating incompletely reversible airway obstruction. The forced expiratory volume in 1 second (FEV₁), a spirometric measure required to make the diagnosis, has been a useful surrogate marker of drug efficacy, but it is far from the ideal measure of disease progression and risk of death. Patients who have frequent exacerbations requiring hospitalization tend to have a tumultuous clinical course. The best predictor of future exacerbations is the patient’s history of exacerbations. Reducing the exacerbation rate improves the quality of life but may not translate to a benefit in terms of the mortality risk.

A lower risk of death is most consistently attained by helping patients stop smoking and, if they have sustained hypoxemia, giving them supplemental oxygen. The former intervention is the population game-changer—yet the US Centers for Disease Control and Prevention reports that 18% of American adults still smoke cigarettes, a number that dropped only slightly between 2005 and 2012. Americans with less education and less income more frequently smoke cigarettes, and it is estimated that one in 13 Americans currently 17 years or younger will die prematurely from the effects of cigarette smoking.

As for newer therapies, many that are applicable to most patients with COPD represent a fine-tuning of drug therapies we have been using for decades. Thus, it is not surprising that no dramatic increase in survival rates has been achieved. The advantage of several of the newer therapies in terms of FEV₁ or exacerbation rate is statistically significant but relatively modest in terms of clinical impact. Their clinical promise (including specific antibiotics in low doses), revealed in recent studies, may be dependent upon using them in the most appropriate patients. Reducing the exacerbation rate is a significant advantage, but I would also like to know which drugs or drug combinations are most likely to permit major reductions in patients’ corticosteroid requirements. Hopefully, these data will come from real-world comparative efficacy studies.

Reading the article by Hatipoğlu and Aboussouan, I was reminded that utilizing our pulmonary colleagues’ expertise is of particular value in individualizing therapy for our patients with COPD—using newer drugs and combinations when most appropriate, not just because they are readily available. As physicians who are not pulmonary specialists, we need to be vigilant in recognizing the treatable comorbidities that contribute to dyspnea and poor outcome in patients with COPD, such as obstructive sleep apnea, congestive heart failure, obesity, and thromboembolism.

But to make the largest impact on the mortality rate, we need to continue to engage in and expand the ongoing war against cigarette use.

Some common diseases outside of my specialty areas of interest have, over time, blended into the background of daily practice. When patients have clearly inadequately controlled disease I refer them back to their internist or relevant subspecialist. Otherwise I find myself accepting the clinical status quo, providing stopgap care when necessary, utilizing my present knowledge of the disease process. But if I am not aware of any paradigm shifts in management, I tend to just peruse the published studies of new drug therapies as they appear in major journals, and not necessarily incorporate new therapies into my practice.

Chronic obstructive pulmonary disease (COPD) is one of those diseases, and the update by Hatipoğlu and Aboussouan in this issue of the Journal provided the opportunity to review some important things I have missed and to take note of the therapeutic principles that haven’t changed that much.

The incidence of COPD seems to be increasing. Cigarette smoking remains the major reversible cause, but one-fourth of current COPD patients have never smoked.

Patients who have early COPD may not be asked about or may not volunteer complaints specific to COPD. Lung examinations are insensitive, and chest radiography, if done, rarely identifies patients with early disease, so it is no surprise that COPD is underdiagnosed. While for many patients it is unclear whether the natural progression of lung damage can be dramatically altered by early diagnosis, other than by stopping smoking, that may not be the case for subsets of patients such as those with alpha-1 antitrypsin deficiency. But COPD generally has to be suspected in order to prompt appropriate screening for it.

COPD is still diagnosed by spirometry, with findings demonstrating incompletely reversible airway obstruction. The forced expiratory volume in 1 second (FEV₁), a spirometric measure required to make the diagnosis, has been a useful surrogate marker of drug efficacy, but it is far from the ideal measure of disease progression and risk of death. Patients who have frequent exacerbations requiring hospitalization tend to have a tumultuous clinical course. The best predictor of future exacerbations is the patient’s history of exacerbations. Reducing the exacerbation rate improves the quality of life but may not translate to a benefit in terms of the mortality risk.

A lower risk of death is most consistently attained by helping patients stop smoking and, if they have sustained hypoxemia, giving them supplemental oxygen. The former intervention is the population game-changer—yet the US Centers for Disease Control and Prevention reports that 18% of American adults still smoke cigarettes, a number that dropped only slightly between 2005 and 2012. Americans with less education and less income more frequently smoke cigarettes, and it is estimated that one in 13 Americans currently 17 years or younger will die prematurely from the effects of cigarette smoking.

As for newer therapies, many that are applicable to most patients with COPD represent a fine-tuning of drug therapies we have been using for decades. Thus, it is not surprising that no dramatic increase in survival rates has been achieved. The advantage of several of the newer therapies in terms of FEV₁ or exacerbation rate is statistically significant but relatively modest in terms of clinical impact. Their clinical promise (including specific antibiotics in low doses), revealed in recent studies, may be dependent upon using them in the most appropriate patients. Reducing the exacerbation rate is a significant advantage, but I would also like to know which drugs or drug combinations are most likely to permit major reductions in patients’ corticosteroid requirements. Hopefully, these data will come from real-world comparative efficacy studies.

Reading the article by Hatipoğlu and Aboussouan, I was reminded that utilizing our pulmonary colleagues’ expertise is of particular value in individualizing therapy for our patients with COPD—using newer drugs and combinations when most appropriate, not just because they are readily available. As physicians who are not pulmonary specialists, we need to be vigilant in recognizing the treatable comorbidities that contribute to dyspnea and poor outcome in patients with COPD, such as obstructive sleep apnea, congestive heart failure, obesity, and thromboembolism.

But to make the largest impact on the mortality rate, we need to continue to engage in and expand the ongoing war against cigarette use.

A key part of medical practice is managing professional relationships. This includes effective communication with each other: primary care provider, specialist, and patient in all permutations. I have previously written about how technologic advances both facilitate and hamper interphysician communication. But as payment models morph, as health systems become more complex and insulated, and as the medicine subspecialty workforce changes, the relationship between generalist and nonprocedural specialist will continue to evolve. I can offer personal testimony to the enormous value of sharing our electronic medical record with my nephrology colleagues within the institution; online (nondisruptive) management “conversation” is common in real time while I am with a patient in the office.

Gone is the time when referral was a necessary mechanism to build a practice, when a primary care physician would send everyone with an elevated alkaline phosphatase to the neighboring gastroenterologist, who in turn would send everyone without a primary care doctor to him or her. But there has always been the potential for professional, ego-based tension between primary care and nonprocedural specialist physicians, although this tension is rarely discussed. When does referral to a specialist by a general internist imply a lack of appropriate knowledge or an unwillingness to do an appropriate literature review? When should a specialist be concerned about “interfering” in primary care—by initiating more aggressive blood pressure control, or by giving the patient a needed vaccination? And what should be done if the patient decides to change the captain of the medical team? Maybe in the new medical care arena we will indeed function and be judged as a team, physician communication and transitions will be seamless, and all that matters will be the patient. Time will tell.

For now, the comanagement of patients with a chronic disease is often a challenge. The discussion by Sakhuja et al of patients with chronic kidney disease (CKD) highlights important clinical issues faced by primary care providers and nephrologists. With the increased diagnosis of early CKD, there may not be enough consulting nephrologists to see all these patients. And when CKD is diagnosed at an early stage, not all patients may warrant a specialist consultation. Yet the gaps in clinical care are clear. Too many patients with “a little” proteinuria or microhematuria do not get an adequate microscopic urinalysis to look for a treatable inflammatory renal disorder. Too many patients with a “slightly” elevated creatinine and blood pressure do not have their pressure aggressively treated, despite evidence that a systolic blood pressure in the high 130s is associated with more rapid progression of CKD. Should we establish expectations for ourselves, or should we just take a step back and refer all these patients to a nephrologist and await guidance? This is where I believe that a few clearly written and widely disseminated guidelines would help. Knowledge of appropriate and basic guidelines for diagnosing and managing common disorders (not just CKD) should be the focus of continuing medical education and should be required for maintaining certification for all internists, including specialists. But, as always, guidelines often need to be tailored for the patient in our examining room.

There are nuances in the care of patients with CKD that, as a nonspecialist, I will not automatically know need to be implemented. As an internist, I should know the value of starting inhibition of the angiotensin pathway in patients with proteinuria, but as CKD progresses in a specific patient, should this be decreased? Should I initiate urate-lowering therapy,¹ hoping to slow the rate of my patient’s renal demise?

When do we know enough to know that we do not need to ask for a specialist’s input? How well do we self-assess our clinical knowledge and skills? How can we achieve the right balance between referral and self-management? We try to save our patient the cost of the time and the copayment to see a specialist, and with bundled care we try to minimize consultant fees and time. But in the meantime, are we ordering unnecessary tests or delaying appropriate therapy?

As we think about the comanagement of patients with CKD, we need to recognize and utilize the nuanced improvements in care that our nephrology colleagues can provide. As non-nephrologists, we should be able to start a thoughtful diagnostic evaluation. For example, an antinuclear antibody test in the absence of evidence of glomerulonephritis is not likely to be informative in determining the cause of an isolated elevated creatinine; a urinalysis is. We should be able to recognize potential renal injury (proteinuria, decreased glomerular filtration rate, microhematuria, hypertension), and initiate aggressive mitigation of factors that are known to enhance progression of the CKD (proteinuria, hypertension) and contribute to the significant morbidity and mortality of CKD-associated cardiovascular disease.

We should already be managing hypertension, diabetes, and hyperlipidemia, but CKD should be a red flag, driving us to more aggressively control these comorbidities, and driving us to do better than control only the estimated 46.4% of hypertensive patients in 2009 and 2010 whose hypertension was adequately controlled.² There is no reason for us to step back and wait for direction in addressing these most common issues. And our specialist colleagues will be there to efficiently assist in refining the nuances of care.

A key part of medical practice is managing professional relationships. This includes effective communication with each other: primary care provider, specialist, and patient in all permutations. I have previously written about how technologic advances both facilitate and hamper interphysician communication. But as payment models morph, as health systems become more complex and insulated, and as the medicine subspecialty workforce changes, the relationship between generalist and nonprocedural specialist will continue to evolve. I can offer personal testimony to the enormous value of sharing our electronic medical record with my nephrology colleagues within the institution; online (nondisruptive) management “conversation” is common in real time while I am with a patient in the office.

Gone is the time when referral was a necessary mechanism to build a practice, when a primary care physician would send everyone with an elevated alkaline phosphatase to the neighboring gastroenterologist, who in turn would send everyone without a primary care doctor to him or her. But there has always been the potential for professional, ego-based tension between primary care and nonprocedural specialist physicians, although this tension is rarely discussed. When does referral to a specialist by a general internist imply a lack of appropriate knowledge or an unwillingness to do an appropriate literature review? When should a specialist be concerned about “interfering” in primary care—by initiating more aggressive blood pressure control, or by giving the patient a needed vaccination? And what should be done if the patient decides to change the captain of the medical team? Maybe in the new medical care arena we will indeed function and be judged as a team, physician communication and transitions will be seamless, and all that matters will be the patient. Time will tell.

For now, the comanagement of patients with a chronic disease is often a challenge. The discussion by Sakhuja et al of patients with chronic kidney disease (CKD) highlights important clinical issues faced by primary care providers and nephrologists. With the increased diagnosis of early CKD, there may not be enough consulting nephrologists to see all these patients. And when CKD is diagnosed at an early stage, not all patients may warrant a specialist consultation. Yet the gaps in clinical care are clear. Too many patients with “a little” proteinuria or microhematuria do not get an adequate microscopic urinalysis to look for a treatable inflammatory renal disorder. Too many patients with a “slightly” elevated creatinine and blood pressure do not have their pressure aggressively treated, despite evidence that a systolic blood pressure in the high 130s is associated with more rapid progression of CKD. Should we establish expectations for ourselves, or should we just take a step back and refer all these patients to a nephrologist and await guidance? This is where I believe that a few clearly written and widely disseminated guidelines would help. Knowledge of appropriate and basic guidelines for diagnosing and managing common disorders (not just CKD) should be the focus of continuing medical education and should be required for maintaining certification for all internists, including specialists. But, as always, guidelines often need to be tailored for the patient in our examining room.

There are nuances in the care of patients with CKD that, as a nonspecialist, I will not automatically know need to be implemented. As an internist, I should know the value of starting inhibition of the angiotensin pathway in patients with proteinuria, but as CKD progresses in a specific patient, should this be decreased? Should I initiate urate-lowering therapy,¹ hoping to slow the rate of my patient’s renal demise?

When do we know enough to know that we do not need to ask for a specialist’s input? How well do we self-assess our clinical knowledge and skills? How can we achieve the right balance between referral and self-management? We try to save our patient the cost of the time and the copayment to see a specialist, and with bundled care we try to minimize consultant fees and time. But in the meantime, are we ordering unnecessary tests or delaying appropriate therapy?

As we think about the comanagement of patients with CKD, we need to recognize and utilize the nuanced improvements in care that our nephrology colleagues can provide. As non-nephrologists, we should be able to start a thoughtful diagnostic evaluation. For example, an antinuclear antibody test in the absence of evidence of glomerulonephritis is not likely to be informative in determining the cause of an isolated elevated creatinine; a urinalysis is. We should be able to recognize potential renal injury (proteinuria, decreased glomerular filtration rate, microhematuria, hypertension), and initiate aggressive mitigation of factors that are known to enhance progression of the CKD (proteinuria, hypertension) and contribute to the significant morbidity and mortality of CKD-associated cardiovascular disease.

We should already be managing hypertension, diabetes, and hyperlipidemia, but CKD should be a red flag, driving us to more aggressively control these comorbidities, and driving us to do better than control only the estimated 46.4% of hypertensive patients in 2009 and 2010 whose hypertension was adequately controlled.² There is no reason for us to step back and wait for direction in addressing these most common issues. And our specialist colleagues will be there to efficiently assist in refining the nuances of care.

A key part of medical practice is managing professional relationships. This includes effective communication with each other: primary care provider, specialist, and patient in all permutations. I have previously written about how technologic advances both facilitate and hamper interphysician communication. But as payment models morph, as health systems become more complex and insulated, and as the medicine subspecialty workforce changes, the relationship between generalist and nonprocedural specialist will continue to evolve. I can offer personal testimony to the enormous value of sharing our electronic medical record with my nephrology colleagues within the institution; online (nondisruptive) management “conversation” is common in real time while I am with a patient in the office.

Gone is the time when referral was a necessary mechanism to build a practice, when a primary care physician would send everyone with an elevated alkaline phosphatase to the neighboring gastroenterologist, who in turn would send everyone without a primary care doctor to him or her. But there has always been the potential for professional, ego-based tension between primary care and nonprocedural specialist physicians, although this tension is rarely discussed. When does referral to a specialist by a general internist imply a lack of appropriate knowledge or an unwillingness to do an appropriate literature review? When should a specialist be concerned about “interfering” in primary care—by initiating more aggressive blood pressure control, or by giving the patient a needed vaccination? And what should be done if the patient decides to change the captain of the medical team? Maybe in the new medical care arena we will indeed function and be judged as a team, physician communication and transitions will be seamless, and all that matters will be the patient. Time will tell.

For now, the comanagement of patients with a chronic disease is often a challenge. The discussion by Sakhuja et al of patients with chronic kidney disease (CKD) highlights important clinical issues faced by primary care providers and nephrologists. With the increased diagnosis of early CKD, there may not be enough consulting nephrologists to see all these patients. And when CKD is diagnosed at an early stage, not all patients may warrant a specialist consultation. Yet the gaps in clinical care are clear. Too many patients with “a little” proteinuria or microhematuria do not get an adequate microscopic urinalysis to look for a treatable inflammatory renal disorder. Too many patients with a “slightly” elevated creatinine and blood pressure do not have their pressure aggressively treated, despite evidence that a systolic blood pressure in the high 130s is associated with more rapid progression of CKD. Should we establish expectations for ourselves, or should we just take a step back and refer all these patients to a nephrologist and await guidance? This is where I believe that a few clearly written and widely disseminated guidelines would help. Knowledge of appropriate and basic guidelines for diagnosing and managing common disorders (not just CKD) should be the focus of continuing medical education and should be required for maintaining certification for all internists, including specialists. But, as always, guidelines often need to be tailored for the patient in our examining room.

There are nuances in the care of patients with CKD that, as a nonspecialist, I will not automatically know need to be implemented. As an internist, I should know the value of starting inhibition of the angiotensin pathway in patients with proteinuria, but as CKD progresses in a specific patient, should this be decreased? Should I initiate urate-lowering therapy,¹ hoping to slow the rate of my patient’s renal demise?

When do we know enough to know that we do not need to ask for a specialist’s input? How well do we self-assess our clinical knowledge and skills? How can we achieve the right balance between referral and self-management? We try to save our patient the cost of the time and the copayment to see a specialist, and with bundled care we try to minimize consultant fees and time. But in the meantime, are we ordering unnecessary tests or delaying appropriate therapy?

As we think about the comanagement of patients with CKD, we need to recognize and utilize the nuanced improvements in care that our nephrology colleagues can provide. As non-nephrologists, we should be able to start a thoughtful diagnostic evaluation. For example, an antinuclear antibody test in the absence of evidence of glomerulonephritis is not likely to be informative in determining the cause of an isolated elevated creatinine; a urinalysis is. We should be able to recognize potential renal injury (proteinuria, decreased glomerular filtration rate, microhematuria, hypertension), and initiate aggressive mitigation of factors that are known to enhance progression of the CKD (proteinuria, hypertension) and contribute to the significant morbidity and mortality of CKD-associated cardiovascular disease.

We should already be managing hypertension, diabetes, and hyperlipidemia, but CKD should be a red flag, driving us to more aggressively control these comorbidities, and driving us to do better than control only the estimated 46.4% of hypertensive patients in 2009 and 2010 whose hypertension was adequately controlled.² There is no reason for us to step back and wait for direction in addressing these most common issues. And our specialist colleagues will be there to efficiently assist in refining the nuances of care.

The article by Dickstein et al on eating disorders in this issue of the Journal made me think about my experience long ago as an internist comanaging patients who had severe eating disorders.

As a rheumatologist, I noticed that these young women had a very high prevalence of fibromyalgia and associated visceral pain syndromes such as irritable bowel syndrome and interstitial cystitis. Because they had been experiencing fatigue and generalized pain, many of them had been tested for lupus. Since about 20% of young women may have a low-positive antinuclear antibody titer, some of these patients had been diagnosed with lupus, and some had been offered therapy.

Other factors reinforced their physicians’ appropriate concerns about possible connective tissue disease. For example, modest leukopenia is not infrequent in malnourished patients, and Raynaud phenomenon is common in young women. Bulimia is associated with gastroesophageal dysmotility, and some of these women had slightly elevated creatine kinase levels. These abnormalities were generally the result of over-vigorous exercise, ipecac use, emesis, and hypokalemia. However, myositis or scleroderma overlap syndromes had occasionally been diagnosed in some patients, especially when the severity of the primary eating disorder was unappreciated.

Many, including myself, have written about the strengths and limitations of evidence-based medicine. We routinely make both evidence- and experience-based clinical decisions, often with little time to reflect on the exact reason for each decision. As I think back on my stint in the eating disorders clinic, recalling individual patients and lessons learned, I am struck by how observation-based my management of those patients was and how those experiences have stuck with me.

Reflective clinical care (also known as anecdotal experience) can have a lasting impact on the way we practice. Twenty-five years later, I still think about eating disorders when I evaluate young women who have severe fibromyalgia.

The article by Dickstein et al on eating disorders in this issue of the Journal made me think about my experience long ago as an internist comanaging patients who had severe eating disorders.

As a rheumatologist, I noticed that these young women had a very high prevalence of fibromyalgia and associated visceral pain syndromes such as irritable bowel syndrome and interstitial cystitis. Because they had been experiencing fatigue and generalized pain, many of them had been tested for lupus. Since about 20% of young women may have a low-positive antinuclear antibody titer, some of these patients had been diagnosed with lupus, and some had been offered therapy.

Other factors reinforced their physicians’ appropriate concerns about possible connective tissue disease. For example, modest leukopenia is not infrequent in malnourished patients, and Raynaud phenomenon is common in young women. Bulimia is associated with gastroesophageal dysmotility, and some of these women had slightly elevated creatine kinase levels. These abnormalities were generally the result of over-vigorous exercise, ipecac use, emesis, and hypokalemia. However, myositis or scleroderma overlap syndromes had occasionally been diagnosed in some patients, especially when the severity of the primary eating disorder was unappreciated.

Many, including myself, have written about the strengths and limitations of evidence-based medicine. We routinely make both evidence- and experience-based clinical decisions, often with little time to reflect on the exact reason for each decision. As I think back on my stint in the eating disorders clinic, recalling individual patients and lessons learned, I am struck by how observation-based my management of those patients was and how those experiences have stuck with me.

Reflective clinical care (also known as anecdotal experience) can have a lasting impact on the way we practice. Twenty-five years later, I still think about eating disorders when I evaluate young women who have severe fibromyalgia.

The article by Dickstein et al on eating disorders in this issue of the Journal made me think about my experience long ago as an internist comanaging patients who had severe eating disorders.

As a rheumatologist, I noticed that these young women had a very high prevalence of fibromyalgia and associated visceral pain syndromes such as irritable bowel syndrome and interstitial cystitis. Because they had been experiencing fatigue and generalized pain, many of them had been tested for lupus. Since about 20% of young women may have a low-positive antinuclear antibody titer, some of these patients had been diagnosed with lupus, and some had been offered therapy.

Other factors reinforced their physicians’ appropriate concerns about possible connective tissue disease. For example, modest leukopenia is not infrequent in malnourished patients, and Raynaud phenomenon is common in young women. Bulimia is associated with gastroesophageal dysmotility, and some of these women had slightly elevated creatine kinase levels. These abnormalities were generally the result of over-vigorous exercise, ipecac use, emesis, and hypokalemia. However, myositis or scleroderma overlap syndromes had occasionally been diagnosed in some patients, especially when the severity of the primary eating disorder was unappreciated.

Many, including myself, have written about the strengths and limitations of evidence-based medicine. We routinely make both evidence- and experience-based clinical decisions, often with little time to reflect on the exact reason for each decision. As I think back on my stint in the eating disorders clinic, recalling individual patients and lessons learned, I am struck by how observation-based my management of those patients was and how those experiences have stuck with me.

Reflective clinical care (also known as anecdotal experience) can have a lasting impact on the way we practice. Twenty-five years later, I still think about eating disorders when I evaluate young women who have severe fibromyalgia.

Recent guidelines have revisited the management of two major modifiable risk factors for cardiovascular morbidity: hypercholesterolemia and hypertension. The authors of each purposefully emphasized high-grade evidence in generating their recommendations. But, as pointed out by Thomas et al in this issue of the Journal,¹ the authors of the hypertension guidelines still resorted to “expert opinion” in five of their 10 recommendations.

The authors of the new hypertension guidelines from the Eighth Joint National Committee (JNC 8),² as well as the new cholesterol guidelines³ discussed by Raymond et al in the January 2014 issue of the Journal,⁴ relied on interventional clinical trial evidence for their recommendations. The good news in the context of pay-for-performance metrics is that both of these new guidelines are easier to adhere to than the previous ones. But will the new guidelines really help us achieve better patient outcomes?

Concerns about these guidelines spring directly from their assumed major strength—ie, that they are based on interventional trial data. Well-run, randomized, controlled trials are the brass ring of evidence-based medical practice, presumably providing the cleanest demonstration of therapeutic efficacy. But with “clean” data potentially come sterile, non-real-world conclusions that may advise but should not limit our practice decisions. Most of our patients do not fit neatly into trial inclusion and exclusion criteria, nor do they exactly match the demographics of trial volunteers. Patients who participate in clinical trials are not the same as the patients who populate our clinics. Nor, unfortunately, is the blood pressure measurement technique likely the same in the clinical trial setting as in many of our offices.

In the clinic, it seems obvious not to be overly zealous about blood pressure control in an elderly, frail, hypertensive patient. But at the same time, aiming for a systolic pressure lower than 150 mm Hg (which is looser than in the last set of guidelines) as a target for those over age 60 is incredibly arbitrary, given that physiology and biologic risk rarely act in a step-function manner. Biologic metrics tend to behave as a continuum. If we recognize that the blood pressure can be readily and safely reduced further in a given patient, and if there are observational data to support the concept that risk for cardiovascular events roughly parallels the systolic blood pressure in a continuous manner to lower than 150 mm Hg, why aim to lower it only slightly? Trial-based guidelines are valuable, but they should not replace sound physiologic reasoning and common sense (also known as “expert opinion”). Yet we must temper this logical reasoning with lessons learned from trials such as ACCORD,⁵ which showed that overly vigorous efforts at reaching theoretical therapeutic targets may be fraught with unexpected adverse outcomes.

Our challenge is to appropriately individualize therapy, usually in the absence of relevant comparative efficacy studies. Trying to apply homogenized clinical trial data to the individual patient in the examination room is not always reasonable. Treating a 59-year-old who has a slowly escalating systolic pressure of 142 mm Hg is not the same as treating a 32-year-old who has a chronic pressure of 138 and an audible S4.

The new hypertension guidelines should be easier to implement than the previous ones in JNC 7. I like some of the specificity of the new recommendations and the disappearance of beta-blockers from the list of recommended early therapies. Yet I think that in the presence of comorbidities and end-organ damage, they may be too lax. And certain groups are left relatively undiscussed, such as patients with cerebrovascular disease, known hypertensive vascular injury, and obstructive sleep apnea, as there were limited trial data to provide guidance (although for some clinical subsets we do have very suggestive observational and experiential data). We can’t always wait for the perfect trial to be done in order to make clinical decisions.

To paraphrase Thomas et al,¹ for these guidelines, one size fits many, but we still must do significant custom tailoring in the office. In the months ahead, we will try to provide some guidance on how to effectively deal with those situations where robust trial evidence is insufficient to direct clinical decision-making.

Recent guidelines have revisited the management of two major modifiable risk factors for cardiovascular morbidity: hypercholesterolemia and hypertension. The authors of each purposefully emphasized high-grade evidence in generating their recommendations. But, as pointed out by Thomas et al in this issue of the Journal,¹ the authors of the hypertension guidelines still resorted to “expert opinion” in five of their 10 recommendations.

The authors of the new hypertension guidelines from the Eighth Joint National Committee (JNC 8),² as well as the new cholesterol guidelines³ discussed by Raymond et al in the January 2014 issue of the Journal,⁴ relied on interventional clinical trial evidence for their recommendations. The good news in the context of pay-for-performance metrics is that both of these new guidelines are easier to adhere to than the previous ones. But will the new guidelines really help us achieve better patient outcomes?

Concerns about these guidelines spring directly from their assumed major strength—ie, that they are based on interventional trial data. Well-run, randomized, controlled trials are the brass ring of evidence-based medical practice, presumably providing the cleanest demonstration of therapeutic efficacy. But with “clean” data potentially come sterile, non-real-world conclusions that may advise but should not limit our practice decisions. Most of our patients do not fit neatly into trial inclusion and exclusion criteria, nor do they exactly match the demographics of trial volunteers. Patients who participate in clinical trials are not the same as the patients who populate our clinics. Nor, unfortunately, is the blood pressure measurement technique likely the same in the clinical trial setting as in many of our offices.

In the clinic, it seems obvious not to be overly zealous about blood pressure control in an elderly, frail, hypertensive patient. But at the same time, aiming for a systolic pressure lower than 150 mm Hg (which is looser than in the last set of guidelines) as a target for those over age 60 is incredibly arbitrary, given that physiology and biologic risk rarely act in a step-function manner. Biologic metrics tend to behave as a continuum. If we recognize that the blood pressure can be readily and safely reduced further in a given patient, and if there are observational data to support the concept that risk for cardiovascular events roughly parallels the systolic blood pressure in a continuous manner to lower than 150 mm Hg, why aim to lower it only slightly? Trial-based guidelines are valuable, but they should not replace sound physiologic reasoning and common sense (also known as “expert opinion”). Yet we must temper this logical reasoning with lessons learned from trials such as ACCORD,⁵ which showed that overly vigorous efforts at reaching theoretical therapeutic targets may be fraught with unexpected adverse outcomes.

Our challenge is to appropriately individualize therapy, usually in the absence of relevant comparative efficacy studies. Trying to apply homogenized clinical trial data to the individual patient in the examination room is not always reasonable. Treating a 59-year-old who has a slowly escalating systolic pressure of 142 mm Hg is not the same as treating a 32-year-old who has a chronic pressure of 138 and an audible S4.

The new hypertension guidelines should be easier to implement than the previous ones in JNC 7. I like some of the specificity of the new recommendations and the disappearance of beta-blockers from the list of recommended early therapies. Yet I think that in the presence of comorbidities and end-organ damage, they may be too lax. And certain groups are left relatively undiscussed, such as patients with cerebrovascular disease, known hypertensive vascular injury, and obstructive sleep apnea, as there were limited trial data to provide guidance (although for some clinical subsets we do have very suggestive observational and experiential data). We can’t always wait for the perfect trial to be done in order to make clinical decisions.

To paraphrase Thomas et al,¹ for these guidelines, one size fits many, but we still must do significant custom tailoring in the office. In the months ahead, we will try to provide some guidance on how to effectively deal with those situations where robust trial evidence is insufficient to direct clinical decision-making.

Recent guidelines have revisited the management of two major modifiable risk factors for cardiovascular morbidity: hypercholesterolemia and hypertension. The authors of each purposefully emphasized high-grade evidence in generating their recommendations. But, as pointed out by Thomas et al in this issue of the Journal,¹ the authors of the hypertension guidelines still resorted to “expert opinion” in five of their 10 recommendations.

The authors of the new hypertension guidelines from the Eighth Joint National Committee (JNC 8),² as well as the new cholesterol guidelines³ discussed by Raymond et al in the January 2014 issue of the Journal,⁴ relied on interventional clinical trial evidence for their recommendations. The good news in the context of pay-for-performance metrics is that both of these new guidelines are easier to adhere to than the previous ones. But will the new guidelines really help us achieve better patient outcomes?

Concerns about these guidelines spring directly from their assumed major strength—ie, that they are based on interventional trial data. Well-run, randomized, controlled trials are the brass ring of evidence-based medical practice, presumably providing the cleanest demonstration of therapeutic efficacy. But with “clean” data potentially come sterile, non-real-world conclusions that may advise but should not limit our practice decisions. Most of our patients do not fit neatly into trial inclusion and exclusion criteria, nor do they exactly match the demographics of trial volunteers. Patients who participate in clinical trials are not the same as the patients who populate our clinics. Nor, unfortunately, is the blood pressure measurement technique likely the same in the clinical trial setting as in many of our offices.

In the clinic, it seems obvious not to be overly zealous about blood pressure control in an elderly, frail, hypertensive patient. But at the same time, aiming for a systolic pressure lower than 150 mm Hg (which is looser than in the last set of guidelines) as a target for those over age 60 is incredibly arbitrary, given that physiology and biologic risk rarely act in a step-function manner. Biologic metrics tend to behave as a continuum. If we recognize that the blood pressure can be readily and safely reduced further in a given patient, and if there are observational data to support the concept that risk for cardiovascular events roughly parallels the systolic blood pressure in a continuous manner to lower than 150 mm Hg, why aim to lower it only slightly? Trial-based guidelines are valuable, but they should not replace sound physiologic reasoning and common sense (also known as “expert opinion”). Yet we must temper this logical reasoning with lessons learned from trials such as ACCORD,⁵ which showed that overly vigorous efforts at reaching theoretical therapeutic targets may be fraught with unexpected adverse outcomes.

Our challenge is to appropriately individualize therapy, usually in the absence of relevant comparative efficacy studies. Trying to apply homogenized clinical trial data to the individual patient in the examination room is not always reasonable. Treating a 59-year-old who has a slowly escalating systolic pressure of 142 mm Hg is not the same as treating a 32-year-old who has a chronic pressure of 138 and an audible S4.

The new hypertension guidelines should be easier to implement than the previous ones in JNC 7. I like some of the specificity of the new recommendations and the disappearance of beta-blockers from the list of recommended early therapies. Yet I think that in the presence of comorbidities and end-organ damage, they may be too lax. And certain groups are left relatively undiscussed, such as patients with cerebrovascular disease, known hypertensive vascular injury, and obstructive sleep apnea, as there were limited trial data to provide guidance (although for some clinical subsets we do have very suggestive observational and experiential data). We can’t always wait for the perfect trial to be done in order to make clinical decisions.

To paraphrase Thomas et al,¹ for these guidelines, one size fits many, but we still must do significant custom tailoring in the office. In the months ahead, we will try to provide some guidance on how to effectively deal with those situations where robust trial evidence is insufficient to direct clinical decision-making.