Articles

Delay in diagnosing blastomycosis cuts a young life short

COUGH, FEVER, AND FLU-LIKE SYMPTOMS for a week prompted a 25-year-old man to visit his physician, who prescribed an antibiotic. When the symptoms didn‘t improve after 3 days, the patient went to a local health care group, where a physician assistant continued the antibiotic, performed a tuberculosis test, and instructed the young man to return in 3 days.

At the return visit, the patient still had the cough and a fever of 101°F, as well as decreased breath sounds and bilateral pain in his lower lungs when reclining. Another physician assistant diagnosed pneumonia and prescribed a different antibiotic, but didn’t order chest radiographs or blood work—or measure oxygen saturation. He wrote the patient a 5-day excuse from work and told him to return if his condition worsened.

A few days later, the patient went to the emergency department, where he was diagnosed with a pulmonary blastomycosis infection. The infection was too far advanced to treat effectively, and the man died shortly thereafter.

PLAINTIFF’S CLAIM The physician assistants were negligent for not having radiographs or blood work done and not consulting the supervising physician. The supervising physician didn’t review the examination and treatment notes.

THE DEFENSE No negligence occurred; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $3.7 million Wisconsin verdict.

COMMENT This case sends shivers down my spine. I really get worried when huge verdicts are returned for failure to diagnose rare conditions. How many times a week do we treat patients for “bronchitis” or community-acquired pneumonia without getting a radiograph or oxygen saturation measurement—especially in a 25-year-old!

A drug overdose, with plenty of blame to go around

AN 85-YEAR-OLD WOMAN was admitted to a nursing home for a temporary stay after she broke her arm shoveling snow in her driveway. Her physician prescribed a medication, to be given once a week, for the woman’s rheumatoid arthritis. But because a nurse transcribed the order incorrectly, the patient was given the medication every day. After 17 days, she died of an overdose.

PLAINTIFF’S CLAIM The nurse was negligent in transcribing the order incorrectly, the doctor was negligent for signing the order without reading the nurse’s note, and the pharmacy was negligent for failing to discover the dosage error.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Ohio settlement.

COMMENT The moral of this story: Don’t sign those nursing home orders on autopilot!

Unexamined mass isn’t benign after all

A PEA-SIZED MASS on a 34-year-old woman’s head was diagnosed as a sebaceous cyst. A physician assistant removed the mass, which was thrown away without being sent for pathologic examination. A year later, the mass reappeared and was identified as a sarcoma. The woman died a year later.

PLAINTIFF’S CLAIM The doctor and physician assistant were negligent in failing to diagnose the mass accurately and failing to send it for pathologic analysis.

THE DEFENSE The mass appeared normal and didn’t require examination.

VERDICT $1.5 million Texas settlement.

COMMENT I make it a policy to send all skin specimens—no matter how innocuous—for pathologic determination. I recently testified for a defendant in a case similar to this one (fortunately the physician won).

Delay in diagnosing blastomycosis cuts a young life short

COUGH, FEVER, AND FLU-LIKE SYMPTOMS for a week prompted a 25-year-old man to visit his physician, who prescribed an antibiotic. When the symptoms didn‘t improve after 3 days, the patient went to a local health care group, where a physician assistant continued the antibiotic, performed a tuberculosis test, and instructed the young man to return in 3 days.

At the return visit, the patient still had the cough and a fever of 101°F, as well as decreased breath sounds and bilateral pain in his lower lungs when reclining. Another physician assistant diagnosed pneumonia and prescribed a different antibiotic, but didn’t order chest radiographs or blood work—or measure oxygen saturation. He wrote the patient a 5-day excuse from work and told him to return if his condition worsened.

A few days later, the patient went to the emergency department, where he was diagnosed with a pulmonary blastomycosis infection. The infection was too far advanced to treat effectively, and the man died shortly thereafter.

PLAINTIFF’S CLAIM The physician assistants were negligent for not having radiographs or blood work done and not consulting the supervising physician. The supervising physician didn’t review the examination and treatment notes.

THE DEFENSE No negligence occurred; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $3.7 million Wisconsin verdict.

COMMENT This case sends shivers down my spine. I really get worried when huge verdicts are returned for failure to diagnose rare conditions. How many times a week do we treat patients for “bronchitis” or community-acquired pneumonia without getting a radiograph or oxygen saturation measurement—especially in a 25-year-old!

A drug overdose, with plenty of blame to go around

AN 85-YEAR-OLD WOMAN was admitted to a nursing home for a temporary stay after she broke her arm shoveling snow in her driveway. Her physician prescribed a medication, to be given once a week, for the woman’s rheumatoid arthritis. But because a nurse transcribed the order incorrectly, the patient was given the medication every day. After 17 days, she died of an overdose.

PLAINTIFF’S CLAIM The nurse was negligent in transcribing the order incorrectly, the doctor was negligent for signing the order without reading the nurse’s note, and the pharmacy was negligent for failing to discover the dosage error.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Ohio settlement.

COMMENT The moral of this story: Don’t sign those nursing home orders on autopilot!

Unexamined mass isn’t benign after all

A PEA-SIZED MASS on a 34-year-old woman’s head was diagnosed as a sebaceous cyst. A physician assistant removed the mass, which was thrown away without being sent for pathologic examination. A year later, the mass reappeared and was identified as a sarcoma. The woman died a year later.

PLAINTIFF’S CLAIM The doctor and physician assistant were negligent in failing to diagnose the mass accurately and failing to send it for pathologic analysis.

THE DEFENSE The mass appeared normal and didn’t require examination.

VERDICT $1.5 million Texas settlement.

COMMENT I make it a policy to send all skin specimens—no matter how innocuous—for pathologic determination. I recently testified for a defendant in a case similar to this one (fortunately the physician won).

Delay in diagnosing blastomycosis cuts a young life short

COUGH, FEVER, AND FLU-LIKE SYMPTOMS for a week prompted a 25-year-old man to visit his physician, who prescribed an antibiotic. When the symptoms didn‘t improve after 3 days, the patient went to a local health care group, where a physician assistant continued the antibiotic, performed a tuberculosis test, and instructed the young man to return in 3 days.

At the return visit, the patient still had the cough and a fever of 101°F, as well as decreased breath sounds and bilateral pain in his lower lungs when reclining. Another physician assistant diagnosed pneumonia and prescribed a different antibiotic, but didn’t order chest radiographs or blood work—or measure oxygen saturation. He wrote the patient a 5-day excuse from work and told him to return if his condition worsened.

A few days later, the patient went to the emergency department, where he was diagnosed with a pulmonary blastomycosis infection. The infection was too far advanced to treat effectively, and the man died shortly thereafter.

PLAINTIFF’S CLAIM The physician assistants were negligent for not having radiographs or blood work done and not consulting the supervising physician. The supervising physician didn’t review the examination and treatment notes.

THE DEFENSE No negligence occurred; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $3.7 million Wisconsin verdict.

COMMENT This case sends shivers down my spine. I really get worried when huge verdicts are returned for failure to diagnose rare conditions. How many times a week do we treat patients for “bronchitis” or community-acquired pneumonia without getting a radiograph or oxygen saturation measurement—especially in a 25-year-old!

A drug overdose, with plenty of blame to go around

AN 85-YEAR-OLD WOMAN was admitted to a nursing home for a temporary stay after she broke her arm shoveling snow in her driveway. Her physician prescribed a medication, to be given once a week, for the woman’s rheumatoid arthritis. But because a nurse transcribed the order incorrectly, the patient was given the medication every day. After 17 days, she died of an overdose.

PLAINTIFF’S CLAIM The nurse was negligent in transcribing the order incorrectly, the doctor was negligent for signing the order without reading the nurse’s note, and the pharmacy was negligent for failing to discover the dosage error.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Ohio settlement.

COMMENT The moral of this story: Don’t sign those nursing home orders on autopilot!

Unexamined mass isn’t benign after all

A PEA-SIZED MASS on a 34-year-old woman’s head was diagnosed as a sebaceous cyst. A physician assistant removed the mass, which was thrown away without being sent for pathologic examination. A year later, the mass reappeared and was identified as a sarcoma. The woman died a year later.

PLAINTIFF’S CLAIM The doctor and physician assistant were negligent in failing to diagnose the mass accurately and failing to send it for pathologic analysis.

THE DEFENSE The mass appeared normal and didn’t require examination.

VERDICT $1.5 million Texas settlement.

COMMENT I make it a policy to send all skin specimens—no matter how innocuous—for pathologic determination. I recently testified for a defendant in a case similar to this one (fortunately the physician won).

Exercise has been used for cardiac stress testing for decades. But testing and imaging techniques and knowledge of the efficacy of this common diagnostic tool continue to evolve. Optimizing your use of stress testing requires that you familiarize yourself with the latest evidence. The evidence-based answers to these 6 questions will help you do just that.

1. How reliable are exercise stress tests?

That depends, of course, on any number of variables, including the protocol utilized, the number of stenotic vessels, the degree of stenosis, and even the sex of the patient.

False-negative and false-positive results are frequent in treadmill testing without imaging. (For more on the different protocols, see “Standard and nuclear exercise stress tests: A look at protocols”) Sensitivity is related to the number of stenotic vessels and the degree of stenosis. For a man with single-vessel disease and ≥70% stenosis, the likelihood of an abnormal test is only 50% to 60%. Even in a man with left main artery disease, the sensitivity is only about 85%.¹

In some cases, failure to reach a cardiac workload sufficient to produce ischemia can lead to a false-negative test, and it is up to the physician performing the test to label it as nondiagnostic. Other reasons for false-positive or false-negative results include preexisting ST segment abnormalities, which can cause false-positive elevation of the ST segment during exercise; the use of digitalis, which affects the ST segment; and the presence of ventricular hypertrophy or cardiomyopathy.¹ Patients with any of these conditions should undergo stress testing with imaging instead.

Nuclear stress testing is indicated for patients who have baseline EKG abnormalities, suspected false-positive or false-negative results from a stress test without imaging, known CAD or previous revascularization, a pacemaker, or a moderate to high likelihood of a CAD diagnosis. The addition of a tracer isotope and imaging boosts the test’s predictive value.¹

The positive predictive value of nuclear stress testing is difficult to calculate because an abnormal test should lead to initiation of therapy designed to reduce the risk of cardiac death or myocardial infarction (MI). Numerous studies have found the rate of cardiac events after a negative radionuclide stress test to be less than 1% per year.² The event rate after a negative test is lower in women than in men; after a positive test, however, the event rate in women is 2 to 3 times higher.^2,3 Overall, stress testing is less sensitive in women than in men, at least in part because of their lower likelihood of CAD associated with any given symptom set.⁴

2. When should you rule out stress testing?

Stress testing is unnecessary in asymptomatic patients. Numerous studies have documented the lack of benefit from screening asymptomatic people for CAD using exercise stress testing.^5,6 The US Preventive Services Task Force gives this a Grade D recommendation—recommending against routine stress testing.⁷

There are also numerous contraindications, both absolute and relative (TABLE).⁸ Relative contraindications, which include severe hypertension, left main coronary stenosis, moderate stenotic valvular disease, electrolyte abnormalities, cardiomyopathy, serious mental or physical impairment, and atrioventricular block are conditions that are likely to interfere with test performance or reliability.

Absolute contraindications, generally related to unstable cardiopulmonary disease, pose a far more serious threat. Indeed, administering a treadmill stress test to a patient with 1 or more absolute contraindications greatly increases the risk of death associated with the test.⁸

Even if a patient does not have any relative or absolute contraindications, there is still some risk of moving forward with the test. There is about a 1 in 2500 risk of MI or death during, or related to, exercise stress testing.⁸ The greater the likelihood that a patient has CAD, the higher the risk.

There is also a risk of hospitalization after the test, usually related to persistent chest pain or arrhythmias. (I generally admit patients whose chest pain is unresponsive to 3 doses of nitroglycerine or who develop EKG changes that persist after 20 minutes at rest.) The test also raises the possibility of injury from the equipment, such as sprains or fractures caused by falling from the treadmill.

Nuclear stress testing also has a small risk of an allergic reaction to the isotope used as a tracer. The radiation dose is 8 to 9 mSV, comparable to a computed tomography (CT) scan of the chest and generally less than that of a coronary angiogram.⁹

TABLE
Stress testing: Absolute and relative contraindications⁸

3. Does the evidence support the use of stress tests for asymptomatic patients with diabetes? Are preop stress tests advisable?

The jury is still out on both questions.

The question of asymptomatic testing for patients with diabetes mellitus, who are more likely than those without the disease to develop CAD, frequently arises. Although individuals with diabetes have higher rates of silent ischemia than the general population, however, estimates of this prevalence vary widely.¹⁰ There are no clear guidelines for evaluation of asymptomatic diabetic patients with exercise stress testing. (See “Test your skills with these 3 cases”)

The addition of nuclide imaging adds diagnostic value to the test, but it is still not clear that this should be the preferred test for patients with diabetes who have normal resting EKGs.^10,11 A recent randomized controlled trial investigating screening with pharmacologic stress testing in asymptomatic patients with type 2 diabetes did not show a reduction in cardiac event rates in patients who were screened compared with those who were not screened.¹²

Similarly, preoperative stress testing is subject to debate.¹³ Many studies have been done to evaluate the utility of preoperative stress testing, with revascularization procedures done before the planned surgery when significant CAD is found. (See “Before surgery: Have you done enough to mitigate risk?” J Fam Pract. 2010;59:202-211.) And, while many demonstrate the predictive power of various parameters that stress tests measure, literature reviews show that—with the exception of patients with unstable CAD—postop event rates are about the same for patients who underwent stress testing and subsequent revascularization vs those who were treated medically instead.^13,14

4. If your patient requires a pharmacologic stress test, what are your options besides adenosine?

While adenosine is the agent of choice, dipyridamole and dobutamine are other options. When any of these agents are used, it’s important to consider the side effects of each, and which drugs your patient will need to avoid prior to the stress test.

Adenosine is a mediator of coronary vasodilation. The drug dilates normal coronary arteries preferentially to stenotic vessels and causes redistribution of blood flow away from areas of the myocardium with compromised circulation.

Dipyridamole, a mediator of adenosine release, is sometimes used instead. Both drugs are given as a 4-minute infusion, with injection of the tracer late in the infusion.

The adverse effects of adenosine occur early in the infusion, and include dyspnea, bronchospasm, chest pain, nausea, and headache. Bradycardia can be marked, and brief periods of complete heart block and long sinus pauses may occur. Hypotension can likewise be profound. Many of these effects are extremely disturbing to the patient under-going the test, but they disappear within 30 seconds of stopping the infusion.

Dipyridamole has similar adverse effects, although heart block is not part of its adverse effect profile. In addition, the drug’s adverse effects occur later in the infusion than those associated with adenosine and last well after it is finished. However, dipyridamole’s side effects can be reversed with intravenous aminophylline without compromising the accuracy of the test.

Drugs to avoid that day. Methylxanthines antagonize adenosine and dipyridamole, and thus must be avoided on the day of the test. Caffeine and theophylline are among the substances to be avoided, although the degree to which they affect test results has been questioned recently.¹⁵

Severe COPD and asthma—especially in patients with uncontrolled wheezing—are relative contraindications to the use of adenosine and dipyridamole.

Interestingly, the cardiovascular effects (and EKG changes) associated with these drugs are not necessarily indicative of CAD. Thus, the entire EKG portion of a pharmacologic stress test is not useful in interpreting the finding. One small study suggests that, unlike exercise stress testing, adenosine stress testing may be safe in patients with severe aortic stenosis.¹⁶

Dobutamine is another alternative for pharmacologic stress testing, for patients who cannot take adenosine or are unable to stop theophylline or similar medications. An infusion of dobutamine with an escalating dose, sometimes including atropine, is used to accelerate the heart rate to 85% of the patient’s age-predicted maximum. The stress is primarily due to the chronotropic effect of the drug, but dobutamine has some coronary vasodilatory activity and may also induce some redistribution of coronary blood flow, similar to the effect of adenosine.

The positive and negative predictive values of pharmacologic stress testing are the same as for nuclear stress testing. Unlike exercise testing, however, functional capacity cannot be inferred from a pharmacologic stress test.

About 10% of patients undergoing pharmacologic stress testing will have a nondiagnostic test. The sensitivity of the test varies among studies, but it is approximately 84%, 95%, and 100% for single-, double-, and triplevessel disease, respectively. Patients with negative tests have an event rate of less than 1% per year.¹⁷

5. Is stress echocardiography comparable to stress testing?

Yes. Stress echocardiography, which involves echocardiographic studies taken before and after stress, can substitute for either exercise or pharmacologic stress testing (the stress can be achieved either with exercise or an infusion of dobutamine), and it has certain advantages: Stress echocardiography is cheaper than nuclear stress testing, and there is no radiation involved. In addition, stress echocardiography yields positive and negative predictive values similar to those seen with nuclear stress testing.^2,3 The presence of ischemia is inferred from localized wall motion abnormalities.

The primary disadvantage of stress echocardiography is that it can be administered only by a cardiologist who has been specially trained in this procedure. In contrast, any community hospital nuclear medicine department has the capacity to perform nuclear imaging, and most radiologists are able to interpret the nuclide scans. In my experience, decisions about whether to order nuclear cardiac stress testing or stress echocardiography are influenced not only by the availability of these modalities, but also by the skill of the physicians who will interpret the tests.

6. Which exercise-induced EKG changes are related to ischemia?

The only changes that correlate with myocardial ischemia are ST depression and ST elevation. J-point depression is almost universally seen with exercise. For this reason, the ST level is measured 80 milliseconds after the J point.

ST depression—the most common abnormal finding—indicates subendocardial ischemia. ST changes are most commonly seen in the inferior and lateral leads, but do not correlate with the location of ischemia. ST depression can be downsloping, horizontal, or upsloping. The first 2 are the most significant patterns, and 1 mm of ST depression is the minimum significant level. Upsloping ST depression is less significant, and 1.5 mm of depression is the minimum significant change.¹ The greater the degree of ST depression, the higher the likelihood that significant occlusion will be seen on coronary angiography. ST depression that develops in the recovery period is a rare occurrence but of equal significance to ST depression that occurs with exercise, and is probably due to ischemia caused by shunting of blood into skeletal muscle and away from the heart.¹

ST elevation is less common, but more ominous than ST depression, as it indicates transmural ischemia.¹ This finding most often indicates high-grade left anterior descending (LAD) or left main CAD. It is most often seen in the anterior leads, and the location of ST changes correlates with the area of ischemia. Bear in mind, however, that the correlation between ST elevation and transmural ischemia is true only if the patient has no history of MI. ST elevation in leads in which Q waves are present at rest usually indicates ventricular dyskinesia or aneurysm and not ischemia.¹

Premenopausal women and women who are taking estrogen supplements, in particular, are more likely than men to have false-positive ST changes, most likely because of a poorly understood effect of estrogen. The molecules of estrogen and of digitalis glycosides have some regions of structural similarity, and it is thought that both molecules can cause ST changes.¹⁰

And what about arrhythmias? Arrhythmias are often seen at rest and with exertion. Supraventricular arrhythmias, including supraventricular tachycardia, are not associated with CAD. Premature ventricular contractions (PVCs) are common at peak exertion. PVCs are probably related to catecholamine release and do not indicate ischemia. (See “A look at the stress test report”)

Ventricular tachycardia, however—defined as 3 or more consecutive PVCs—has a 90% correlation with significant coronary artery stenosis, as shown on angiography.¹

Rate-dependent conduction disturbances, including 2-to-1 atrioventricular block and bundle-branch blocks, may also be seen. These may be associated with ischemia, but are not highly predictive of coronary artery stenosis. Further testing may be indicated to determine whether stenosis is present.¹

CORRESPONDENCE Mark A. Knox, MD, UPMC Shadyside Family Medicine Residency Program, 5230 Centre Avenue, Pittsburgh, PA 15232; [email protected]

Exercise has been used for cardiac stress testing for decades. But testing and imaging techniques and knowledge of the efficacy of this common diagnostic tool continue to evolve. Optimizing your use of stress testing requires that you familiarize yourself with the latest evidence. The evidence-based answers to these 6 questions will help you do just that.

1. How reliable are exercise stress tests?

That depends, of course, on any number of variables, including the protocol utilized, the number of stenotic vessels, the degree of stenosis, and even the sex of the patient.

False-negative and false-positive results are frequent in treadmill testing without imaging. (For more on the different protocols, see “Standard and nuclear exercise stress tests: A look at protocols”) Sensitivity is related to the number of stenotic vessels and the degree of stenosis. For a man with single-vessel disease and ≥70% stenosis, the likelihood of an abnormal test is only 50% to 60%. Even in a man with left main artery disease, the sensitivity is only about 85%.¹

In some cases, failure to reach a cardiac workload sufficient to produce ischemia can lead to a false-negative test, and it is up to the physician performing the test to label it as nondiagnostic. Other reasons for false-positive or false-negative results include preexisting ST segment abnormalities, which can cause false-positive elevation of the ST segment during exercise; the use of digitalis, which affects the ST segment; and the presence of ventricular hypertrophy or cardiomyopathy.¹ Patients with any of these conditions should undergo stress testing with imaging instead.

Nuclear stress testing is indicated for patients who have baseline EKG abnormalities, suspected false-positive or false-negative results from a stress test without imaging, known CAD or previous revascularization, a pacemaker, or a moderate to high likelihood of a CAD diagnosis. The addition of a tracer isotope and imaging boosts the test’s predictive value.¹

The positive predictive value of nuclear stress testing is difficult to calculate because an abnormal test should lead to initiation of therapy designed to reduce the risk of cardiac death or myocardial infarction (MI). Numerous studies have found the rate of cardiac events after a negative radionuclide stress test to be less than 1% per year.² The event rate after a negative test is lower in women than in men; after a positive test, however, the event rate in women is 2 to 3 times higher.^2,3 Overall, stress testing is less sensitive in women than in men, at least in part because of their lower likelihood of CAD associated with any given symptom set.⁴

2. When should you rule out stress testing?

Stress testing is unnecessary in asymptomatic patients. Numerous studies have documented the lack of benefit from screening asymptomatic people for CAD using exercise stress testing.^5,6 The US Preventive Services Task Force gives this a Grade D recommendation—recommending against routine stress testing.⁷

There are also numerous contraindications, both absolute and relative (TABLE).⁸ Relative contraindications, which include severe hypertension, left main coronary stenosis, moderate stenotic valvular disease, electrolyte abnormalities, cardiomyopathy, serious mental or physical impairment, and atrioventricular block are conditions that are likely to interfere with test performance or reliability.

Absolute contraindications, generally related to unstable cardiopulmonary disease, pose a far more serious threat. Indeed, administering a treadmill stress test to a patient with 1 or more absolute contraindications greatly increases the risk of death associated with the test.⁸

Even if a patient does not have any relative or absolute contraindications, there is still some risk of moving forward with the test. There is about a 1 in 2500 risk of MI or death during, or related to, exercise stress testing.⁸ The greater the likelihood that a patient has CAD, the higher the risk.

There is also a risk of hospitalization after the test, usually related to persistent chest pain or arrhythmias. (I generally admit patients whose chest pain is unresponsive to 3 doses of nitroglycerine or who develop EKG changes that persist after 20 minutes at rest.) The test also raises the possibility of injury from the equipment, such as sprains or fractures caused by falling from the treadmill.

Nuclear stress testing also has a small risk of an allergic reaction to the isotope used as a tracer. The radiation dose is 8 to 9 mSV, comparable to a computed tomography (CT) scan of the chest and generally less than that of a coronary angiogram.⁹

TABLE
Stress testing: Absolute and relative contraindications⁸

3. Does the evidence support the use of stress tests for asymptomatic patients with diabetes? Are preop stress tests advisable?

The jury is still out on both questions.

The question of asymptomatic testing for patients with diabetes mellitus, who are more likely than those without the disease to develop CAD, frequently arises. Although individuals with diabetes have higher rates of silent ischemia than the general population, however, estimates of this prevalence vary widely.¹⁰ There are no clear guidelines for evaluation of asymptomatic diabetic patients with exercise stress testing. (See “Test your skills with these 3 cases”)

The addition of nuclide imaging adds diagnostic value to the test, but it is still not clear that this should be the preferred test for patients with diabetes who have normal resting EKGs.^10,11 A recent randomized controlled trial investigating screening with pharmacologic stress testing in asymptomatic patients with type 2 diabetes did not show a reduction in cardiac event rates in patients who were screened compared with those who were not screened.¹²

Similarly, preoperative stress testing is subject to debate.¹³ Many studies have been done to evaluate the utility of preoperative stress testing, with revascularization procedures done before the planned surgery when significant CAD is found. (See “Before surgery: Have you done enough to mitigate risk?” J Fam Pract. 2010;59:202-211.) And, while many demonstrate the predictive power of various parameters that stress tests measure, literature reviews show that—with the exception of patients with unstable CAD—postop event rates are about the same for patients who underwent stress testing and subsequent revascularization vs those who were treated medically instead.^13,14

4. If your patient requires a pharmacologic stress test, what are your options besides adenosine?

While adenosine is the agent of choice, dipyridamole and dobutamine are other options. When any of these agents are used, it’s important to consider the side effects of each, and which drugs your patient will need to avoid prior to the stress test.

Adenosine is a mediator of coronary vasodilation. The drug dilates normal coronary arteries preferentially to stenotic vessels and causes redistribution of blood flow away from areas of the myocardium with compromised circulation.

Dipyridamole, a mediator of adenosine release, is sometimes used instead. Both drugs are given as a 4-minute infusion, with injection of the tracer late in the infusion.

The adverse effects of adenosine occur early in the infusion, and include dyspnea, bronchospasm, chest pain, nausea, and headache. Bradycardia can be marked, and brief periods of complete heart block and long sinus pauses may occur. Hypotension can likewise be profound. Many of these effects are extremely disturbing to the patient under-going the test, but they disappear within 30 seconds of stopping the infusion.

Dipyridamole has similar adverse effects, although heart block is not part of its adverse effect profile. In addition, the drug’s adverse effects occur later in the infusion than those associated with adenosine and last well after it is finished. However, dipyridamole’s side effects can be reversed with intravenous aminophylline without compromising the accuracy of the test.

Drugs to avoid that day. Methylxanthines antagonize adenosine and dipyridamole, and thus must be avoided on the day of the test. Caffeine and theophylline are among the substances to be avoided, although the degree to which they affect test results has been questioned recently.¹⁵

Severe COPD and asthma—especially in patients with uncontrolled wheezing—are relative contraindications to the use of adenosine and dipyridamole.

Interestingly, the cardiovascular effects (and EKG changes) associated with these drugs are not necessarily indicative of CAD. Thus, the entire EKG portion of a pharmacologic stress test is not useful in interpreting the finding. One small study suggests that, unlike exercise stress testing, adenosine stress testing may be safe in patients with severe aortic stenosis.¹⁶

Dobutamine is another alternative for pharmacologic stress testing, for patients who cannot take adenosine or are unable to stop theophylline or similar medications. An infusion of dobutamine with an escalating dose, sometimes including atropine, is used to accelerate the heart rate to 85% of the patient’s age-predicted maximum. The stress is primarily due to the chronotropic effect of the drug, but dobutamine has some coronary vasodilatory activity and may also induce some redistribution of coronary blood flow, similar to the effect of adenosine.

The positive and negative predictive values of pharmacologic stress testing are the same as for nuclear stress testing. Unlike exercise testing, however, functional capacity cannot be inferred from a pharmacologic stress test.

About 10% of patients undergoing pharmacologic stress testing will have a nondiagnostic test. The sensitivity of the test varies among studies, but it is approximately 84%, 95%, and 100% for single-, double-, and triplevessel disease, respectively. Patients with negative tests have an event rate of less than 1% per year.¹⁷

5. Is stress echocardiography comparable to stress testing?

Yes. Stress echocardiography, which involves echocardiographic studies taken before and after stress, can substitute for either exercise or pharmacologic stress testing (the stress can be achieved either with exercise or an infusion of dobutamine), and it has certain advantages: Stress echocardiography is cheaper than nuclear stress testing, and there is no radiation involved. In addition, stress echocardiography yields positive and negative predictive values similar to those seen with nuclear stress testing.^2,3 The presence of ischemia is inferred from localized wall motion abnormalities.

The primary disadvantage of stress echocardiography is that it can be administered only by a cardiologist who has been specially trained in this procedure. In contrast, any community hospital nuclear medicine department has the capacity to perform nuclear imaging, and most radiologists are able to interpret the nuclide scans. In my experience, decisions about whether to order nuclear cardiac stress testing or stress echocardiography are influenced not only by the availability of these modalities, but also by the skill of the physicians who will interpret the tests.

6. Which exercise-induced EKG changes are related to ischemia?

The only changes that correlate with myocardial ischemia are ST depression and ST elevation. J-point depression is almost universally seen with exercise. For this reason, the ST level is measured 80 milliseconds after the J point.

ST depression—the most common abnormal finding—indicates subendocardial ischemia. ST changes are most commonly seen in the inferior and lateral leads, but do not correlate with the location of ischemia. ST depression can be downsloping, horizontal, or upsloping. The first 2 are the most significant patterns, and 1 mm of ST depression is the minimum significant level. Upsloping ST depression is less significant, and 1.5 mm of depression is the minimum significant change.¹ The greater the degree of ST depression, the higher the likelihood that significant occlusion will be seen on coronary angiography. ST depression that develops in the recovery period is a rare occurrence but of equal significance to ST depression that occurs with exercise, and is probably due to ischemia caused by shunting of blood into skeletal muscle and away from the heart.¹

ST elevation is less common, but more ominous than ST depression, as it indicates transmural ischemia.¹ This finding most often indicates high-grade left anterior descending (LAD) or left main CAD. It is most often seen in the anterior leads, and the location of ST changes correlates with the area of ischemia. Bear in mind, however, that the correlation between ST elevation and transmural ischemia is true only if the patient has no history of MI. ST elevation in leads in which Q waves are present at rest usually indicates ventricular dyskinesia or aneurysm and not ischemia.¹

Premenopausal women and women who are taking estrogen supplements, in particular, are more likely than men to have false-positive ST changes, most likely because of a poorly understood effect of estrogen. The molecules of estrogen and of digitalis glycosides have some regions of structural similarity, and it is thought that both molecules can cause ST changes.¹⁰

And what about arrhythmias? Arrhythmias are often seen at rest and with exertion. Supraventricular arrhythmias, including supraventricular tachycardia, are not associated with CAD. Premature ventricular contractions (PVCs) are common at peak exertion. PVCs are probably related to catecholamine release and do not indicate ischemia. (See “A look at the stress test report”)

Ventricular tachycardia, however—defined as 3 or more consecutive PVCs—has a 90% correlation with significant coronary artery stenosis, as shown on angiography.¹

Rate-dependent conduction disturbances, including 2-to-1 atrioventricular block and bundle-branch blocks, may also be seen. These may be associated with ischemia, but are not highly predictive of coronary artery stenosis. Further testing may be indicated to determine whether stenosis is present.¹

CORRESPONDENCE Mark A. Knox, MD, UPMC Shadyside Family Medicine Residency Program, 5230 Centre Avenue, Pittsburgh, PA 15232; [email protected]

Exercise has been used for cardiac stress testing for decades. But testing and imaging techniques and knowledge of the efficacy of this common diagnostic tool continue to evolve. Optimizing your use of stress testing requires that you familiarize yourself with the latest evidence. The evidence-based answers to these 6 questions will help you do just that.

1. How reliable are exercise stress tests?

That depends, of course, on any number of variables, including the protocol utilized, the number of stenotic vessels, the degree of stenosis, and even the sex of the patient.

False-negative and false-positive results are frequent in treadmill testing without imaging. (For more on the different protocols, see “Standard and nuclear exercise stress tests: A look at protocols”) Sensitivity is related to the number of stenotic vessels and the degree of stenosis. For a man with single-vessel disease and ≥70% stenosis, the likelihood of an abnormal test is only 50% to 60%. Even in a man with left main artery disease, the sensitivity is only about 85%.¹

In some cases, failure to reach a cardiac workload sufficient to produce ischemia can lead to a false-negative test, and it is up to the physician performing the test to label it as nondiagnostic. Other reasons for false-positive or false-negative results include preexisting ST segment abnormalities, which can cause false-positive elevation of the ST segment during exercise; the use of digitalis, which affects the ST segment; and the presence of ventricular hypertrophy or cardiomyopathy.¹ Patients with any of these conditions should undergo stress testing with imaging instead.

Nuclear stress testing is indicated for patients who have baseline EKG abnormalities, suspected false-positive or false-negative results from a stress test without imaging, known CAD or previous revascularization, a pacemaker, or a moderate to high likelihood of a CAD diagnosis. The addition of a tracer isotope and imaging boosts the test’s predictive value.¹

The positive predictive value of nuclear stress testing is difficult to calculate because an abnormal test should lead to initiation of therapy designed to reduce the risk of cardiac death or myocardial infarction (MI). Numerous studies have found the rate of cardiac events after a negative radionuclide stress test to be less than 1% per year.² The event rate after a negative test is lower in women than in men; after a positive test, however, the event rate in women is 2 to 3 times higher.^2,3 Overall, stress testing is less sensitive in women than in men, at least in part because of their lower likelihood of CAD associated with any given symptom set.⁴

2. When should you rule out stress testing?

Stress testing is unnecessary in asymptomatic patients. Numerous studies have documented the lack of benefit from screening asymptomatic people for CAD using exercise stress testing.^5,6 The US Preventive Services Task Force gives this a Grade D recommendation—recommending against routine stress testing.⁷

There are also numerous contraindications, both absolute and relative (TABLE).⁸ Relative contraindications, which include severe hypertension, left main coronary stenosis, moderate stenotic valvular disease, electrolyte abnormalities, cardiomyopathy, serious mental or physical impairment, and atrioventricular block are conditions that are likely to interfere with test performance or reliability.

Absolute contraindications, generally related to unstable cardiopulmonary disease, pose a far more serious threat. Indeed, administering a treadmill stress test to a patient with 1 or more absolute contraindications greatly increases the risk of death associated with the test.⁸

Even if a patient does not have any relative or absolute contraindications, there is still some risk of moving forward with the test. There is about a 1 in 2500 risk of MI or death during, or related to, exercise stress testing.⁸ The greater the likelihood that a patient has CAD, the higher the risk.

There is also a risk of hospitalization after the test, usually related to persistent chest pain or arrhythmias. (I generally admit patients whose chest pain is unresponsive to 3 doses of nitroglycerine or who develop EKG changes that persist after 20 minutes at rest.) The test also raises the possibility of injury from the equipment, such as sprains or fractures caused by falling from the treadmill.

Nuclear stress testing also has a small risk of an allergic reaction to the isotope used as a tracer. The radiation dose is 8 to 9 mSV, comparable to a computed tomography (CT) scan of the chest and generally less than that of a coronary angiogram.⁹

TABLE
Stress testing: Absolute and relative contraindications⁸

3. Does the evidence support the use of stress tests for asymptomatic patients with diabetes? Are preop stress tests advisable?

The jury is still out on both questions.

The question of asymptomatic testing for patients with diabetes mellitus, who are more likely than those without the disease to develop CAD, frequently arises. Although individuals with diabetes have higher rates of silent ischemia than the general population, however, estimates of this prevalence vary widely.¹⁰ There are no clear guidelines for evaluation of asymptomatic diabetic patients with exercise stress testing. (See “Test your skills with these 3 cases”)

The addition of nuclide imaging adds diagnostic value to the test, but it is still not clear that this should be the preferred test for patients with diabetes who have normal resting EKGs.^10,11 A recent randomized controlled trial investigating screening with pharmacologic stress testing in asymptomatic patients with type 2 diabetes did not show a reduction in cardiac event rates in patients who were screened compared with those who were not screened.¹²

Similarly, preoperative stress testing is subject to debate.¹³ Many studies have been done to evaluate the utility of preoperative stress testing, with revascularization procedures done before the planned surgery when significant CAD is found. (See “Before surgery: Have you done enough to mitigate risk?” J Fam Pract. 2010;59:202-211.) And, while many demonstrate the predictive power of various parameters that stress tests measure, literature reviews show that—with the exception of patients with unstable CAD—postop event rates are about the same for patients who underwent stress testing and subsequent revascularization vs those who were treated medically instead.^13,14

4. If your patient requires a pharmacologic stress test, what are your options besides adenosine?

While adenosine is the agent of choice, dipyridamole and dobutamine are other options. When any of these agents are used, it’s important to consider the side effects of each, and which drugs your patient will need to avoid prior to the stress test.

Adenosine is a mediator of coronary vasodilation. The drug dilates normal coronary arteries preferentially to stenotic vessels and causes redistribution of blood flow away from areas of the myocardium with compromised circulation.

Dipyridamole, a mediator of adenosine release, is sometimes used instead. Both drugs are given as a 4-minute infusion, with injection of the tracer late in the infusion.

The adverse effects of adenosine occur early in the infusion, and include dyspnea, bronchospasm, chest pain, nausea, and headache. Bradycardia can be marked, and brief periods of complete heart block and long sinus pauses may occur. Hypotension can likewise be profound. Many of these effects are extremely disturbing to the patient under-going the test, but they disappear within 30 seconds of stopping the infusion.

Dipyridamole has similar adverse effects, although heart block is not part of its adverse effect profile. In addition, the drug’s adverse effects occur later in the infusion than those associated with adenosine and last well after it is finished. However, dipyridamole’s side effects can be reversed with intravenous aminophylline without compromising the accuracy of the test.

Drugs to avoid that day. Methylxanthines antagonize adenosine and dipyridamole, and thus must be avoided on the day of the test. Caffeine and theophylline are among the substances to be avoided, although the degree to which they affect test results has been questioned recently.¹⁵

Severe COPD and asthma—especially in patients with uncontrolled wheezing—are relative contraindications to the use of adenosine and dipyridamole.

Interestingly, the cardiovascular effects (and EKG changes) associated with these drugs are not necessarily indicative of CAD. Thus, the entire EKG portion of a pharmacologic stress test is not useful in interpreting the finding. One small study suggests that, unlike exercise stress testing, adenosine stress testing may be safe in patients with severe aortic stenosis.¹⁶

Dobutamine is another alternative for pharmacologic stress testing, for patients who cannot take adenosine or are unable to stop theophylline or similar medications. An infusion of dobutamine with an escalating dose, sometimes including atropine, is used to accelerate the heart rate to 85% of the patient’s age-predicted maximum. The stress is primarily due to the chronotropic effect of the drug, but dobutamine has some coronary vasodilatory activity and may also induce some redistribution of coronary blood flow, similar to the effect of adenosine.

The positive and negative predictive values of pharmacologic stress testing are the same as for nuclear stress testing. Unlike exercise testing, however, functional capacity cannot be inferred from a pharmacologic stress test.

About 10% of patients undergoing pharmacologic stress testing will have a nondiagnostic test. The sensitivity of the test varies among studies, but it is approximately 84%, 95%, and 100% for single-, double-, and triplevessel disease, respectively. Patients with negative tests have an event rate of less than 1% per year.¹⁷

5. Is stress echocardiography comparable to stress testing?

Yes. Stress echocardiography, which involves echocardiographic studies taken before and after stress, can substitute for either exercise or pharmacologic stress testing (the stress can be achieved either with exercise or an infusion of dobutamine), and it has certain advantages: Stress echocardiography is cheaper than nuclear stress testing, and there is no radiation involved. In addition, stress echocardiography yields positive and negative predictive values similar to those seen with nuclear stress testing.^2,3 The presence of ischemia is inferred from localized wall motion abnormalities.

The primary disadvantage of stress echocardiography is that it can be administered only by a cardiologist who has been specially trained in this procedure. In contrast, any community hospital nuclear medicine department has the capacity to perform nuclear imaging, and most radiologists are able to interpret the nuclide scans. In my experience, decisions about whether to order nuclear cardiac stress testing or stress echocardiography are influenced not only by the availability of these modalities, but also by the skill of the physicians who will interpret the tests.

6. Which exercise-induced EKG changes are related to ischemia?

The only changes that correlate with myocardial ischemia are ST depression and ST elevation. J-point depression is almost universally seen with exercise. For this reason, the ST level is measured 80 milliseconds after the J point.

ST depression—the most common abnormal finding—indicates subendocardial ischemia. ST changes are most commonly seen in the inferior and lateral leads, but do not correlate with the location of ischemia. ST depression can be downsloping, horizontal, or upsloping. The first 2 are the most significant patterns, and 1 mm of ST depression is the minimum significant level. Upsloping ST depression is less significant, and 1.5 mm of depression is the minimum significant change.¹ The greater the degree of ST depression, the higher the likelihood that significant occlusion will be seen on coronary angiography. ST depression that develops in the recovery period is a rare occurrence but of equal significance to ST depression that occurs with exercise, and is probably due to ischemia caused by shunting of blood into skeletal muscle and away from the heart.¹

ST elevation is less common, but more ominous than ST depression, as it indicates transmural ischemia.¹ This finding most often indicates high-grade left anterior descending (LAD) or left main CAD. It is most often seen in the anterior leads, and the location of ST changes correlates with the area of ischemia. Bear in mind, however, that the correlation between ST elevation and transmural ischemia is true only if the patient has no history of MI. ST elevation in leads in which Q waves are present at rest usually indicates ventricular dyskinesia or aneurysm and not ischemia.¹

Premenopausal women and women who are taking estrogen supplements, in particular, are more likely than men to have false-positive ST changes, most likely because of a poorly understood effect of estrogen. The molecules of estrogen and of digitalis glycosides have some regions of structural similarity, and it is thought that both molecules can cause ST changes.¹⁰

And what about arrhythmias? Arrhythmias are often seen at rest and with exertion. Supraventricular arrhythmias, including supraventricular tachycardia, are not associated with CAD. Premature ventricular contractions (PVCs) are common at peak exertion. PVCs are probably related to catecholamine release and do not indicate ischemia. (See “A look at the stress test report”)

Ventricular tachycardia, however—defined as 3 or more consecutive PVCs—has a 90% correlation with significant coronary artery stenosis, as shown on angiography.¹

Rate-dependent conduction disturbances, including 2-to-1 atrioventricular block and bundle-branch blocks, may also be seen. These may be associated with ischemia, but are not highly predictive of coronary artery stenosis. Further testing may be indicated to determine whether stenosis is present.¹

CORRESPONDENCE Mark A. Knox, MD, UPMC Shadyside Family Medicine Residency Program, 5230 Centre Avenue, Pittsburgh, PA 15232; [email protected]

CASE: A 28-year-old woman (G6P1) at 33 weeks’ gestation was transferred from an outside hospital with worsening tachypnea, increasing oxygen requirement, and worsening infiltrates on chest radiograph.

A week earlier she had presented to a local emergency department (ED) with a 1-day history of nonproductive cough, fever, congestion, and decreased fetal movement. She also complained of vomiting. Examination was notable for an oxygen saturation of 99% on room air, heart rate of 126 bpm, temperature of 37.9°C (100.2°F), and blood pressure (BP) of 104/70 mm Hg. Rapid influenza A/B nasopharyngeal swab and group A Streptococcus direct probe were both negative. She was transferred to labor and delivery for fetal monitoring and discharged later that day.

Later in the week she returned to 2 other hospitals due to continued symptoms. She was diagnosed with right upper lobe pneumonia on her third ED visit and transferred to our facility, with increasing respiratory distress. Her examination was notable for a temperature of 36.8°C (98.2°F), pulse of 103 bpm, BP of 98/56 mm Hg, respiratory rate of 27 breaths per minute, and oxygen saturation of 94%. The patient had ulcerations on her tongue, dry mucous membranes, and lower extremity edema; on lung exam she had right lower lobe crackles and occasional wheezes.

Lab results were notable for a serum hemoglobin of 9.3 g/dL and platelet count of 75,000/mm³. The leukocyte count was 8.3×10⁹/L, with differential remarkable for 24% bands. Potassium was 3.3 mEq/L and bicarbonate was 19 mEq/L; the basic metabolic panel was otherwise normal. Lactic acid was elevated at 2.4 mg/dL. Coagulation levels were normal. Urinalysis was negative. Chest radiograph (FIGURE) was read as “right upper lobe pneumonia and probable small bilateral pleural effusions with lower lung airspace disease, which may relate to atelectasis; however, superimposed multi-focal pneumonia is not excluded.”

Overnight, she had an increasing oxygen requirement of up to 15 liters, axillary temperature 40.8°C (105.6°F), and heart rate in the 140s; fetal heart rate was in the 200s. The next day, a chest x-ray revealed worsening pulmonary infiltrates. The patient was tachypneic, with a BP of 99/50 mm Hg. She continued to worsen and required intubation for hypoxic respiratory distress.

FIGURE
Right upper lobe pneumonia

WHAT IS THE MOST LIKELY EXPLANATION FOR HER CONDITION?

H1N1 pneumonia

The patient’s physician initiated broad-spectrum antibiotics and oseltamivir for a presumptive diagnosis of 2009 H1N1 pneumonia and possible aspiration pneumonia. Although the patient had negative rapid influenza tests, the sensitivity of these tests is 10% to 70% in 2009 H1N1 influenza infection.¹

Pregnant women and those in the first 2 weeks postpartum (or who have experienced a pregnancy loss) are considered to be at high risk for complications of influenza infection.¹ Influenza A infection in pregnancy is associated with preterm labor, preterm birth, pneumonia, acute respiratory distress syndrome, and death.² Although many pregnant patients may present with mild or moderate symptoms, the clinical progression with 2009 H1N1 appears to be more rapid than what has been seen with previous seasonal influenza outbreaks.³

According to 1 study, hospital admission rates during the first month of the outbreak were higher for pregnant women compared with the general population: 0.32 vs 0.076 per 100,000.⁴ The Centers for Disease Control and Prevention (CDC) indicates that while 1% of the population is pregnant at any given time, 6% of confirmed deaths from H1N1 in the United States in 2009 were pregnant women.⁵ Two prospective observational studies published in the Journal of the American Medical Association revealed the percentages of critically ill H1N1 patients who were pregnant. In Canada, 7.7% of critically ill patients with H1N1 were pregnant. In California, 10% were pregnant, and 6% of fatal cases in patients over age 18 were pregnant women.^6,7

Why are pregnant women more susceptible to flu complications?
The immune system changes that make pregnant women more susceptible to complications of influenza infection are not well understood. Normal physiologic changes to the respiratory system during pregnancy may be a contributing factor. These include increased minute ventilation in the first trimester due to an increase in progesterone levels, increased tidal volume, decreased residual volume and functional residual capacity due to the mechanical effect of a gravid uterus, and increased oxygen consumption and basal metabolic rate due to increased demand.⁸

What can be done to decrease their risk?
The first step is preventing infection. For the 2009-2010 season, vaccination against seasonal and 2009 H1N1 influenza is strongly recommended for all pregnant women. Only the intramuscular injection is approved for pregnant women. Patients can receive the seasonal influenza vaccine at the same time as the H1N1 vaccine using an alternate injection site.

Maternal immunization against seasonal influenza benefits mothers and has also been shown to lower infection rates in infants. A study published in The New England Journal of Medicine showed that the seasonal influenza vaccination given to pregnant women reduced influenza-like illness in their infants younger than 6 months of age by 63%.⁹ Also important is providing chemoprophylaxis for pregnant women who have close contacts with suspected or confirmed influenza infection. For 2009 H1N1 chemoprophylaxis, a 10-day course of once-daily oseltamivir or zanamivir is acceptable. Zanamivir is an inhaled medication and should not be prescribed to patients with asthma or other respiratory conditions.

Confirmed case? Tx for the pregnant patient

The 2009 H1N1 virus is susceptible to oseltamivir and zanamivir.¹ Both antivirals are Category C in pregnancy. The CDC recommends that patients with suspected or confirmed 2009 H1N1 infection who are in high-risk groups (which includes pregnant women) be treated with oseltamivir.

Antiviral medications such as oseltamivir and zanamivir act at the viral replication stage, which peaks at 24 to 72 hours in influenza.¹⁰ This helps explain evidence that the earlier treatment of influenza is initiated—within the first 48 hours—the more effective it is in reducing fever, relieving symptoms, and decreasing time to return to baseline activity.¹¹ A study of pregnant women in California with severe 2009 H1N1 infection found that later treatment (>2 days after symptom onset) was associated with 4 times the risk of admission and death.³ For these reasons, treatment should not be delayed while test results are pending.

That said, in hospitalized patients with seasonal influenza, initiating treatment after 48 hours of symptom onset has been shown to provide some benefit in some observational studies.^1,12 Consequently, the CDC recommends initiating treatment of high-risk patients who seek care more than 48 hours after symptom onset.¹

The standard course of oseltamivir is 75 mg twice daily for 5 days. Longer courses may be beneficial in hospitalized patients.¹ Oseltamivir and zanamivir can also be continued while breastfeeding.¹³

Our patient’s outcome

The patient received a 10-day course of oseltamivir (rather than the standard 5-day course), as well as empiric broad-spectrum antibiotic coverage for community-acquired pneumonia and aspiration pneumonia, including coverage for Streptococcus pneumoniae (the most common bacterial cause of secondary pneumonia in influenza¹⁴).

The cultures come back. Nasopharyngeal cultures were negative × 2 for type A influenza. Blood cultures were negative throughout the admission. Sputum cultures were negative, as well. Bronchoscopy cultures, however, were positive for type A influenza and negative for bacterial and fungal pathogens, confirming a diagnosis of primary pneumonia from 2009 H1N1 infection.

The patient was extubated 1 week after her arrival at our hospital and continued to recover during the rest of her hospital stay. She was discharged in stable condition. Several weeks later, she delivered a full-term infant with average weight and normal Apgar scores.

CORRESPONDENCE: Christopher Bernheisel, MD, Director, Family Medicine Inpatient Service, The University of Cincinnati, 2123 Auburn Ave., Suite 340, Cincinnati, OH 45219; [email protected]

CASE: A 28-year-old woman (G6P1) at 33 weeks’ gestation was transferred from an outside hospital with worsening tachypnea, increasing oxygen requirement, and worsening infiltrates on chest radiograph.

A week earlier she had presented to a local emergency department (ED) with a 1-day history of nonproductive cough, fever, congestion, and decreased fetal movement. She also complained of vomiting. Examination was notable for an oxygen saturation of 99% on room air, heart rate of 126 bpm, temperature of 37.9°C (100.2°F), and blood pressure (BP) of 104/70 mm Hg. Rapid influenza A/B nasopharyngeal swab and group A Streptococcus direct probe were both negative. She was transferred to labor and delivery for fetal monitoring and discharged later that day.

Later in the week she returned to 2 other hospitals due to continued symptoms. She was diagnosed with right upper lobe pneumonia on her third ED visit and transferred to our facility, with increasing respiratory distress. Her examination was notable for a temperature of 36.8°C (98.2°F), pulse of 103 bpm, BP of 98/56 mm Hg, respiratory rate of 27 breaths per minute, and oxygen saturation of 94%. The patient had ulcerations on her tongue, dry mucous membranes, and lower extremity edema; on lung exam she had right lower lobe crackles and occasional wheezes.

Lab results were notable for a serum hemoglobin of 9.3 g/dL and platelet count of 75,000/mm³. The leukocyte count was 8.3×10⁹/L, with differential remarkable for 24% bands. Potassium was 3.3 mEq/L and bicarbonate was 19 mEq/L; the basic metabolic panel was otherwise normal. Lactic acid was elevated at 2.4 mg/dL. Coagulation levels were normal. Urinalysis was negative. Chest radiograph (FIGURE) was read as “right upper lobe pneumonia and probable small bilateral pleural effusions with lower lung airspace disease, which may relate to atelectasis; however, superimposed multi-focal pneumonia is not excluded.”

Overnight, she had an increasing oxygen requirement of up to 15 liters, axillary temperature 40.8°C (105.6°F), and heart rate in the 140s; fetal heart rate was in the 200s. The next day, a chest x-ray revealed worsening pulmonary infiltrates. The patient was tachypneic, with a BP of 99/50 mm Hg. She continued to worsen and required intubation for hypoxic respiratory distress.

FIGURE
Right upper lobe pneumonia

WHAT IS THE MOST LIKELY EXPLANATION FOR HER CONDITION?

H1N1 pneumonia

The patient’s physician initiated broad-spectrum antibiotics and oseltamivir for a presumptive diagnosis of 2009 H1N1 pneumonia and possible aspiration pneumonia. Although the patient had negative rapid influenza tests, the sensitivity of these tests is 10% to 70% in 2009 H1N1 influenza infection.¹

Pregnant women and those in the first 2 weeks postpartum (or who have experienced a pregnancy loss) are considered to be at high risk for complications of influenza infection.¹ Influenza A infection in pregnancy is associated with preterm labor, preterm birth, pneumonia, acute respiratory distress syndrome, and death.² Although many pregnant patients may present with mild or moderate symptoms, the clinical progression with 2009 H1N1 appears to be more rapid than what has been seen with previous seasonal influenza outbreaks.³

According to 1 study, hospital admission rates during the first month of the outbreak were higher for pregnant women compared with the general population: 0.32 vs 0.076 per 100,000.⁴ The Centers for Disease Control and Prevention (CDC) indicates that while 1% of the population is pregnant at any given time, 6% of confirmed deaths from H1N1 in the United States in 2009 were pregnant women.⁵ Two prospective observational studies published in the Journal of the American Medical Association revealed the percentages of critically ill H1N1 patients who were pregnant. In Canada, 7.7% of critically ill patients with H1N1 were pregnant. In California, 10% were pregnant, and 6% of fatal cases in patients over age 18 were pregnant women.^6,7

Why are pregnant women more susceptible to flu complications?
The immune system changes that make pregnant women more susceptible to complications of influenza infection are not well understood. Normal physiologic changes to the respiratory system during pregnancy may be a contributing factor. These include increased minute ventilation in the first trimester due to an increase in progesterone levels, increased tidal volume, decreased residual volume and functional residual capacity due to the mechanical effect of a gravid uterus, and increased oxygen consumption and basal metabolic rate due to increased demand.⁸

What can be done to decrease their risk?
The first step is preventing infection. For the 2009-2010 season, vaccination against seasonal and 2009 H1N1 influenza is strongly recommended for all pregnant women. Only the intramuscular injection is approved for pregnant women. Patients can receive the seasonal influenza vaccine at the same time as the H1N1 vaccine using an alternate injection site.

Maternal immunization against seasonal influenza benefits mothers and has also been shown to lower infection rates in infants. A study published in The New England Journal of Medicine showed that the seasonal influenza vaccination given to pregnant women reduced influenza-like illness in their infants younger than 6 months of age by 63%.⁹ Also important is providing chemoprophylaxis for pregnant women who have close contacts with suspected or confirmed influenza infection. For 2009 H1N1 chemoprophylaxis, a 10-day course of once-daily oseltamivir or zanamivir is acceptable. Zanamivir is an inhaled medication and should not be prescribed to patients with asthma or other respiratory conditions.

Confirmed case? Tx for the pregnant patient

The 2009 H1N1 virus is susceptible to oseltamivir and zanamivir.¹ Both antivirals are Category C in pregnancy. The CDC recommends that patients with suspected or confirmed 2009 H1N1 infection who are in high-risk groups (which includes pregnant women) be treated with oseltamivir.

Antiviral medications such as oseltamivir and zanamivir act at the viral replication stage, which peaks at 24 to 72 hours in influenza.¹⁰ This helps explain evidence that the earlier treatment of influenza is initiated—within the first 48 hours—the more effective it is in reducing fever, relieving symptoms, and decreasing time to return to baseline activity.¹¹ A study of pregnant women in California with severe 2009 H1N1 infection found that later treatment (>2 days after symptom onset) was associated with 4 times the risk of admission and death.³ For these reasons, treatment should not be delayed while test results are pending.

That said, in hospitalized patients with seasonal influenza, initiating treatment after 48 hours of symptom onset has been shown to provide some benefit in some observational studies.^1,12 Consequently, the CDC recommends initiating treatment of high-risk patients who seek care more than 48 hours after symptom onset.¹

The standard course of oseltamivir is 75 mg twice daily for 5 days. Longer courses may be beneficial in hospitalized patients.¹ Oseltamivir and zanamivir can also be continued while breastfeeding.¹³

Our patient’s outcome

The patient received a 10-day course of oseltamivir (rather than the standard 5-day course), as well as empiric broad-spectrum antibiotic coverage for community-acquired pneumonia and aspiration pneumonia, including coverage for Streptococcus pneumoniae (the most common bacterial cause of secondary pneumonia in influenza¹⁴).

The cultures come back. Nasopharyngeal cultures were negative × 2 for type A influenza. Blood cultures were negative throughout the admission. Sputum cultures were negative, as well. Bronchoscopy cultures, however, were positive for type A influenza and negative for bacterial and fungal pathogens, confirming a diagnosis of primary pneumonia from 2009 H1N1 infection.

The patient was extubated 1 week after her arrival at our hospital and continued to recover during the rest of her hospital stay. She was discharged in stable condition. Several weeks later, she delivered a full-term infant with average weight and normal Apgar scores.

CORRESPONDENCE: Christopher Bernheisel, MD, Director, Family Medicine Inpatient Service, The University of Cincinnati, 2123 Auburn Ave., Suite 340, Cincinnati, OH 45219; [email protected]

CASE: A 28-year-old woman (G6P1) at 33 weeks’ gestation was transferred from an outside hospital with worsening tachypnea, increasing oxygen requirement, and worsening infiltrates on chest radiograph.

A week earlier she had presented to a local emergency department (ED) with a 1-day history of nonproductive cough, fever, congestion, and decreased fetal movement. She also complained of vomiting. Examination was notable for an oxygen saturation of 99% on room air, heart rate of 126 bpm, temperature of 37.9°C (100.2°F), and blood pressure (BP) of 104/70 mm Hg. Rapid influenza A/B nasopharyngeal swab and group A Streptococcus direct probe were both negative. She was transferred to labor and delivery for fetal monitoring and discharged later that day.

Later in the week she returned to 2 other hospitals due to continued symptoms. She was diagnosed with right upper lobe pneumonia on her third ED visit and transferred to our facility, with increasing respiratory distress. Her examination was notable for a temperature of 36.8°C (98.2°F), pulse of 103 bpm, BP of 98/56 mm Hg, respiratory rate of 27 breaths per minute, and oxygen saturation of 94%. The patient had ulcerations on her tongue, dry mucous membranes, and lower extremity edema; on lung exam she had right lower lobe crackles and occasional wheezes.

Lab results were notable for a serum hemoglobin of 9.3 g/dL and platelet count of 75,000/mm³. The leukocyte count was 8.3×10⁹/L, with differential remarkable for 24% bands. Potassium was 3.3 mEq/L and bicarbonate was 19 mEq/L; the basic metabolic panel was otherwise normal. Lactic acid was elevated at 2.4 mg/dL. Coagulation levels were normal. Urinalysis was negative. Chest radiograph (FIGURE) was read as “right upper lobe pneumonia and probable small bilateral pleural effusions with lower lung airspace disease, which may relate to atelectasis; however, superimposed multi-focal pneumonia is not excluded.”

Overnight, she had an increasing oxygen requirement of up to 15 liters, axillary temperature 40.8°C (105.6°F), and heart rate in the 140s; fetal heart rate was in the 200s. The next day, a chest x-ray revealed worsening pulmonary infiltrates. The patient was tachypneic, with a BP of 99/50 mm Hg. She continued to worsen and required intubation for hypoxic respiratory distress.

FIGURE
Right upper lobe pneumonia

WHAT IS THE MOST LIKELY EXPLANATION FOR HER CONDITION?

H1N1 pneumonia

The patient’s physician initiated broad-spectrum antibiotics and oseltamivir for a presumptive diagnosis of 2009 H1N1 pneumonia and possible aspiration pneumonia. Although the patient had negative rapid influenza tests, the sensitivity of these tests is 10% to 70% in 2009 H1N1 influenza infection.¹

Pregnant women and those in the first 2 weeks postpartum (or who have experienced a pregnancy loss) are considered to be at high risk for complications of influenza infection.¹ Influenza A infection in pregnancy is associated with preterm labor, preterm birth, pneumonia, acute respiratory distress syndrome, and death.² Although many pregnant patients may present with mild or moderate symptoms, the clinical progression with 2009 H1N1 appears to be more rapid than what has been seen with previous seasonal influenza outbreaks.³

According to 1 study, hospital admission rates during the first month of the outbreak were higher for pregnant women compared with the general population: 0.32 vs 0.076 per 100,000.⁴ The Centers for Disease Control and Prevention (CDC) indicates that while 1% of the population is pregnant at any given time, 6% of confirmed deaths from H1N1 in the United States in 2009 were pregnant women.⁵ Two prospective observational studies published in the Journal of the American Medical Association revealed the percentages of critically ill H1N1 patients who were pregnant. In Canada, 7.7% of critically ill patients with H1N1 were pregnant. In California, 10% were pregnant, and 6% of fatal cases in patients over age 18 were pregnant women.^6,7

Why are pregnant women more susceptible to flu complications?
The immune system changes that make pregnant women more susceptible to complications of influenza infection are not well understood. Normal physiologic changes to the respiratory system during pregnancy may be a contributing factor. These include increased minute ventilation in the first trimester due to an increase in progesterone levels, increased tidal volume, decreased residual volume and functional residual capacity due to the mechanical effect of a gravid uterus, and increased oxygen consumption and basal metabolic rate due to increased demand.⁸

What can be done to decrease their risk?
The first step is preventing infection. For the 2009-2010 season, vaccination against seasonal and 2009 H1N1 influenza is strongly recommended for all pregnant women. Only the intramuscular injection is approved for pregnant women. Patients can receive the seasonal influenza vaccine at the same time as the H1N1 vaccine using an alternate injection site.

Maternal immunization against seasonal influenza benefits mothers and has also been shown to lower infection rates in infants. A study published in The New England Journal of Medicine showed that the seasonal influenza vaccination given to pregnant women reduced influenza-like illness in their infants younger than 6 months of age by 63%.⁹ Also important is providing chemoprophylaxis for pregnant women who have close contacts with suspected or confirmed influenza infection. For 2009 H1N1 chemoprophylaxis, a 10-day course of once-daily oseltamivir or zanamivir is acceptable. Zanamivir is an inhaled medication and should not be prescribed to patients with asthma or other respiratory conditions.

Confirmed case? Tx for the pregnant patient

The 2009 H1N1 virus is susceptible to oseltamivir and zanamivir.¹ Both antivirals are Category C in pregnancy. The CDC recommends that patients with suspected or confirmed 2009 H1N1 infection who are in high-risk groups (which includes pregnant women) be treated with oseltamivir.

Antiviral medications such as oseltamivir and zanamivir act at the viral replication stage, which peaks at 24 to 72 hours in influenza.¹⁰ This helps explain evidence that the earlier treatment of influenza is initiated—within the first 48 hours—the more effective it is in reducing fever, relieving symptoms, and decreasing time to return to baseline activity.¹¹ A study of pregnant women in California with severe 2009 H1N1 infection found that later treatment (>2 days after symptom onset) was associated with 4 times the risk of admission and death.³ For these reasons, treatment should not be delayed while test results are pending.

That said, in hospitalized patients with seasonal influenza, initiating treatment after 48 hours of symptom onset has been shown to provide some benefit in some observational studies.^1,12 Consequently, the CDC recommends initiating treatment of high-risk patients who seek care more than 48 hours after symptom onset.¹

The standard course of oseltamivir is 75 mg twice daily for 5 days. Longer courses may be beneficial in hospitalized patients.¹ Oseltamivir and zanamivir can also be continued while breastfeeding.¹³

Our patient’s outcome

The patient received a 10-day course of oseltamivir (rather than the standard 5-day course), as well as empiric broad-spectrum antibiotic coverage for community-acquired pneumonia and aspiration pneumonia, including coverage for Streptococcus pneumoniae (the most common bacterial cause of secondary pneumonia in influenza¹⁴).

The cultures come back. Nasopharyngeal cultures were negative × 2 for type A influenza. Blood cultures were negative throughout the admission. Sputum cultures were negative, as well. Bronchoscopy cultures, however, were positive for type A influenza and negative for bacterial and fungal pathogens, confirming a diagnosis of primary pneumonia from 2009 H1N1 infection.

The patient was extubated 1 week after her arrival at our hospital and continued to recover during the rest of her hospital stay. She was discharged in stable condition. Several weeks later, she delivered a full-term infant with average weight and normal Apgar scores.

CORRESPONDENCE: Christopher Bernheisel, MD, Director, Family Medicine Inpatient Service, The University of Cincinnati, 2123 Auburn Ave., Suite 340, Cincinnati, OH 45219; [email protected]

Follow-up foul-up leads to metastatic disease

A PRECANCEROUS POLYP was found in the stomach of a 50-year-old man during diagnostic gastroscopy. The pathologist’s report noted that an adjacent or underlying malignant process could not be ruled out and recommended additional tissue sampling. Upon reading the report, the gastroenterologist who had performed the gastroscopy wrote that another biopsy should be done within a few months.

The patient was seen subsequently by his primary care physician, whose office note mentioned the precancerous biopsy findings and indicated that another biopsy was necessary; the physician also wrote that malignancy in the stomach would have to be ruled out eventually. The doctor’s plan called for a repeat gastroscopy to reevaluate the dysplastic polyp. However, neither the primary care physician nor the gastroenterologist took additional steps to order, perform, or refer the patient for a follow-up endoscopy and biopsy of the lesion.

Three years later, the patient developed difficulty swallowing and lost weight rapidly. Diagnostic testing revealed a malignant tumor, at the same location as the polyp, and malignant-appearing lymph nodes.

The patient received a feeding jejunostomy tube and underwent concomitant radiation and chemotherapy. Surgery was planned, but the disease metastasized and was deemed inoperable. Despite additional treatment, the patient died at age 54.

PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.

DOCTORS’ DEFENSE The primary care physician argued that both he and the gastroenterologist were responsible for making sure the follow-up was done; the gastroenterologist claimed that the primary care physician was solely responsible for follow-up testing.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Poor coordination of care and follow-up of results is a common source of malpractice actions. Keep a paper or electronic “tickler file” for important follow-up issues.

Unaddressed cardiovascular risks prove fatal

A 46-YEAR-OLD MAN went to the hospital, where he was seen by a family practitioner. The physician noted that the patient had a history of smoking, high cholesterol, and thyroid problems.

Early the following month, the patient died of cardiopulmonary arrest. Autopsy results showed arteriosclerotic disease, acute dissection of the coronary plaques, and left ventricular hypertrophy.

PLAINTIFF’S CLAIM The family practitioner failed to take a careful history and prescribe aspirin therapy and cholesterol-lowering medication. The patient should have been referred for a cardiac work-up.

DOCTOR’S DEFENSE The patient was advised of the importance of treatment to correct his condition.

VERDICT $575,000 Michigan settlement.

COMMENT I’m seeing a great increase in cases involving failure to address cardiovascular risk factors. Be sure to thoroughly document refusal of interventions or nonadherence.

Lack of surveillance delays lung cancer diagnosis

A 64-YEAR-OLD MAN was referred to a pulmonary specialist in January by his primary care physician after a computed tomography (CT) scan showed a spiculated density adjacent to the right main-stem bronchus and a prominent right hilar lymph node. The CT scan also revealed a noncalcified nodule in the right middle lobe.

Before examining the patient, the pulmonary specialist ordered a positron emission tomography (PET) scan, which he interpreted as showing no significant uptake and considered negative. He attributed the prominent lymph node to bronchitis and ordered surveillance at 3-month intervals.

A CT scan in May showed no change, but the radiologist noted that “the possibility of malignancy cannot be excluded.” When the patient saw the specialist in early June, the doctor recommended another CT scan in 3 months.

The patient did not return to the specialist until September of the following year. By that time, a CT scan taken a couple of months before (June) as part of preoperative clearance for knee surgery showed that the irregular mass had grown significantly since the CT scan in May of the previous year. A bronchoscopy done in September to evaluate the mass was negative. In November, however, a lymph node biopsy revealed that the patient had metastatic lung cancer. He died about a month later.

PLAINTIFF’S CLAIM Because the patient had a history of smoking and the CT scan revealed a density, the suspicion for cancer should have been high despite a negative PET scan. A specimen should have been obtained by thoracoscopy or thoracotomy to rule out cancer.

THE DEFENSE The pulmonary specialist followed the correct protocol; failure to diagnose cancer at the September visit didn’t affect the outcome because the cancer was already metastatic and incurable. The patient didn’t quit smoking or follow up regularly with his primary care physician. Moreover, the cancer was at least stage IIA when the primary care physician referred the patient to the specialist.

VERDICT Pennsylvania defense verdict.

COMMENT Although a defense verdict was ultimately returned, wouldn’t a “tickler file” or a reminder to the patient (and documentation if the patient failed to follow up as recommended) have been easier?

Follow-up foul-up leads to metastatic disease

A PRECANCEROUS POLYP was found in the stomach of a 50-year-old man during diagnostic gastroscopy. The pathologist’s report noted that an adjacent or underlying malignant process could not be ruled out and recommended additional tissue sampling. Upon reading the report, the gastroenterologist who had performed the gastroscopy wrote that another biopsy should be done within a few months.

The patient was seen subsequently by his primary care physician, whose office note mentioned the precancerous biopsy findings and indicated that another biopsy was necessary; the physician also wrote that malignancy in the stomach would have to be ruled out eventually. The doctor’s plan called for a repeat gastroscopy to reevaluate the dysplastic polyp. However, neither the primary care physician nor the gastroenterologist took additional steps to order, perform, or refer the patient for a follow-up endoscopy and biopsy of the lesion.

Three years later, the patient developed difficulty swallowing and lost weight rapidly. Diagnostic testing revealed a malignant tumor, at the same location as the polyp, and malignant-appearing lymph nodes.

The patient received a feeding jejunostomy tube and underwent concomitant radiation and chemotherapy. Surgery was planned, but the disease metastasized and was deemed inoperable. Despite additional treatment, the patient died at age 54.

PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.

DOCTORS’ DEFENSE The primary care physician argued that both he and the gastroenterologist were responsible for making sure the follow-up was done; the gastroenterologist claimed that the primary care physician was solely responsible for follow-up testing.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Poor coordination of care and follow-up of results is a common source of malpractice actions. Keep a paper or electronic “tickler file” for important follow-up issues.

Unaddressed cardiovascular risks prove fatal

A 46-YEAR-OLD MAN went to the hospital, where he was seen by a family practitioner. The physician noted that the patient had a history of smoking, high cholesterol, and thyroid problems.

Early the following month, the patient died of cardiopulmonary arrest. Autopsy results showed arteriosclerotic disease, acute dissection of the coronary plaques, and left ventricular hypertrophy.

PLAINTIFF’S CLAIM The family practitioner failed to take a careful history and prescribe aspirin therapy and cholesterol-lowering medication. The patient should have been referred for a cardiac work-up.

DOCTOR’S DEFENSE The patient was advised of the importance of treatment to correct his condition.

VERDICT $575,000 Michigan settlement.

COMMENT I’m seeing a great increase in cases involving failure to address cardiovascular risk factors. Be sure to thoroughly document refusal of interventions or nonadherence.

Lack of surveillance delays lung cancer diagnosis

A 64-YEAR-OLD MAN was referred to a pulmonary specialist in January by his primary care physician after a computed tomography (CT) scan showed a spiculated density adjacent to the right main-stem bronchus and a prominent right hilar lymph node. The CT scan also revealed a noncalcified nodule in the right middle lobe.

Before examining the patient, the pulmonary specialist ordered a positron emission tomography (PET) scan, which he interpreted as showing no significant uptake and considered negative. He attributed the prominent lymph node to bronchitis and ordered surveillance at 3-month intervals.

A CT scan in May showed no change, but the radiologist noted that “the possibility of malignancy cannot be excluded.” When the patient saw the specialist in early June, the doctor recommended another CT scan in 3 months.

The patient did not return to the specialist until September of the following year. By that time, a CT scan taken a couple of months before (June) as part of preoperative clearance for knee surgery showed that the irregular mass had grown significantly since the CT scan in May of the previous year. A bronchoscopy done in September to evaluate the mass was negative. In November, however, a lymph node biopsy revealed that the patient had metastatic lung cancer. He died about a month later.

PLAINTIFF’S CLAIM Because the patient had a history of smoking and the CT scan revealed a density, the suspicion for cancer should have been high despite a negative PET scan. A specimen should have been obtained by thoracoscopy or thoracotomy to rule out cancer.

THE DEFENSE The pulmonary specialist followed the correct protocol; failure to diagnose cancer at the September visit didn’t affect the outcome because the cancer was already metastatic and incurable. The patient didn’t quit smoking or follow up regularly with his primary care physician. Moreover, the cancer was at least stage IIA when the primary care physician referred the patient to the specialist.

VERDICT Pennsylvania defense verdict.

COMMENT Although a defense verdict was ultimately returned, wouldn’t a “tickler file” or a reminder to the patient (and documentation if the patient failed to follow up as recommended) have been easier?

Follow-up foul-up leads to metastatic disease

A PRECANCEROUS POLYP was found in the stomach of a 50-year-old man during diagnostic gastroscopy. The pathologist’s report noted that an adjacent or underlying malignant process could not be ruled out and recommended additional tissue sampling. Upon reading the report, the gastroenterologist who had performed the gastroscopy wrote that another biopsy should be done within a few months.

The patient was seen subsequently by his primary care physician, whose office note mentioned the precancerous biopsy findings and indicated that another biopsy was necessary; the physician also wrote that malignancy in the stomach would have to be ruled out eventually. The doctor’s plan called for a repeat gastroscopy to reevaluate the dysplastic polyp. However, neither the primary care physician nor the gastroenterologist took additional steps to order, perform, or refer the patient for a follow-up endoscopy and biopsy of the lesion.

Three years later, the patient developed difficulty swallowing and lost weight rapidly. Diagnostic testing revealed a malignant tumor, at the same location as the polyp, and malignant-appearing lymph nodes.

The patient received a feeding jejunostomy tube and underwent concomitant radiation and chemotherapy. Surgery was planned, but the disease metastasized and was deemed inoperable. Despite additional treatment, the patient died at age 54.

PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.

DOCTORS’ DEFENSE The primary care physician argued that both he and the gastroenterologist were responsible for making sure the follow-up was done; the gastroenterologist claimed that the primary care physician was solely responsible for follow-up testing.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Poor coordination of care and follow-up of results is a common source of malpractice actions. Keep a paper or electronic “tickler file” for important follow-up issues.

Unaddressed cardiovascular risks prove fatal

A 46-YEAR-OLD MAN went to the hospital, where he was seen by a family practitioner. The physician noted that the patient had a history of smoking, high cholesterol, and thyroid problems.

Early the following month, the patient died of cardiopulmonary arrest. Autopsy results showed arteriosclerotic disease, acute dissection of the coronary plaques, and left ventricular hypertrophy.

PLAINTIFF’S CLAIM The family practitioner failed to take a careful history and prescribe aspirin therapy and cholesterol-lowering medication. The patient should have been referred for a cardiac work-up.

DOCTOR’S DEFENSE The patient was advised of the importance of treatment to correct his condition.

VERDICT $575,000 Michigan settlement.

COMMENT I’m seeing a great increase in cases involving failure to address cardiovascular risk factors. Be sure to thoroughly document refusal of interventions or nonadherence.

Lack of surveillance delays lung cancer diagnosis

A 64-YEAR-OLD MAN was referred to a pulmonary specialist in January by his primary care physician after a computed tomography (CT) scan showed a spiculated density adjacent to the right main-stem bronchus and a prominent right hilar lymph node. The CT scan also revealed a noncalcified nodule in the right middle lobe.

Before examining the patient, the pulmonary specialist ordered a positron emission tomography (PET) scan, which he interpreted as showing no significant uptake and considered negative. He attributed the prominent lymph node to bronchitis and ordered surveillance at 3-month intervals.

A CT scan in May showed no change, but the radiologist noted that “the possibility of malignancy cannot be excluded.” When the patient saw the specialist in early June, the doctor recommended another CT scan in 3 months.

The patient did not return to the specialist until September of the following year. By that time, a CT scan taken a couple of months before (June) as part of preoperative clearance for knee surgery showed that the irregular mass had grown significantly since the CT scan in May of the previous year. A bronchoscopy done in September to evaluate the mass was negative. In November, however, a lymph node biopsy revealed that the patient had metastatic lung cancer. He died about a month later.

PLAINTIFF’S CLAIM Because the patient had a history of smoking and the CT scan revealed a density, the suspicion for cancer should have been high despite a negative PET scan. A specimen should have been obtained by thoracoscopy or thoracotomy to rule out cancer.

THE DEFENSE The pulmonary specialist followed the correct protocol; failure to diagnose cancer at the September visit didn’t affect the outcome because the cancer was already metastatic and incurable. The patient didn’t quit smoking or follow up regularly with his primary care physician. Moreover, the cancer was at least stage IIA when the primary care physician referred the patient to the specialist.

VERDICT Pennsylvania defense verdict.

COMMENT Although a defense verdict was ultimately returned, wouldn’t a “tickler file” or a reminder to the patient (and documentation if the patient failed to follow up as recommended) have been easier?

Evidence summary

A 5-year retrospective cohort study of 9170 patients evaluated the effect of pneumococcal vaccination on incidence and length of all-cause hospitalizations and hospitalizations related to respiratory and otorhinolaryngologic syndromes, including asthma and pneumonia.¹ The vaccine was given to all patients older than 64 years (7834 patients [85%]) and any patient at risk for pneumococcal infection or complications, including patients with asthma, chronic obstructive pulmonary disease (COPD), bronchitis, chronic respiratory disease, cardiovascular disease, chronic renal failure, diabetes mellitus, immunodeficiency, and functional or anatomic asplenia (1336 patients [15%]).

The number of all-cause hospitalizations was reduced by 58% in patients who received the pneumococcal vaccine (relative risk [RR]=0.96; 95% confidence interval [CI], 0.94-0.98). In vaccinated patients with asthma (793 patients [8.7%]), asthma-related hospitalizations decreased by 78% (RR=1.82; 95% CI, 1.35-2.45; NNT=49) and average asthma-related length of hospital stay was shortened by about 2 days (P=.039). The study found no difference in pneumonia-related hospitalizations among all vaccinated patients.

Effect on younger patients is unclear

Because the investigators didn’t analyze asthma-related or pneumonia-related hospitalizations among asthmatic patients 64 years and younger, the effect of pneumococcal vaccination on this younger subgroup can’t be differentiated from the entire group of patients with asthma.¹

What about pneumococcal hospitalization?

A retrospective, case-controlled cohort study examined the impact of pneumococcal vaccination on any pneumococcal-related hospitalization in patients with COPD or asthma.² The study included 2746 adults with asthma (74.2% younger than 64 years) who were followed for about 2.1 years before and 2.6 years after vaccination.

Investigators found no significant differences in risk of pneumococcal-related hospitalization between asthma patients and controls throughout the study. They didn’t evaluate asthma-related hospital admissions.

Impact of vaccine on invasive disease in younger asthma patients?

A retrospective, nested, case-controlled study examined the relationship between asthma and invasive pneumococcal disease (IPD) in 6985 patients enrolled in Tennessee’s Medicaid program.³ Patients 2 to 49 years of age with any IPD diagnosis were identified using International Classification of Diseases (ICD-9-CM) codes and followed for 8 years.

Asthma patients without coexisting conditions that confer a high risk of IPD (such as diabetes, cardiac disease, and infection with human immunodeficiency virus) had a 14.7% risk of IPD compared with a risk of only 7.4% in age-matched controls (adjusted odds ratio=2.4; 95% CI, 1.7-3.4). The authors concluded that this Medicaid population with asthma had an increased incidence of IPD of 1 to 3 cases annually per 10,000 people. The effect of pneumococcal vaccination on the incidence of IPD in these younger asthma patients is unknown, however.³

Recommendations

The National Asthma Education and Prevention Program (NAEPP)⁴ and the Global Initiative for Asthma (GINA)⁵ make no recommendations regarding the administration of the pneumococcal vaccine.

The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all adults 65 years and older and adults 19 years and older with chronic lung disease, including asthma, or other chronic medical conditions such as cardiovascular diseases, diabetes, chronic liver diseases, chronic alcoholism, chronic renal failure, asplenia, and other immunocompromising conditions.⁶

The British Department of Health recommends vaccination with either the 7-valent conjugate or the 23-valent polysaccharide pneumococcal vaccine for all asthma patients taking systemic steroids longer than 1 month at a dose equivalent to prednisolone 20 mg daily and for children weighing less than 20 kg who take daily steroids at a dose of ≥1 mg/kg. Efficacy studies aren’t available to support this recommendation.⁷

Evidence summary

A 5-year retrospective cohort study of 9170 patients evaluated the effect of pneumococcal vaccination on incidence and length of all-cause hospitalizations and hospitalizations related to respiratory and otorhinolaryngologic syndromes, including asthma and pneumonia.¹ The vaccine was given to all patients older than 64 years (7834 patients [85%]) and any patient at risk for pneumococcal infection or complications, including patients with asthma, chronic obstructive pulmonary disease (COPD), bronchitis, chronic respiratory disease, cardiovascular disease, chronic renal failure, diabetes mellitus, immunodeficiency, and functional or anatomic asplenia (1336 patients [15%]).

The number of all-cause hospitalizations was reduced by 58% in patients who received the pneumococcal vaccine (relative risk [RR]=0.96; 95% confidence interval [CI], 0.94-0.98). In vaccinated patients with asthma (793 patients [8.7%]), asthma-related hospitalizations decreased by 78% (RR=1.82; 95% CI, 1.35-2.45; NNT=49) and average asthma-related length of hospital stay was shortened by about 2 days (P=.039). The study found no difference in pneumonia-related hospitalizations among all vaccinated patients.

Effect on younger patients is unclear

Because the investigators didn’t analyze asthma-related or pneumonia-related hospitalizations among asthmatic patients 64 years and younger, the effect of pneumococcal vaccination on this younger subgroup can’t be differentiated from the entire group of patients with asthma.¹

What about pneumococcal hospitalization?

A retrospective, case-controlled cohort study examined the impact of pneumococcal vaccination on any pneumococcal-related hospitalization in patients with COPD or asthma.² The study included 2746 adults with asthma (74.2% younger than 64 years) who were followed for about 2.1 years before and 2.6 years after vaccination.

Investigators found no significant differences in risk of pneumococcal-related hospitalization between asthma patients and controls throughout the study. They didn’t evaluate asthma-related hospital admissions.

Impact of vaccine on invasive disease in younger asthma patients?

A retrospective, nested, case-controlled study examined the relationship between asthma and invasive pneumococcal disease (IPD) in 6985 patients enrolled in Tennessee’s Medicaid program.³ Patients 2 to 49 years of age with any IPD diagnosis were identified using International Classification of Diseases (ICD-9-CM) codes and followed for 8 years.

Asthma patients without coexisting conditions that confer a high risk of IPD (such as diabetes, cardiac disease, and infection with human immunodeficiency virus) had a 14.7% risk of IPD compared with a risk of only 7.4% in age-matched controls (adjusted odds ratio=2.4; 95% CI, 1.7-3.4). The authors concluded that this Medicaid population with asthma had an increased incidence of IPD of 1 to 3 cases annually per 10,000 people. The effect of pneumococcal vaccination on the incidence of IPD in these younger asthma patients is unknown, however.³

Recommendations

The National Asthma Education and Prevention Program (NAEPP)⁴ and the Global Initiative for Asthma (GINA)⁵ make no recommendations regarding the administration of the pneumococcal vaccine.

The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all adults 65 years and older and adults 19 years and older with chronic lung disease, including asthma, or other chronic medical conditions such as cardiovascular diseases, diabetes, chronic liver diseases, chronic alcoholism, chronic renal failure, asplenia, and other immunocompromising conditions.⁶

The British Department of Health recommends vaccination with either the 7-valent conjugate or the 23-valent polysaccharide pneumococcal vaccine for all asthma patients taking systemic steroids longer than 1 month at a dose equivalent to prednisolone 20 mg daily and for children weighing less than 20 kg who take daily steroids at a dose of ≥1 mg/kg. Efficacy studies aren’t available to support this recommendation.⁷

Evidence summary

A 5-year retrospective cohort study of 9170 patients evaluated the effect of pneumococcal vaccination on incidence and length of all-cause hospitalizations and hospitalizations related to respiratory and otorhinolaryngologic syndromes, including asthma and pneumonia.¹ The vaccine was given to all patients older than 64 years (7834 patients [85%]) and any patient at risk for pneumococcal infection or complications, including patients with asthma, chronic obstructive pulmonary disease (COPD), bronchitis, chronic respiratory disease, cardiovascular disease, chronic renal failure, diabetes mellitus, immunodeficiency, and functional or anatomic asplenia (1336 patients [15%]).

The number of all-cause hospitalizations was reduced by 58% in patients who received the pneumococcal vaccine (relative risk [RR]=0.96; 95% confidence interval [CI], 0.94-0.98). In vaccinated patients with asthma (793 patients [8.7%]), asthma-related hospitalizations decreased by 78% (RR=1.82; 95% CI, 1.35-2.45; NNT=49) and average asthma-related length of hospital stay was shortened by about 2 days (P=.039). The study found no difference in pneumonia-related hospitalizations among all vaccinated patients.

Effect on younger patients is unclear

Because the investigators didn’t analyze asthma-related or pneumonia-related hospitalizations among asthmatic patients 64 years and younger, the effect of pneumococcal vaccination on this younger subgroup can’t be differentiated from the entire group of patients with asthma.¹

What about pneumococcal hospitalization?

A retrospective, case-controlled cohort study examined the impact of pneumococcal vaccination on any pneumococcal-related hospitalization in patients with COPD or asthma.² The study included 2746 adults with asthma (74.2% younger than 64 years) who were followed for about 2.1 years before and 2.6 years after vaccination.

Investigators found no significant differences in risk of pneumococcal-related hospitalization between asthma patients and controls throughout the study. They didn’t evaluate asthma-related hospital admissions.

Impact of vaccine on invasive disease in younger asthma patients?

A retrospective, nested, case-controlled study examined the relationship between asthma and invasive pneumococcal disease (IPD) in 6985 patients enrolled in Tennessee’s Medicaid program.³ Patients 2 to 49 years of age with any IPD diagnosis were identified using International Classification of Diseases (ICD-9-CM) codes and followed for 8 years.

Asthma patients without coexisting conditions that confer a high risk of IPD (such as diabetes, cardiac disease, and infection with human immunodeficiency virus) had a 14.7% risk of IPD compared with a risk of only 7.4% in age-matched controls (adjusted odds ratio=2.4; 95% CI, 1.7-3.4). The authors concluded that this Medicaid population with asthma had an increased incidence of IPD of 1 to 3 cases annually per 10,000 people. The effect of pneumococcal vaccination on the incidence of IPD in these younger asthma patients is unknown, however.³

Recommendations

The National Asthma Education and Prevention Program (NAEPP)⁴ and the Global Initiative for Asthma (GINA)⁵ make no recommendations regarding the administration of the pneumococcal vaccine.

The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all adults 65 years and older and adults 19 years and older with chronic lung disease, including asthma, or other chronic medical conditions such as cardiovascular diseases, diabetes, chronic liver diseases, chronic alcoholism, chronic renal failure, asplenia, and other immunocompromising conditions.⁶

The British Department of Health recommends vaccination with either the 7-valent conjugate or the 23-valent polysaccharide pneumococcal vaccine for all asthma patients taking systemic steroids longer than 1 month at a dose equivalent to prednisolone 20 mg daily and for children weighing less than 20 kg who take daily steroids at a dose of ≥1 mg/kg. Efficacy studies aren’t available to support this recommendation.⁷

Being able to identify the hallmark signs of disease is not always enough. Clinicians may recognize the taut and contracted, statue-like skin that characterizes scleroderma, but failure to identify the systemic manifestations of the disease can have deadly results. Scleroderma can affect multiple systems and virtually every body organ. Earlier diagnosis of the disease’s systemic form can help improve prognosis and ultimately increase survival rates for affected patients.

Systemic scleroderma (SSc), also known as systemic sclerosis, is a chronic connective tissue disease that is characterized by vasculopathy, autoimmunity, and inflammation.^1,2 As SSc develops, the body’s fibroblasts produce too much collagen, leading to fibrosis of the skin and the internal organs.^1,3 It was not until the 20th century that scleroderma was shown to affect the internal organs—resulting in the devastating outcomes that are now associated with SSc.

SSc is more prevalent than many clinicians realize. About 300,000 people in the United States have a form of scleroderma, and nearly one-third of these (perhaps 75,000 to 100,000) are believed to be affected by its systemic variant.^1,4,5

When SSc invades the major internal organs, especially the lungs, kidneys, and heart, the prognosis is poor. SSc carries a survival rate of only 55% at 10 years postdiagnosis—the highest risk of fatality among connective tissue diseases.¹ Therefore, when any form of scleroderma is suspected, it is imperative that the patient be examined for multisystem involvement. 

Disease Classification
Patient presentation varies, depending on the form of scleroderma. To recognize the symptoms, the clinician must first understand the various classifications of the disease. Scleroderma is often seen as a spectrum of illness, ranging from mild to life-threatening. The two major variants are localized scleroderma (with fibrosis restricted to the skin) and systemic scleroderma (in which fibrosis affects the internal organs).⁶

Localized scleroderma may manifest as linear scleroderma, with band-like thickened skin lesions that begin to develop during childhood and usually affect one area, such as an arm or a leg; involvement of the forehead, face, or scalp is referred to as en coup de sabre (“cut of the sword”). By contrast, morphia (which can be limited or generalized) appears as circumscribed sclerotic patches or plaques on the skin and can be intermittent. These lesions vary in size but are usually round or oval, with purple edges and a waxy appearance⁶ (see Figure 1).

Systemic scleroderma comprises both cutaneous and noncutaneous involvement (although scleroderma sine sclerosis, fibrosis of the internal organs with no skin lesions, is rare). Typically, limited systemic scleroderma affects only the hands, the face, and the distal extremities (see Figure 2). It was originally referred to as CREST syndrome, an acronym for calcinosis of the digits, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.⁶ The lungs may eventually be affected.⁷

Diffuse systemic scleroderma usually begins with Raynaud’s phenomenon, followed by sclerosis of the proximal extremities, the trunk, and the face, and progresses to dysfunction of the lungs, kidneys, heart, and gastrointestinal (GI) system.^1,8 For the purposes of this review, further mentions of “SSc” will refer to the diffuse form.

Raynaud’s Phenomenon
Although presentation varies in patients with SSc, vascular changes are among its earliest presenting signs (see Table 1^6,8,9 for a list of clinical manifestations). Raynaud’s phenomenon accounts for 70% of SSc patients’ first reported symptoms, and it occurs in 90% to 99% of patients with systemic disease.^10,11

Raynaud’s phenomenon is the episodic constriction of blood vessels in response to environmental factors such as cold, stress, or emotional changes. This circulation disturbance is evidenced by color changes in the digits and the development of digital ulcers resulting from ischemia (found in almost half of all patients).^11,12 It manifests as a series of changes in appearance: white or pale as a result of vasospasm, cyanotic from ischemia, then red or flushed as the blood flow returns.^10,11

Raynaud’s phenomenon may be present for many years before any other clinically significant symptoms or systemic manifestations occur. Even among patients who do not experience all of the skin changes associated with Raynaud’s phenomenon, most report digital pallor¹¹ (see Figure 3). Care of digital ulcers is required to prevent potentially serious sequelae, including osteomyelitis and soft-tissue necrosis^12,13 (see Figure 4).

Cutaneous Changes
Once patients with SSc have begun to experience circulation problems and blood vessel damage, cutaneous changes result. Skin edema occurs, manifesting in swollen, pruritic hands and digits.¹⁴ Over time, the skin hardens and thickens over the digits, extremities, face, and trunk—all resulting from vascular dysfunction and oxidative stress, followed by immunologic activation and inflammation.^1,3,15 The tight, fibrotic skin that results is the hallmark of SSc^1,3 (see Figure 5).

Skin changes tend to peak within the first five years. Patients who experience them rapidly are at increased risk for severe internal organ involvement.⁶ With disease progression come facial changes, including a shrunken nose, microglossia, small lips, furrowing around the mouth, telangiectasias, hyperpigmentation (resembling that seen in patients with Addison’s disease), and sclerosis that limits facial expressions, leaving a mask-like appearance.^6,10

Calcinosis, the buildup of calcium deposits under the skin, appears in the form of painful, hard nodules, especially in the digits, elbows, knees, and other joints. This occurs in 40% of SSc patients.¹¹ In addition to the already thickened sclerotic skin, calcinosis causes flexion contractures leading to restricted mobility, articular deformities, and dissolution of the distal phalanges.^10,16

Noncutaneous Manifestations
In addition to vascular and cutaneous changes, patients affected by SSc may develop a multitude of musculoskeletal complaints, including nonspecific joint pain. These symptoms can manifest as arthritis and cause discomfort in the tendons and muscles. Patients may even develop myopathies and muscle weakness over time.¹⁷

GI tract complaints are almost universally seen in patients with SSc; more than 85% of patients experience dysphagia, phagodynia, or other esophageal problems.¹⁰ These symptoms usually result from peristaltic abnormalities: reflux, Barrett’s metaplasia, hypomotility, and/or fibrotic strictures. Subsequent complaints may include nausea, vomiting, abdominal pain, and constipation due to colonic hypomotility.^18,19 In some patients, malabsorption syndrome can advance to a stage at which parenteral nutrition is required.¹²

Pulmonary impairment is another common manifestation, affecting possibly 80% to 90% of patients with SSc.^2,7 Patients who present with dyspnea or a dry, irritating cough may have underlying lung fibrosis.^6,11 Those who report shortness of breath, fatigue, fast heart rates, or blackouts may have pulmonary hypertension, which is seen in one in seven patients.¹¹ Pulmonary hypertension reduces the five-year survival rate from 90% to as low as 50%, making it a significant cause of SSc-related death.¹⁰

The most devastating clinical manifestations in SSc patients are renal and heart involvement.²⁰ Among all the possibilities of organ involvement, kidney damage incurs the worst prognosis and the highest mortality. Of patients not treated for this development, only 16% survive longer than one year; with treatment, such patients’ five-year survival is 45%.¹⁰

Sclerodermal renal crisis is apparent in patients who meet the diagnostic criteria of proteinuria, azotemia, arterial hypertension, a reduced glomerular filtration rate, hematuria, and microangiopathic hemolytic anemia.^20-25 Patients may also present with retrosternal pain, possibly signifying myocardial fibrosis. This complication, in addition to kidney failure, can lead to arrhythmias and ultimately heart failure.

Patient History
Particularly important components of the patient history include gender, race, age, family history, and work environment. Although anyone can develop scleroderma, women are four times more likely than men to develop SSc, and pregnancy increases women’s risk tenfold.¹¹ For unknown reasons, African-Americans are more frequently affected than whites and are at increased risk for serious systemic involvement.⁴

Symptom onset is most common between ages 25 and 55, although children and elderly persons can be affected.^11,26,27

Most research suggests that SSc is not directly inherited, although (as in the case of other autoimmune diseases) genetic factors can predispose people with additional external triggers.^21,28,29 A positive family history is a strong risk factor for SSc. In a large cohort-based study, patients with SSc invariably had at least one first-degree relative who was also affected.²⁹

Although the exact cause of SSc remains unknown, substantial research suggests that environmental factors, especially exposure to certain metals and chemical compounds (eg, solvents, pesticides, silica), play a major role in its development.^1,16,30 Farmers, factory and construction workers, coal miners, and others may be exposed to these chemicals, so it is important to ask about potentially hazardous occupations.

Physical Examination
Patients in whom any form of scleroderma is suspected should undergo a thorough physical examination. It is here that preliminary signs of internal organ involvement and fibrosis must be detected.

Clinicians should observe the skin for signs of inflammation. Any changes in the skin’s appearance or texture, including tight, hardened, and sclerotic changes of the hands, face, mouth, trunk, and/or digits, should also be noted. The examiner may notice furrowing around the mouth, telangiectasias, and hyperpigmentation.^6,10 Signs of vascular damage may be identified, including digital discoloration and ulcers associated with Raynaud’s phenomenon.²²

Examination of the skin (with palpation) will reveal information about the disease’s activity, involvement, and severity.³¹ Active cutaneous disease indicated by inflammatory signs (eg, edema) correlates with active internal disease, such as renal crisis or fibrosing alveolitis.10 Inactive skin disease manifests as sclerotic skin resembling a scar.³¹

If skin sclerosis is sufficient for suspicion of SSc, additional steps are required. In the ear-nose-throat examination, for example, the mucosal membranes should be observed for signs of Sjögren’s syndrome, since it is associated with SSc.³² The mouth should also be examined for telangiectasias and microglossia.

A musculoskeletal exam may also prove helpful. Range of motion and joint mobility should be assessed, especially if sclerotic skin causes flexion contractures, producing shortened fingers or articular deformities.¹⁶

Diagnostic Work-up
If suspicion of SSc persists, the disease can be further assessed through laboratory values and imaging. No one test ensures a definitive diagnosis, but serologic testing for autoantibodies is helpful.^5,33

The provider may order an antinuclear antibody (ANA) test or rheumatoid factor testing to confirm connective tissue disease (CTD). However, it is important to remember that a positive ANA result is found in patients with other CTDs, including 30% of those with rheumatoid arthritis and 95% of those with systemic lupus erythematosus.³³ Since anticentromere antibodies are present in 70% to 80% of patients, and antibodies against topoisomerase I DNA (anti-Scl-70) exist in about 40% of patients, confirmed presence of either has a specificity of 95% to 99% for the diagnosis of SSc.³⁴

Imaging and other tests help to assess the involvement of SSc and the extent of associated fibrosis in internal organs. X-ray of the hands can reveal intra-articular calcifications and osteopenia, as well as soft-tissue calcinosis.^11,17

Chest x-ray and CT can detect interstitial lung disease.³³ Imaging will also help differentiate active alveolitis (ground-glass appearance) from pulmonary fibrosis (honeycombing).⁶ Clinicians may order pulmonary function testing to confirm restrictive lung disease. Doppler echocardiography will show cardiac and pulmonary vascular involvement and can confirm the presence of pulmonary hypertension. ECG, Holter monitoring, and ultrasonography can be used to further assess suspected myocardial disease and arrhythmias.³⁵

GI changes, including esophageal stricture and Barrett’s esophagus, can be investigated through esophageal manometry and endoscopy.^3,18 In addition to renal function testing, urinalysis and peripheral blood smear are necessary to confirm renal crisis, especially in patients with worsening hypertension or with new anemia not associated with blood loss.⁶

Classification
Diagnosis of SSc is made based on the patient’s clinical presentation, but the degree of organ involvement must also be determined by symptoms, history, physical examination, laboratory work-up, and imaging studies, as detailed above. The 1980 Preliminary Criteria for the Classification of Systemic Sclerosis³⁶ is 97% sensitive and 98% specific for SSc,^37,38 although additional criteria (eg, certain autoantibodies, nail-fold capillary changes) have been proposed to improve sensitivity for limited SSc.^9,38 (For the major and minor criteria from the 1980 document, see Table 2^6,10,36).

Accurate, early classification of SSc is critical. Patients are most likely to respond to therapeutic efforts in the disease’s early stages, and prognosis depends on the degree of disease severity and organ involvement.^37,38

Treatment
No treatment modality has yet been found to reverse the fibrotic damage of SSc, but several therapies can slow disease progression.³⁹ Because of the heterogeneous nature of the disease, management is individualized according to patient symptoms and organ involvement.⁴⁰ Treatment is directed at preventing vascular damage, immune cell activation, and fibrosis.^10,41 Table 3^2,12,41,42 shows treatment strategies to address all three disease processes.

In early SSc, vascular intervention and immunosuppressive treatment are most important because they can prevent later stages that involve fibrosis.² Vasodilators (calcium channel blockers, such as amlodipine and nifedipine; ACE inhibitors, including enalapril and captopril; and angiotensin receptor blockers, such as losartan) have been found effective, particularly for treatment of Raynaud’s phenomenon and to prevent further renal damage.^12,41 An abundance of recent evidence suggests that bosentan, an endothelium receptor antagonist, is helpful in treating pulmonary hypertension and preventing digital ulcers by regulating the inflammatory response.^{2,12,13,30,39,43}

Cyclophosphamide is used for patients with interstitial lung disease and any associated alveolitis.^5,41 In one randomized double-blind trial, methotrexate improved skin scores (ie, softened fibrosis), creatinine clearance, and overall well-being in 68% of patients who received it over a 24-week period.⁴²

In later stages of SSc, suppressing fibrosis is the goal. d-Penicillamine is considered a first-line agent, because it interferes with collagen cross-linking.⁴¹ No conclusive data exist to support its dosing and efficacy, although findings vary from no effect to 70% benefit in improving skin scores and decreasing five-year mortality rates.^2,6,41

Patient Education
Patient compliance will require education, as several months’ treatment may be required before results are evident. Supportive and symptomatic therapy will greatly improve quality of life as well.

Patients should be told that GI reflux and motility disorders can be controlled with proton pump inhibitors.⁴¹ They should also be advised to elevate the head when in bed and to eat small, frequent meals.

Arthralgias, arthritis, and deep tissue fibrosis that cause joint contractures and tendon friction rubs may be controlled by NSAIDs.41 The manifestations of Raynaud’s phenomenon can be minimized by avoiding exposure to cold temperatures and wearing warm clothes; smoking cessation is also advised.⁵

Colchicine may help alleviate inflammation, pain, and calcinosis. Physiotherapy can help prevent deformities, and an exercise routine is important to maintain joint mobility.^5,41 Lubrication with emollients is essential for dry, sclerotic skin.

In addition, psychologic guidance through counseling is important for the patient’s self-confidence and self-image. SSc can be disfiguring, with the face and hands affected in almost all cases.¹¹

Monitoring and Follow-Up
Emphasizing regular visits and routine screening procedures is crucial in the management of SSc. A team of specialists should be involved in treating the complex, diverse symptoms of SSc and in monitoring the disease to prevent further organ fibrosis and dysfunction.

Conclusion
Systemic sclerosis is a complex, multisystem disease. Because it is highly variable in expression and clinical presentation, diagnosis is difficult and often overlooked, even by the most attentive clinicians. Widespread involvement of SSc and potential fibrosis of organs beyond the skin (including the kidneys, heart, lungs, muscles, joints, and GI tract) contribute to SSc’s devastating morbidity and mortality.

Treatment is aimed at controlling the vasculopathy, autoimmunity, and fibrosis associated with the disease. Since there is no cure for SSc, close monitoring and management by a team of health care professionals are essential in slowing disease progression.

Being able to identify the hallmark signs of disease is not always enough. Clinicians may recognize the taut and contracted, statue-like skin that characterizes scleroderma, but failure to identify the systemic manifestations of the disease can have deadly results. Scleroderma can affect multiple systems and virtually every body organ. Earlier diagnosis of the disease’s systemic form can help improve prognosis and ultimately increase survival rates for affected patients.

Systemic scleroderma (SSc), also known as systemic sclerosis, is a chronic connective tissue disease that is characterized by vasculopathy, autoimmunity, and inflammation.^1,2 As SSc develops, the body’s fibroblasts produce too much collagen, leading to fibrosis of the skin and the internal organs.^1,3 It was not until the 20th century that scleroderma was shown to affect the internal organs—resulting in the devastating outcomes that are now associated with SSc.

SSc is more prevalent than many clinicians realize. About 300,000 people in the United States have a form of scleroderma, and nearly one-third of these (perhaps 75,000 to 100,000) are believed to be affected by its systemic variant.^1,4,5

When SSc invades the major internal organs, especially the lungs, kidneys, and heart, the prognosis is poor. SSc carries a survival rate of only 55% at 10 years postdiagnosis—the highest risk of fatality among connective tissue diseases.¹ Therefore, when any form of scleroderma is suspected, it is imperative that the patient be examined for multisystem involvement. 

Disease Classification
Patient presentation varies, depending on the form of scleroderma. To recognize the symptoms, the clinician must first understand the various classifications of the disease. Scleroderma is often seen as a spectrum of illness, ranging from mild to life-threatening. The two major variants are localized scleroderma (with fibrosis restricted to the skin) and systemic scleroderma (in which fibrosis affects the internal organs).⁶

Localized scleroderma may manifest as linear scleroderma, with band-like thickened skin lesions that begin to develop during childhood and usually affect one area, such as an arm or a leg; involvement of the forehead, face, or scalp is referred to as en coup de sabre (“cut of the sword”). By contrast, morphia (which can be limited or generalized) appears as circumscribed sclerotic patches or plaques on the skin and can be intermittent. These lesions vary in size but are usually round or oval, with purple edges and a waxy appearance⁶ (see Figure 1).

Systemic scleroderma comprises both cutaneous and noncutaneous involvement (although scleroderma sine sclerosis, fibrosis of the internal organs with no skin lesions, is rare). Typically, limited systemic scleroderma affects only the hands, the face, and the distal extremities (see Figure 2). It was originally referred to as CREST syndrome, an acronym for calcinosis of the digits, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.⁶ The lungs may eventually be affected.⁷

Diffuse systemic scleroderma usually begins with Raynaud’s phenomenon, followed by sclerosis of the proximal extremities, the trunk, and the face, and progresses to dysfunction of the lungs, kidneys, heart, and gastrointestinal (GI) system.^1,8 For the purposes of this review, further mentions of “SSc” will refer to the diffuse form.

Raynaud’s Phenomenon
Although presentation varies in patients with SSc, vascular changes are among its earliest presenting signs (see Table 1^6,8,9 for a list of clinical manifestations). Raynaud’s phenomenon accounts for 70% of SSc patients’ first reported symptoms, and it occurs in 90% to 99% of patients with systemic disease.^10,11

Raynaud’s phenomenon is the episodic constriction of blood vessels in response to environmental factors such as cold, stress, or emotional changes. This circulation disturbance is evidenced by color changes in the digits and the development of digital ulcers resulting from ischemia (found in almost half of all patients).^11,12 It manifests as a series of changes in appearance: white or pale as a result of vasospasm, cyanotic from ischemia, then red or flushed as the blood flow returns.^10,11

Raynaud’s phenomenon may be present for many years before any other clinically significant symptoms or systemic manifestations occur. Even among patients who do not experience all of the skin changes associated with Raynaud’s phenomenon, most report digital pallor¹¹ (see Figure 3). Care of digital ulcers is required to prevent potentially serious sequelae, including osteomyelitis and soft-tissue necrosis^12,13 (see Figure 4).

Cutaneous Changes
Once patients with SSc have begun to experience circulation problems and blood vessel damage, cutaneous changes result. Skin edema occurs, manifesting in swollen, pruritic hands and digits.¹⁴ Over time, the skin hardens and thickens over the digits, extremities, face, and trunk—all resulting from vascular dysfunction and oxidative stress, followed by immunologic activation and inflammation.^1,3,15 The tight, fibrotic skin that results is the hallmark of SSc^1,3 (see Figure 5).

Skin changes tend to peak within the first five years. Patients who experience them rapidly are at increased risk for severe internal organ involvement.⁶ With disease progression come facial changes, including a shrunken nose, microglossia, small lips, furrowing around the mouth, telangiectasias, hyperpigmentation (resembling that seen in patients with Addison’s disease), and sclerosis that limits facial expressions, leaving a mask-like appearance.^6,10

Calcinosis, the buildup of calcium deposits under the skin, appears in the form of painful, hard nodules, especially in the digits, elbows, knees, and other joints. This occurs in 40% of SSc patients.¹¹ In addition to the already thickened sclerotic skin, calcinosis causes flexion contractures leading to restricted mobility, articular deformities, and dissolution of the distal phalanges.^10,16

Noncutaneous Manifestations
In addition to vascular and cutaneous changes, patients affected by SSc may develop a multitude of musculoskeletal complaints, including nonspecific joint pain. These symptoms can manifest as arthritis and cause discomfort in the tendons and muscles. Patients may even develop myopathies and muscle weakness over time.¹⁷

GI tract complaints are almost universally seen in patients with SSc; more than 85% of patients experience dysphagia, phagodynia, or other esophageal problems.¹⁰ These symptoms usually result from peristaltic abnormalities: reflux, Barrett’s metaplasia, hypomotility, and/or fibrotic strictures. Subsequent complaints may include nausea, vomiting, abdominal pain, and constipation due to colonic hypomotility.^18,19 In some patients, malabsorption syndrome can advance to a stage at which parenteral nutrition is required.¹²

Pulmonary impairment is another common manifestation, affecting possibly 80% to 90% of patients with SSc.^2,7 Patients who present with dyspnea or a dry, irritating cough may have underlying lung fibrosis.^6,11 Those who report shortness of breath, fatigue, fast heart rates, or blackouts may have pulmonary hypertension, which is seen in one in seven patients.¹¹ Pulmonary hypertension reduces the five-year survival rate from 90% to as low as 50%, making it a significant cause of SSc-related death.¹⁰

The most devastating clinical manifestations in SSc patients are renal and heart involvement.²⁰ Among all the possibilities of organ involvement, kidney damage incurs the worst prognosis and the highest mortality. Of patients not treated for this development, only 16% survive longer than one year; with treatment, such patients’ five-year survival is 45%.¹⁰

Sclerodermal renal crisis is apparent in patients who meet the diagnostic criteria of proteinuria, azotemia, arterial hypertension, a reduced glomerular filtration rate, hematuria, and microangiopathic hemolytic anemia.^20-25 Patients may also present with retrosternal pain, possibly signifying myocardial fibrosis. This complication, in addition to kidney failure, can lead to arrhythmias and ultimately heart failure.

Patient History
Particularly important components of the patient history include gender, race, age, family history, and work environment. Although anyone can develop scleroderma, women are four times more likely than men to develop SSc, and pregnancy increases women’s risk tenfold.¹¹ For unknown reasons, African-Americans are more frequently affected than whites and are at increased risk for serious systemic involvement.⁴

Symptom onset is most common between ages 25 and 55, although children and elderly persons can be affected.^11,26,27

Most research suggests that SSc is not directly inherited, although (as in the case of other autoimmune diseases) genetic factors can predispose people with additional external triggers.^21,28,29 A positive family history is a strong risk factor for SSc. In a large cohort-based study, patients with SSc invariably had at least one first-degree relative who was also affected.²⁹

Although the exact cause of SSc remains unknown, substantial research suggests that environmental factors, especially exposure to certain metals and chemical compounds (eg, solvents, pesticides, silica), play a major role in its development.^1,16,30 Farmers, factory and construction workers, coal miners, and others may be exposed to these chemicals, so it is important to ask about potentially hazardous occupations.

Physical Examination
Patients in whom any form of scleroderma is suspected should undergo a thorough physical examination. It is here that preliminary signs of internal organ involvement and fibrosis must be detected.

Clinicians should observe the skin for signs of inflammation. Any changes in the skin’s appearance or texture, including tight, hardened, and sclerotic changes of the hands, face, mouth, trunk, and/or digits, should also be noted. The examiner may notice furrowing around the mouth, telangiectasias, and hyperpigmentation.^6,10 Signs of vascular damage may be identified, including digital discoloration and ulcers associated with Raynaud’s phenomenon.²²

Examination of the skin (with palpation) will reveal information about the disease’s activity, involvement, and severity.³¹ Active cutaneous disease indicated by inflammatory signs (eg, edema) correlates with active internal disease, such as renal crisis or fibrosing alveolitis.10 Inactive skin disease manifests as sclerotic skin resembling a scar.³¹

If skin sclerosis is sufficient for suspicion of SSc, additional steps are required. In the ear-nose-throat examination, for example, the mucosal membranes should be observed for signs of Sjögren’s syndrome, since it is associated with SSc.³² The mouth should also be examined for telangiectasias and microglossia.

A musculoskeletal exam may also prove helpful. Range of motion and joint mobility should be assessed, especially if sclerotic skin causes flexion contractures, producing shortened fingers or articular deformities.¹⁶

Diagnostic Work-up
If suspicion of SSc persists, the disease can be further assessed through laboratory values and imaging. No one test ensures a definitive diagnosis, but serologic testing for autoantibodies is helpful.^5,33

The provider may order an antinuclear antibody (ANA) test or rheumatoid factor testing to confirm connective tissue disease (CTD). However, it is important to remember that a positive ANA result is found in patients with other CTDs, including 30% of those with rheumatoid arthritis and 95% of those with systemic lupus erythematosus.³³ Since anticentromere antibodies are present in 70% to 80% of patients, and antibodies against topoisomerase I DNA (anti-Scl-70) exist in about 40% of patients, confirmed presence of either has a specificity of 95% to 99% for the diagnosis of SSc.³⁴

Imaging and other tests help to assess the involvement of SSc and the extent of associated fibrosis in internal organs. X-ray of the hands can reveal intra-articular calcifications and osteopenia, as well as soft-tissue calcinosis.^11,17

Chest x-ray and CT can detect interstitial lung disease.³³ Imaging will also help differentiate active alveolitis (ground-glass appearance) from pulmonary fibrosis (honeycombing).⁶ Clinicians may order pulmonary function testing to confirm restrictive lung disease. Doppler echocardiography will show cardiac and pulmonary vascular involvement and can confirm the presence of pulmonary hypertension. ECG, Holter monitoring, and ultrasonography can be used to further assess suspected myocardial disease and arrhythmias.³⁵

GI changes, including esophageal stricture and Barrett’s esophagus, can be investigated through esophageal manometry and endoscopy.^3,18 In addition to renal function testing, urinalysis and peripheral blood smear are necessary to confirm renal crisis, especially in patients with worsening hypertension or with new anemia not associated with blood loss.⁶

Classification
Diagnosis of SSc is made based on the patient’s clinical presentation, but the degree of organ involvement must also be determined by symptoms, history, physical examination, laboratory work-up, and imaging studies, as detailed above. The 1980 Preliminary Criteria for the Classification of Systemic Sclerosis³⁶ is 97% sensitive and 98% specific for SSc,^37,38 although additional criteria (eg, certain autoantibodies, nail-fold capillary changes) have been proposed to improve sensitivity for limited SSc.^9,38 (For the major and minor criteria from the 1980 document, see Table 2^6,10,36).

Accurate, early classification of SSc is critical. Patients are most likely to respond to therapeutic efforts in the disease’s early stages, and prognosis depends on the degree of disease severity and organ involvement.^37,38

Treatment
No treatment modality has yet been found to reverse the fibrotic damage of SSc, but several therapies can slow disease progression.³⁹ Because of the heterogeneous nature of the disease, management is individualized according to patient symptoms and organ involvement.⁴⁰ Treatment is directed at preventing vascular damage, immune cell activation, and fibrosis.^10,41 Table 3^2,12,41,42 shows treatment strategies to address all three disease processes.

In early SSc, vascular intervention and immunosuppressive treatment are most important because they can prevent later stages that involve fibrosis.² Vasodilators (calcium channel blockers, such as amlodipine and nifedipine; ACE inhibitors, including enalapril and captopril; and angiotensin receptor blockers, such as losartan) have been found effective, particularly for treatment of Raynaud’s phenomenon and to prevent further renal damage.^12,41 An abundance of recent evidence suggests that bosentan, an endothelium receptor antagonist, is helpful in treating pulmonary hypertension and preventing digital ulcers by regulating the inflammatory response.^{2,12,13,30,39,43}

Cyclophosphamide is used for patients with interstitial lung disease and any associated alveolitis.^5,41 In one randomized double-blind trial, methotrexate improved skin scores (ie, softened fibrosis), creatinine clearance, and overall well-being in 68% of patients who received it over a 24-week period.⁴²

In later stages of SSc, suppressing fibrosis is the goal. d-Penicillamine is considered a first-line agent, because it interferes with collagen cross-linking.⁴¹ No conclusive data exist to support its dosing and efficacy, although findings vary from no effect to 70% benefit in improving skin scores and decreasing five-year mortality rates.^2,6,41

Patient Education
Patient compliance will require education, as several months’ treatment may be required before results are evident. Supportive and symptomatic therapy will greatly improve quality of life as well.

Patients should be told that GI reflux and motility disorders can be controlled with proton pump inhibitors.⁴¹ They should also be advised to elevate the head when in bed and to eat small, frequent meals.

Arthralgias, arthritis, and deep tissue fibrosis that cause joint contractures and tendon friction rubs may be controlled by NSAIDs.41 The manifestations of Raynaud’s phenomenon can be minimized by avoiding exposure to cold temperatures and wearing warm clothes; smoking cessation is also advised.⁵

Colchicine may help alleviate inflammation, pain, and calcinosis. Physiotherapy can help prevent deformities, and an exercise routine is important to maintain joint mobility.^5,41 Lubrication with emollients is essential for dry, sclerotic skin.

In addition, psychologic guidance through counseling is important for the patient’s self-confidence and self-image. SSc can be disfiguring, with the face and hands affected in almost all cases.¹¹

Monitoring and Follow-Up
Emphasizing regular visits and routine screening procedures is crucial in the management of SSc. A team of specialists should be involved in treating the complex, diverse symptoms of SSc and in monitoring the disease to prevent further organ fibrosis and dysfunction.

Conclusion
Systemic sclerosis is a complex, multisystem disease. Because it is highly variable in expression and clinical presentation, diagnosis is difficult and often overlooked, even by the most attentive clinicians. Widespread involvement of SSc and potential fibrosis of organs beyond the skin (including the kidneys, heart, lungs, muscles, joints, and GI tract) contribute to SSc’s devastating morbidity and mortality.

Treatment is aimed at controlling the vasculopathy, autoimmunity, and fibrosis associated with the disease. Since there is no cure for SSc, close monitoring and management by a team of health care professionals are essential in slowing disease progression.

Being able to identify the hallmark signs of disease is not always enough. Clinicians may recognize the taut and contracted, statue-like skin that characterizes scleroderma, but failure to identify the systemic manifestations of the disease can have deadly results. Scleroderma can affect multiple systems and virtually every body organ. Earlier diagnosis of the disease’s systemic form can help improve prognosis and ultimately increase survival rates for affected patients.

Systemic scleroderma (SSc), also known as systemic sclerosis, is a chronic connective tissue disease that is characterized by vasculopathy, autoimmunity, and inflammation.^1,2 As SSc develops, the body’s fibroblasts produce too much collagen, leading to fibrosis of the skin and the internal organs.^1,3 It was not until the 20th century that scleroderma was shown to affect the internal organs—resulting in the devastating outcomes that are now associated with SSc.

SSc is more prevalent than many clinicians realize. About 300,000 people in the United States have a form of scleroderma, and nearly one-third of these (perhaps 75,000 to 100,000) are believed to be affected by its systemic variant.^1,4,5

When SSc invades the major internal organs, especially the lungs, kidneys, and heart, the prognosis is poor. SSc carries a survival rate of only 55% at 10 years postdiagnosis—the highest risk of fatality among connective tissue diseases.¹ Therefore, when any form of scleroderma is suspected, it is imperative that the patient be examined for multisystem involvement. 

Disease Classification
Patient presentation varies, depending on the form of scleroderma. To recognize the symptoms, the clinician must first understand the various classifications of the disease. Scleroderma is often seen as a spectrum of illness, ranging from mild to life-threatening. The two major variants are localized scleroderma (with fibrosis restricted to the skin) and systemic scleroderma (in which fibrosis affects the internal organs).⁶

Localized scleroderma may manifest as linear scleroderma, with band-like thickened skin lesions that begin to develop during childhood and usually affect one area, such as an arm or a leg; involvement of the forehead, face, or scalp is referred to as en coup de sabre (“cut of the sword”). By contrast, morphia (which can be limited or generalized) appears as circumscribed sclerotic patches or plaques on the skin and can be intermittent. These lesions vary in size but are usually round or oval, with purple edges and a waxy appearance⁶ (see Figure 1).

Systemic scleroderma comprises both cutaneous and noncutaneous involvement (although scleroderma sine sclerosis, fibrosis of the internal organs with no skin lesions, is rare). Typically, limited systemic scleroderma affects only the hands, the face, and the distal extremities (see Figure 2). It was originally referred to as CREST syndrome, an acronym for calcinosis of the digits, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.⁶ The lungs may eventually be affected.⁷

Diffuse systemic scleroderma usually begins with Raynaud’s phenomenon, followed by sclerosis of the proximal extremities, the trunk, and the face, and progresses to dysfunction of the lungs, kidneys, heart, and gastrointestinal (GI) system.^1,8 For the purposes of this review, further mentions of “SSc” will refer to the diffuse form.

Raynaud’s Phenomenon
Although presentation varies in patients with SSc, vascular changes are among its earliest presenting signs (see Table 1^6,8,9 for a list of clinical manifestations). Raynaud’s phenomenon accounts for 70% of SSc patients’ first reported symptoms, and it occurs in 90% to 99% of patients with systemic disease.^10,11

Raynaud’s phenomenon is the episodic constriction of blood vessels in response to environmental factors such as cold, stress, or emotional changes. This circulation disturbance is evidenced by color changes in the digits and the development of digital ulcers resulting from ischemia (found in almost half of all patients).^11,12 It manifests as a series of changes in appearance: white or pale as a result of vasospasm, cyanotic from ischemia, then red or flushed as the blood flow returns.^10,11

Raynaud’s phenomenon may be present for many years before any other clinically significant symptoms or systemic manifestations occur. Even among patients who do not experience all of the skin changes associated with Raynaud’s phenomenon, most report digital pallor¹¹ (see Figure 3). Care of digital ulcers is required to prevent potentially serious sequelae, including osteomyelitis and soft-tissue necrosis^12,13 (see Figure 4).

Cutaneous Changes
Once patients with SSc have begun to experience circulation problems and blood vessel damage, cutaneous changes result. Skin edema occurs, manifesting in swollen, pruritic hands and digits.¹⁴ Over time, the skin hardens and thickens over the digits, extremities, face, and trunk—all resulting from vascular dysfunction and oxidative stress, followed by immunologic activation and inflammation.^1,3,15 The tight, fibrotic skin that results is the hallmark of SSc^1,3 (see Figure 5).

Skin changes tend to peak within the first five years. Patients who experience them rapidly are at increased risk for severe internal organ involvement.⁶ With disease progression come facial changes, including a shrunken nose, microglossia, small lips, furrowing around the mouth, telangiectasias, hyperpigmentation (resembling that seen in patients with Addison’s disease), and sclerosis that limits facial expressions, leaving a mask-like appearance.^6,10

Calcinosis, the buildup of calcium deposits under the skin, appears in the form of painful, hard nodules, especially in the digits, elbows, knees, and other joints. This occurs in 40% of SSc patients.¹¹ In addition to the already thickened sclerotic skin, calcinosis causes flexion contractures leading to restricted mobility, articular deformities, and dissolution of the distal phalanges.^10,16

Noncutaneous Manifestations
In addition to vascular and cutaneous changes, patients affected by SSc may develop a multitude of musculoskeletal complaints, including nonspecific joint pain. These symptoms can manifest as arthritis and cause discomfort in the tendons and muscles. Patients may even develop myopathies and muscle weakness over time.¹⁷

GI tract complaints are almost universally seen in patients with SSc; more than 85% of patients experience dysphagia, phagodynia, or other esophageal problems.¹⁰ These symptoms usually result from peristaltic abnormalities: reflux, Barrett’s metaplasia, hypomotility, and/or fibrotic strictures. Subsequent complaints may include nausea, vomiting, abdominal pain, and constipation due to colonic hypomotility.^18,19 In some patients, malabsorption syndrome can advance to a stage at which parenteral nutrition is required.¹²

Pulmonary impairment is another common manifestation, affecting possibly 80% to 90% of patients with SSc.^2,7 Patients who present with dyspnea or a dry, irritating cough may have underlying lung fibrosis.^6,11 Those who report shortness of breath, fatigue, fast heart rates, or blackouts may have pulmonary hypertension, which is seen in one in seven patients.¹¹ Pulmonary hypertension reduces the five-year survival rate from 90% to as low as 50%, making it a significant cause of SSc-related death.¹⁰

The most devastating clinical manifestations in SSc patients are renal and heart involvement.²⁰ Among all the possibilities of organ involvement, kidney damage incurs the worst prognosis and the highest mortality. Of patients not treated for this development, only 16% survive longer than one year; with treatment, such patients’ five-year survival is 45%.¹⁰

Sclerodermal renal crisis is apparent in patients who meet the diagnostic criteria of proteinuria, azotemia, arterial hypertension, a reduced glomerular filtration rate, hematuria, and microangiopathic hemolytic anemia.^20-25 Patients may also present with retrosternal pain, possibly signifying myocardial fibrosis. This complication, in addition to kidney failure, can lead to arrhythmias and ultimately heart failure.

Patient History
Particularly important components of the patient history include gender, race, age, family history, and work environment. Although anyone can develop scleroderma, women are four times more likely than men to develop SSc, and pregnancy increases women’s risk tenfold.¹¹ For unknown reasons, African-Americans are more frequently affected than whites and are at increased risk for serious systemic involvement.⁴

Symptom onset is most common between ages 25 and 55, although children and elderly persons can be affected.^11,26,27

Most research suggests that SSc is not directly inherited, although (as in the case of other autoimmune diseases) genetic factors can predispose people with additional external triggers.^21,28,29 A positive family history is a strong risk factor for SSc. In a large cohort-based study, patients with SSc invariably had at least one first-degree relative who was also affected.²⁹

Although the exact cause of SSc remains unknown, substantial research suggests that environmental factors, especially exposure to certain metals and chemical compounds (eg, solvents, pesticides, silica), play a major role in its development.^1,16,30 Farmers, factory and construction workers, coal miners, and others may be exposed to these chemicals, so it is important to ask about potentially hazardous occupations.

Physical Examination
Patients in whom any form of scleroderma is suspected should undergo a thorough physical examination. It is here that preliminary signs of internal organ involvement and fibrosis must be detected.

Clinicians should observe the skin for signs of inflammation. Any changes in the skin’s appearance or texture, including tight, hardened, and sclerotic changes of the hands, face, mouth, trunk, and/or digits, should also be noted. The examiner may notice furrowing around the mouth, telangiectasias, and hyperpigmentation.^6,10 Signs of vascular damage may be identified, including digital discoloration and ulcers associated with Raynaud’s phenomenon.²²

Examination of the skin (with palpation) will reveal information about the disease’s activity, involvement, and severity.³¹ Active cutaneous disease indicated by inflammatory signs (eg, edema) correlates with active internal disease, such as renal crisis or fibrosing alveolitis.10 Inactive skin disease manifests as sclerotic skin resembling a scar.³¹

If skin sclerosis is sufficient for suspicion of SSc, additional steps are required. In the ear-nose-throat examination, for example, the mucosal membranes should be observed for signs of Sjögren’s syndrome, since it is associated with SSc.³² The mouth should also be examined for telangiectasias and microglossia.

A musculoskeletal exam may also prove helpful. Range of motion and joint mobility should be assessed, especially if sclerotic skin causes flexion contractures, producing shortened fingers or articular deformities.¹⁶

Diagnostic Work-up
If suspicion of SSc persists, the disease can be further assessed through laboratory values and imaging. No one test ensures a definitive diagnosis, but serologic testing for autoantibodies is helpful.^5,33

The provider may order an antinuclear antibody (ANA) test or rheumatoid factor testing to confirm connective tissue disease (CTD). However, it is important to remember that a positive ANA result is found in patients with other CTDs, including 30% of those with rheumatoid arthritis and 95% of those with systemic lupus erythematosus.³³ Since anticentromere antibodies are present in 70% to 80% of patients, and antibodies against topoisomerase I DNA (anti-Scl-70) exist in about 40% of patients, confirmed presence of either has a specificity of 95% to 99% for the diagnosis of SSc.³⁴

Imaging and other tests help to assess the involvement of SSc and the extent of associated fibrosis in internal organs. X-ray of the hands can reveal intra-articular calcifications and osteopenia, as well as soft-tissue calcinosis.^11,17

Chest x-ray and CT can detect interstitial lung disease.³³ Imaging will also help differentiate active alveolitis (ground-glass appearance) from pulmonary fibrosis (honeycombing).⁶ Clinicians may order pulmonary function testing to confirm restrictive lung disease. Doppler echocardiography will show cardiac and pulmonary vascular involvement and can confirm the presence of pulmonary hypertension. ECG, Holter monitoring, and ultrasonography can be used to further assess suspected myocardial disease and arrhythmias.³⁵

GI changes, including esophageal stricture and Barrett’s esophagus, can be investigated through esophageal manometry and endoscopy.^3,18 In addition to renal function testing, urinalysis and peripheral blood smear are necessary to confirm renal crisis, especially in patients with worsening hypertension or with new anemia not associated with blood loss.⁶

Classification
Diagnosis of SSc is made based on the patient’s clinical presentation, but the degree of organ involvement must also be determined by symptoms, history, physical examination, laboratory work-up, and imaging studies, as detailed above. The 1980 Preliminary Criteria for the Classification of Systemic Sclerosis³⁶ is 97% sensitive and 98% specific for SSc,^37,38 although additional criteria (eg, certain autoantibodies, nail-fold capillary changes) have been proposed to improve sensitivity for limited SSc.^9,38 (For the major and minor criteria from the 1980 document, see Table 2^6,10,36).

Accurate, early classification of SSc is critical. Patients are most likely to respond to therapeutic efforts in the disease’s early stages, and prognosis depends on the degree of disease severity and organ involvement.^37,38

Treatment
No treatment modality has yet been found to reverse the fibrotic damage of SSc, but several therapies can slow disease progression.³⁹ Because of the heterogeneous nature of the disease, management is individualized according to patient symptoms and organ involvement.⁴⁰ Treatment is directed at preventing vascular damage, immune cell activation, and fibrosis.^10,41 Table 3^2,12,41,42 shows treatment strategies to address all three disease processes.

In early SSc, vascular intervention and immunosuppressive treatment are most important because they can prevent later stages that involve fibrosis.² Vasodilators (calcium channel blockers, such as amlodipine and nifedipine; ACE inhibitors, including enalapril and captopril; and angiotensin receptor blockers, such as losartan) have been found effective, particularly for treatment of Raynaud’s phenomenon and to prevent further renal damage.^12,41 An abundance of recent evidence suggests that bosentan, an endothelium receptor antagonist, is helpful in treating pulmonary hypertension and preventing digital ulcers by regulating the inflammatory response.^{2,12,13,30,39,43}

Cyclophosphamide is used for patients with interstitial lung disease and any associated alveolitis.^5,41 In one randomized double-blind trial, methotrexate improved skin scores (ie, softened fibrosis), creatinine clearance, and overall well-being in 68% of patients who received it over a 24-week period.⁴²

In later stages of SSc, suppressing fibrosis is the goal. d-Penicillamine is considered a first-line agent, because it interferes with collagen cross-linking.⁴¹ No conclusive data exist to support its dosing and efficacy, although findings vary from no effect to 70% benefit in improving skin scores and decreasing five-year mortality rates.^2,6,41

Patient Education
Patient compliance will require education, as several months’ treatment may be required before results are evident. Supportive and symptomatic therapy will greatly improve quality of life as well.

Patients should be told that GI reflux and motility disorders can be controlled with proton pump inhibitors.⁴¹ They should also be advised to elevate the head when in bed and to eat small, frequent meals.

Arthralgias, arthritis, and deep tissue fibrosis that cause joint contractures and tendon friction rubs may be controlled by NSAIDs.41 The manifestations of Raynaud’s phenomenon can be minimized by avoiding exposure to cold temperatures and wearing warm clothes; smoking cessation is also advised.⁵

Colchicine may help alleviate inflammation, pain, and calcinosis. Physiotherapy can help prevent deformities, and an exercise routine is important to maintain joint mobility.^5,41 Lubrication with emollients is essential for dry, sclerotic skin.

In addition, psychologic guidance through counseling is important for the patient’s self-confidence and self-image. SSc can be disfiguring, with the face and hands affected in almost all cases.¹¹

Monitoring and Follow-Up
Emphasizing regular visits and routine screening procedures is crucial in the management of SSc. A team of specialists should be involved in treating the complex, diverse symptoms of SSc and in monitoring the disease to prevent further organ fibrosis and dysfunction.

Conclusion
Systemic sclerosis is a complex, multisystem disease. Because it is highly variable in expression and clinical presentation, diagnosis is difficult and often overlooked, even by the most attentive clinicians. Widespread involvement of SSc and potential fibrosis of organs beyond the skin (including the kidneys, heart, lungs, muscles, joints, and GI tract) contribute to SSc’s devastating morbidity and mortality.

Treatment is aimed at controlling the vasculopathy, autoimmunity, and fibrosis associated with the disease. Since there is no cure for SSc, close monitoring and management by a team of health care professionals are essential in slowing disease progression.