Cleveland Clinic Journal of Medicine

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.

Supplement Editor:
Leonard Calabrese, DO

Contents

Introduction: Progressive multifocal leukoencephalopathy in the biologic era
Leonard Calabrese, DO

History and current concepts in the pathogenesis of PML
Eugene O. Major, PhD

The clinical features of PML
Joseph R. Berger, MD

Pharmacovigilance and PML in the oncology setting
Charles L. Bennett, MD, PhD, MPP

Multiple sclerosis, natalizumab, and PML: Helping patients decide
Richard R. Rudick, MD

HIV-associated PML: Changing epidemiology and clinical approach
David M. Simpson, MD, FRCP, MRCPI

PML and rheumatology: The contribution of disease and drugs
Eamonn S. Molloy, MD, MS, MRCPI

Advances in the management of PML: Focus on natalizumab
Robert Fox, MD

A rational approach to PML for the clinician
Leonard Calabrese, DO

Supplement Editor:
Leonard Calabrese, DO

Contents

Introduction: Progressive multifocal leukoencephalopathy in the biologic era
Leonard Calabrese, DO

History and current concepts in the pathogenesis of PML
Eugene O. Major, PhD

The clinical features of PML
Joseph R. Berger, MD

Pharmacovigilance and PML in the oncology setting
Charles L. Bennett, MD, PhD, MPP

Multiple sclerosis, natalizumab, and PML: Helping patients decide
Richard R. Rudick, MD

HIV-associated PML: Changing epidemiology and clinical approach
David M. Simpson, MD, FRCP, MRCPI

PML and rheumatology: The contribution of disease and drugs
Eamonn S. Molloy, MD, MS, MRCPI

Advances in the management of PML: Focus on natalizumab
Robert Fox, MD

A rational approach to PML for the clinician
Leonard Calabrese, DO

Supplement Editor:
Leonard Calabrese, DO

Contents

Introduction: Progressive multifocal leukoencephalopathy in the biologic era
Leonard Calabrese, DO

History and current concepts in the pathogenesis of PML
Eugene O. Major, PhD

The clinical features of PML
Joseph R. Berger, MD

Pharmacovigilance and PML in the oncology setting
Charles L. Bennett, MD, PhD, MPP

Multiple sclerosis, natalizumab, and PML: Helping patients decide
Richard R. Rudick, MD

HIV-associated PML: Changing epidemiology and clinical approach
David M. Simpson, MD, FRCP, MRCPI

PML and rheumatology: The contribution of disease and drugs
Eamonn S. Molloy, MD, MS, MRCPI

Advances in the management of PML: Focus on natalizumab
Robert Fox, MD

A rational approach to PML for the clinician
Leonard Calabrese, DO

The neuropathology of progressive multifocal leukoencephalopathy (PML) was first reported in 1958 following examination of brain tissue from two cases of chronic lymphocytic leukemia and one case of Hodgkin lymphoma.¹ The classic triad of symptoms of PML—cognitive impairment, visual deficits, and motor dysfunction—had been observed previously but had not been formally described.²

Until PML was discovered in patients with autoimmune diseases treated with biologic therapies that do not directly suppress immunity, PML had been considered a very rare, virus-induced demyelinating disease of the white matter that occurred in immune-compromised patients. The incidence of PML rose sharply in the mid-1980s with the pandemic of human immunodeficiency virus (HIV)-1 infection and continues as an acquired immunodeficiency syndrome–defining illness at a rate of approximately 1% to 3% of HIV-1 seropositive individuals; more recently, it has been seen in approximately 1 in 850 natalizumab-treated individuals who have multiple sclerosis (MS). The incidence of PML in natalizumab-treated MS patients increases with dosing; among those who receive 24 or more doses, the incidence is 1 in 400.

The cause of PML was unknown until 1971, when viral particles were observed by electron microscopy in PML brain lesions and subsequently isolated at the University of Wisconsin, Madison, in cultures of human fetal brain tissue.³ The designation of JC virus (JCV) was derived from the initials of the patient whose brain tissue was used for culture and isolation. Variants in the noncoding region of the genome were then serially identified as Mad 1, Mad 2, and so on, representing the geographic location, Madison, Wisconsin, where the virus was identified.

The JCV, a polyomavirus, is a nonenveloped DNA virus with icosahedral structure containing double-stranded DNA genomes. The circular genome of JCV contains early and late transcription units, the latter of which encodes three virion structural proteins—VPl, VP2, and VP3. Humans generate antibodies directed against the amino terminal end of VP1 and perhaps VP2 and VP3.

JC VIRUS PATHOGENESIS

JCV pathogenesis is studied in cell cultures derived from human fetal brain tissue. In vitro, JCV robustly infects astrocytes, making it important to identify the culture’s cellular phenotypes. A cell line was developed that allows multiplication of JCV and, more recently, human multipotential progenitor cells were isolated and are being grown from the human developing brain at various gestational stages. The lineage pathways of these cells can be differentiated into astrocytes, oligodendrocytes, and neurons. Initiating infection in progenitor cells with JC virions made it possible to determine which cells were susceptible to infection. JCV susceptibility is evident in progenitor-derived astrocytes and glial cells, which reflects the pathologic process in PML brain tissue. Neuronal cells, by contrast, are not susceptible to infection.⁴

JC VIRUS CHARACTERISTICS: GLOBAL DISTRIBUTION, TRIAD OF SYMPTOMS

Subcortical multifocal white matter lesions are the classic feature of PML on neuroimaging. Seroepidemiology of JCV has revealed ubiquitous distribution, with 50% to 60% of adults aged 20 to 50 years demonstrating antibody to JCV.⁵ The percentage of the population with antibody increases with age, but may vary among geographic regions. Prevalence is lower among remote populations.

Although the initial site of JCV infection is not well characterized, we know that the primary infection is not in the brain. The JCV has a selective tropism for replication in glial cells in the human brain, but the absence of an animal model for PML has hindered our understanding of the JCV migration to the brain and the initiation and development of central nervous system infection.

Although humans carry JCV-specific antibodies, the clinical significance of these antibodies is unknown. Antibody levels rise during active infection, at times to very high titers, but offer no protection. T-cell–mediated immune responses directed to structural and nonstructural proteins are important in controlling infection.

A high index of suspicion for PML is warranted in individuals who demonstrate the classic triad of symptoms (cognitive impairment, visual deficits, and motor dysfunction) and in whom magnetic resonance imaging shows evidence of demyelinated plaque lesions; however, evidence of the presence of JCV DNA in pathologic tissue is necessary to confirm a diagnosis of PML.

The development of an in situ DNA hybridization assay using a biotinylated probe has facilitated identification of JCV DNA in the infected nuclei of the pathologic tissue. The presence of JCV DNA in cerebrospinal fluid (CSF) samples can be detected using a quantitative polymerase chain reaction assay, targeting the viral genome in the amino terminal end of the viral T protein.⁶ This T protein coding region was targeted because it does not crossreact, even with other human polyomaviruses, and it is intolerant of mutations. This assay is certified by the Clinical Laboratory Improvement Amendments, licensed by the National Institutes of Health; it is the most sensitive (to levels of 10 copies/mL sample) assay available.

JC VIRUS SUSCEPTIBILITY FACTORS

Despite the high prevalence of JCV infection, PML is rare, suggesting important barriers to its development. Although the receptor for JCV has been identified as alpha 2,6-linked sialic acid, the host range for productive infection is controlled by factors within the cell nucleus that bind to the viral promoter; this process initiates transcription of mRNA for the coordinated synthesis of viral proteins. Only certain cells have the necessary DNA binding proteins in high enough concentrations to allow lytic infection to take place, spreading by cell-to-cell contact. These cells include oligodendrocytes, the primary target for JCV, whose destruction leads to PML; astrocytes; and the CD34+ and CD19+ cells of the immune system. JCV can also be found in urine, at times in very high concentrations. It is present in the uroepithelial cells and multiplies without apparent pathologic consequences. Virus isolated from the urine has not been grown in cell culture systems in the laboratory setting.

Bone marrow CD34+ hematopoietic progenitor cells represent a potential pathway of JCV pathogenesis: in six people with PML, latent JCV DNA was demonstrated in pathologic tissue from lymph, spleen, or bone marrow biopsies taken months to years before the patient developed neurologic disease.⁷

Upon immunosuppression, reactivation of the virus occurs, with evidence of the virus found in CD10 and CD19/20 lymphocytes in the peripheral blood of some individuals. Blood-to-brain viral dissemination results in infection of oligodendrocytes, astrocytes, and progenitor cells.

Susceptibility to PML is associated with promoter/enhancer nucleotide sequences. The tandem repeat nucleotide structure has been found in the peripheral blood leukocytes and the CSF of patients with PML. Although the arrangement of nucleotide sequences in the viral regulatory region is highly variable among patients with PML, there are no alterations in the sequence within the origin of DNA replication. These highly conserved sequences contain regions for DNA-binding proteins that drive transcription, initiating the life cycle of the virus.

The nuclear transcription factor NF-1 is a cell-specific regulator of JCV promoter/enhancer activity. In humans, the NF-1 family of DNA-binding proteins is encoded by four discrete genes, one of which is NF-1 class X (NF-1X), a critical transcription factor that affects JCV cells. The human brain makes NF-1X in concentrations greater than the concentrations of other NF-1 transcription family members of DNA-binding proteins. NF-1X is located adjacent to and interacts with another family of transcription factors, activator protein-1, which has also been associated with JC viral activity.

Spi-B expression a factor in natalizumab-treated patients

Another transcription factor, Spi-B, binds to sequences present in the JCV promoter/enhancer. Spi-B is a regulator of JCV gene expression in susceptible cells and appears to play an important role in JCV activity. The expression of Spi-B is upregulated in patients with MS who are treated with the monoclonal antibody natalizumab, a population of patients in whom PML has been recently described.^11–15

Reprinted, with permission, from The New England Journal of Medicine (Major EO. Reemergence of PML in natalizumab-treated patients: new cases, same concerns. N Engl J Med 2009; 361:1041–1043). © 2009 Massachusetts Medical Society. All rights reserved.

Natalizumab binds to the alpha-4 integrin molecule, preventing hematopoietic stem cells and developing B cells from attaching to a vascular-cell adhesion molecule and forcing them to migrate from the bone marrow (Figure 2).¹⁶ An ideal environment is created for JCV when the natalizumab-induced increase in CD34+ cells in the circulation is combined with upregulation of gene cells involved in B-cell maturation. JCV can reside in the bone marrow in a latent state and can use B cells and their DNA-binding proteins to initiate viral multiplication, eventually gaining entry into the brain to cause PML.

In addition to natalizumab, PML has been described in patients treated with efalizumab, another biologic agent that binds alpha-4 integrin molecules on the surface of T and B cells, preventing their entry into the brain, gut, and skin, and forcing migration of bone marrow CD34+ into peripheral circulation for long periods.^9,17,18 Rituximab, another monoclonal antibody, binds the CD20 surface molecule on B cells, causing their depletion from the peripheral circulation through complement-mediated cytolysis.⁷

Risk factors for development of PML

Measurable risk factors for PML include:

• Rising antibody titers
• Evidence of viremia, especially persistent viremia associated with repeat sequences in the regulatory region of the viral genome
• Ineffective T-cell (CD4 and CD8) responses
• Molecular host factors (ie, Spi-B expression in B cells) that support JCV infection in potentially susceptible cells.

The presence of more than one of these risk factors is necessary for development of PML.

VIRAL LATENCY IN B LYMPHOCYTES IN BONE MARROW

A strong link between JCV infection in cells of the immune system and those of the nervous system points to the importance of the tissue origin of JCV latency. Bone marrow harbors CD34+ cells that migrate into the peripheral circulation and undergo differentiation to pre-B and mature B cells, augmenting JCV growth. The emergence of PML in patients treated with natalizumab, rituximab, efalizumab, and other immune-altering drugs underscores this observation.

As noted, the incidence of PML in natalizumab-treated patients with MS and Crohn disease rises as the number of doses increases. Analysis of blood samples collected from patients treated with natalizumab at baseline and again during treatment at months 1 to 12 and beyond 24 months demonstrates that the frequency of CD34+ cells in the peripheral circulation increases with the duration of therapy, adding credence to the theory that CD34+ cells act as a reservoir for latent virus. A higher frequency of CD34+ cells is associated with viremia.

The role of Spi-B in JC virus latency

Understanding the role of Spi-B during JCV latency and reactivation is increasingly important as the number of patients treated with immunomodulatory agents that can develop PML continues to rise. Spi-B is highly represented in the B cell and CD34+ cell fractions. Spi-B expression in B cells correlates with reactivation of JCV in immune cells in natalizumab-treated patients. In a sample of four patients with MS treated with natalizumab who developed PML, T-cell responses have been ineffective (absent or aberrant). Two patients had no detectable T-cell response to JCV; the other two demonstrated response, but their CD4 T-cell responses were dominated by interleukin-10–producing cells.

Longitudinal examination of CSF samples from 13 MS patients who were treated with natalizumab and subsequently developed PML revealed persistence of viral load even though all patients experienced immune reconstitution inflammatory syndrome and most had high levels of anti-JCV antibodies.¹⁹

Despite the prevalence of JCV in the population, the development of PML is rare. Levels of JCV antibody rise during the course of active JCV infection, but they do not protect against infection. T-cell responses directed to structural and nonstructural proteins play a role in controlling infection. Latency of JCV is associated with specific cells of the immune system, and its reactivation can follow alteration of normal immune cell function—either immunosuppression or immunomodulation. Risk factors for the development of PML include rising antibody titers and ineffective T-cell (CD4 and CD8) responses.

DISCUSSION

Dr. Berger: Does natalizumab upregulate Spi-B in glial cells?

Dr. Major: We never tested this directly. From human brain cultures, we know that Spi-B is made in glial cells, not in neurons. We are considering the idea that wherever JCV binds, it takes advantage of certain types of DNA-binding proteins in the molecular regulation. If the binding takes place in an immune system cell, for example, Spi-B plays an important role.

Dr. Berger: Koralnik et al demonstrated JCV excretion in urine in MS patients after 12 months of treatment with natalizumab, and at 18 months, viremia in 60% of the patients.²⁰ Yet, repeated studies of patients taking natalizumab have failed to demonstrate viremia or conversion of virus in the archetype. How do these findings correlate with your thoughts on the action of natalizumab in the pathogenesis of PML?

Dr. Major: We certainly know that natalizumab forces migration of hematopoietic stem cells and pre-B cells out of the marrow, but our findings have differed somewhat from those of Koralnik’s laboratory. For example, in the several hundred nucleotide sequences we have looked at in PML brain tissue, we have found the Mad 1 genotype once. We consider Mad 1 to be a potential laboratory contamination, so if we find Mad 1 we resequence the sample. We never clone because cloning can introduce alterations; we sequence directly from the clinical tissue. We can identify Mad 1 because our assay is very sensitive. In normal individuals, CD34+ cells compose approximately 0.01% of the peripheral circulation; in individuals treated with natalizumab, however, their composition is 0.1% to 0.3%. So if there is a potential for latent infection, we have an opportunity to find it in those cells. Its presence does not necessarily mean that the individual is going to develop PML, however; there are other controlling factors.

Dr. Rudick: Have you found the virus in B cells in healthy people?

Dr. Major: Yes we have, in about one-third. It is higher than what we would expect to see in the normal population.

Dr. Rudick: How can that finding be turned into something that’s clinically useful?

Dr. Major: If you’re trying to identify persons who are more susceptible to PML given underlying risk factors—treatment with natalizumab or rituximab, presence of HIV infection, or some other immune-altering condition—looking at one parameter isn’t going to help. Based on the available data, rising antibody titers signals an active infection, and viremia of any kind means probable latent infection. Because this is a small event in very few cells, you will not have the numbers of cells needed to identify susceptibility in a normal population. For now, we monitor patients at risk and, if we find viremia, we assess the cell population to determine whether a molecular factor like Spi-B is upregulated. We hope to develop an assay in which we can obtain one test tube of blood and report T-cell responses, molecular factors, antibody titer, and presence or absence of viremia. Such an assay would provide the data necessary to make a clinical decision.

The neuropathology of progressive multifocal leukoencephalopathy (PML) was first reported in 1958 following examination of brain tissue from two cases of chronic lymphocytic leukemia and one case of Hodgkin lymphoma.¹ The classic triad of symptoms of PML—cognitive impairment, visual deficits, and motor dysfunction—had been observed previously but had not been formally described.²

Until PML was discovered in patients with autoimmune diseases treated with biologic therapies that do not directly suppress immunity, PML had been considered a very rare, virus-induced demyelinating disease of the white matter that occurred in immune-compromised patients. The incidence of PML rose sharply in the mid-1980s with the pandemic of human immunodeficiency virus (HIV)-1 infection and continues as an acquired immunodeficiency syndrome–defining illness at a rate of approximately 1% to 3% of HIV-1 seropositive individuals; more recently, it has been seen in approximately 1 in 850 natalizumab-treated individuals who have multiple sclerosis (MS). The incidence of PML in natalizumab-treated MS patients increases with dosing; among those who receive 24 or more doses, the incidence is 1 in 400.

The cause of PML was unknown until 1971, when viral particles were observed by electron microscopy in PML brain lesions and subsequently isolated at the University of Wisconsin, Madison, in cultures of human fetal brain tissue.³ The designation of JC virus (JCV) was derived from the initials of the patient whose brain tissue was used for culture and isolation. Variants in the noncoding region of the genome were then serially identified as Mad 1, Mad 2, and so on, representing the geographic location, Madison, Wisconsin, where the virus was identified.

The JCV, a polyomavirus, is a nonenveloped DNA virus with icosahedral structure containing double-stranded DNA genomes. The circular genome of JCV contains early and late transcription units, the latter of which encodes three virion structural proteins—VPl, VP2, and VP3. Humans generate antibodies directed against the amino terminal end of VP1 and perhaps VP2 and VP3.

JC VIRUS PATHOGENESIS

JCV pathogenesis is studied in cell cultures derived from human fetal brain tissue. In vitro, JCV robustly infects astrocytes, making it important to identify the culture’s cellular phenotypes. A cell line was developed that allows multiplication of JCV and, more recently, human multipotential progenitor cells were isolated and are being grown from the human developing brain at various gestational stages. The lineage pathways of these cells can be differentiated into astrocytes, oligodendrocytes, and neurons. Initiating infection in progenitor cells with JC virions made it possible to determine which cells were susceptible to infection. JCV susceptibility is evident in progenitor-derived astrocytes and glial cells, which reflects the pathologic process in PML brain tissue. Neuronal cells, by contrast, are not susceptible to infection.⁴

JC VIRUS CHARACTERISTICS: GLOBAL DISTRIBUTION, TRIAD OF SYMPTOMS

Subcortical multifocal white matter lesions are the classic feature of PML on neuroimaging. Seroepidemiology of JCV has revealed ubiquitous distribution, with 50% to 60% of adults aged 20 to 50 years demonstrating antibody to JCV.⁵ The percentage of the population with antibody increases with age, but may vary among geographic regions. Prevalence is lower among remote populations.

Although the initial site of JCV infection is not well characterized, we know that the primary infection is not in the brain. The JCV has a selective tropism for replication in glial cells in the human brain, but the absence of an animal model for PML has hindered our understanding of the JCV migration to the brain and the initiation and development of central nervous system infection.

Although humans carry JCV-specific antibodies, the clinical significance of these antibodies is unknown. Antibody levels rise during active infection, at times to very high titers, but offer no protection. T-cell–mediated immune responses directed to structural and nonstructural proteins are important in controlling infection.

A high index of suspicion for PML is warranted in individuals who demonstrate the classic triad of symptoms (cognitive impairment, visual deficits, and motor dysfunction) and in whom magnetic resonance imaging shows evidence of demyelinated plaque lesions; however, evidence of the presence of JCV DNA in pathologic tissue is necessary to confirm a diagnosis of PML.

The development of an in situ DNA hybridization assay using a biotinylated probe has facilitated identification of JCV DNA in the infected nuclei of the pathologic tissue. The presence of JCV DNA in cerebrospinal fluid (CSF) samples can be detected using a quantitative polymerase chain reaction assay, targeting the viral genome in the amino terminal end of the viral T protein.⁶ This T protein coding region was targeted because it does not crossreact, even with other human polyomaviruses, and it is intolerant of mutations. This assay is certified by the Clinical Laboratory Improvement Amendments, licensed by the National Institutes of Health; it is the most sensitive (to levels of 10 copies/mL sample) assay available.

JC VIRUS SUSCEPTIBILITY FACTORS

Despite the high prevalence of JCV infection, PML is rare, suggesting important barriers to its development. Although the receptor for JCV has been identified as alpha 2,6-linked sialic acid, the host range for productive infection is controlled by factors within the cell nucleus that bind to the viral promoter; this process initiates transcription of mRNA for the coordinated synthesis of viral proteins. Only certain cells have the necessary DNA binding proteins in high enough concentrations to allow lytic infection to take place, spreading by cell-to-cell contact. These cells include oligodendrocytes, the primary target for JCV, whose destruction leads to PML; astrocytes; and the CD34+ and CD19+ cells of the immune system. JCV can also be found in urine, at times in very high concentrations. It is present in the uroepithelial cells and multiplies without apparent pathologic consequences. Virus isolated from the urine has not been grown in cell culture systems in the laboratory setting.

Bone marrow CD34+ hematopoietic progenitor cells represent a potential pathway of JCV pathogenesis: in six people with PML, latent JCV DNA was demonstrated in pathologic tissue from lymph, spleen, or bone marrow biopsies taken months to years before the patient developed neurologic disease.⁷

Upon immunosuppression, reactivation of the virus occurs, with evidence of the virus found in CD10 and CD19/20 lymphocytes in the peripheral blood of some individuals. Blood-to-brain viral dissemination results in infection of oligodendrocytes, astrocytes, and progenitor cells.

Susceptibility to PML is associated with promoter/enhancer nucleotide sequences. The tandem repeat nucleotide structure has been found in the peripheral blood leukocytes and the CSF of patients with PML. Although the arrangement of nucleotide sequences in the viral regulatory region is highly variable among patients with PML, there are no alterations in the sequence within the origin of DNA replication. These highly conserved sequences contain regions for DNA-binding proteins that drive transcription, initiating the life cycle of the virus.

The nuclear transcription factor NF-1 is a cell-specific regulator of JCV promoter/enhancer activity. In humans, the NF-1 family of DNA-binding proteins is encoded by four discrete genes, one of which is NF-1 class X (NF-1X), a critical transcription factor that affects JCV cells. The human brain makes NF-1X in concentrations greater than the concentrations of other NF-1 transcription family members of DNA-binding proteins. NF-1X is located adjacent to and interacts with another family of transcription factors, activator protein-1, which has also been associated with JC viral activity.

Spi-B expression a factor in natalizumab-treated patients

Another transcription factor, Spi-B, binds to sequences present in the JCV promoter/enhancer. Spi-B is a regulator of JCV gene expression in susceptible cells and appears to play an important role in JCV activity. The expression of Spi-B is upregulated in patients with MS who are treated with the monoclonal antibody natalizumab, a population of patients in whom PML has been recently described.^11–15

Reprinted, with permission, from The New England Journal of Medicine (Major EO. Reemergence of PML in natalizumab-treated patients: new cases, same concerns. N Engl J Med 2009; 361:1041–1043). © 2009 Massachusetts Medical Society. All rights reserved.

Natalizumab binds to the alpha-4 integrin molecule, preventing hematopoietic stem cells and developing B cells from attaching to a vascular-cell adhesion molecule and forcing them to migrate from the bone marrow (Figure 2).¹⁶ An ideal environment is created for JCV when the natalizumab-induced increase in CD34+ cells in the circulation is combined with upregulation of gene cells involved in B-cell maturation. JCV can reside in the bone marrow in a latent state and can use B cells and their DNA-binding proteins to initiate viral multiplication, eventually gaining entry into the brain to cause PML.

In addition to natalizumab, PML has been described in patients treated with efalizumab, another biologic agent that binds alpha-4 integrin molecules on the surface of T and B cells, preventing their entry into the brain, gut, and skin, and forcing migration of bone marrow CD34+ into peripheral circulation for long periods.^9,17,18 Rituximab, another monoclonal antibody, binds the CD20 surface molecule on B cells, causing their depletion from the peripheral circulation through complement-mediated cytolysis.⁷

Risk factors for development of PML

Measurable risk factors for PML include:

• Rising antibody titers
• Evidence of viremia, especially persistent viremia associated with repeat sequences in the regulatory region of the viral genome
• Ineffective T-cell (CD4 and CD8) responses
• Molecular host factors (ie, Spi-B expression in B cells) that support JCV infection in potentially susceptible cells.

The presence of more than one of these risk factors is necessary for development of PML.

VIRAL LATENCY IN B LYMPHOCYTES IN BONE MARROW

A strong link between JCV infection in cells of the immune system and those of the nervous system points to the importance of the tissue origin of JCV latency. Bone marrow harbors CD34+ cells that migrate into the peripheral circulation and undergo differentiation to pre-B and mature B cells, augmenting JCV growth. The emergence of PML in patients treated with natalizumab, rituximab, efalizumab, and other immune-altering drugs underscores this observation.

As noted, the incidence of PML in natalizumab-treated patients with MS and Crohn disease rises as the number of doses increases. Analysis of blood samples collected from patients treated with natalizumab at baseline and again during treatment at months 1 to 12 and beyond 24 months demonstrates that the frequency of CD34+ cells in the peripheral circulation increases with the duration of therapy, adding credence to the theory that CD34+ cells act as a reservoir for latent virus. A higher frequency of CD34+ cells is associated with viremia.

The role of Spi-B in JC virus latency

Understanding the role of Spi-B during JCV latency and reactivation is increasingly important as the number of patients treated with immunomodulatory agents that can develop PML continues to rise. Spi-B is highly represented in the B cell and CD34+ cell fractions. Spi-B expression in B cells correlates with reactivation of JCV in immune cells in natalizumab-treated patients. In a sample of four patients with MS treated with natalizumab who developed PML, T-cell responses have been ineffective (absent or aberrant). Two patients had no detectable T-cell response to JCV; the other two demonstrated response, but their CD4 T-cell responses were dominated by interleukin-10–producing cells.

Longitudinal examination of CSF samples from 13 MS patients who were treated with natalizumab and subsequently developed PML revealed persistence of viral load even though all patients experienced immune reconstitution inflammatory syndrome and most had high levels of anti-JCV antibodies.¹⁹

Despite the prevalence of JCV in the population, the development of PML is rare. Levels of JCV antibody rise during the course of active JCV infection, but they do not protect against infection. T-cell responses directed to structural and nonstructural proteins play a role in controlling infection. Latency of JCV is associated with specific cells of the immune system, and its reactivation can follow alteration of normal immune cell function—either immunosuppression or immunomodulation. Risk factors for the development of PML include rising antibody titers and ineffective T-cell (CD4 and CD8) responses.

DISCUSSION

Dr. Berger: Does natalizumab upregulate Spi-B in glial cells?

Dr. Major: We never tested this directly. From human brain cultures, we know that Spi-B is made in glial cells, not in neurons. We are considering the idea that wherever JCV binds, it takes advantage of certain types of DNA-binding proteins in the molecular regulation. If the binding takes place in an immune system cell, for example, Spi-B plays an important role.

Dr. Berger: Koralnik et al demonstrated JCV excretion in urine in MS patients after 12 months of treatment with natalizumab, and at 18 months, viremia in 60% of the patients.²⁰ Yet, repeated studies of patients taking natalizumab have failed to demonstrate viremia or conversion of virus in the archetype. How do these findings correlate with your thoughts on the action of natalizumab in the pathogenesis of PML?

Dr. Major: We certainly know that natalizumab forces migration of hematopoietic stem cells and pre-B cells out of the marrow, but our findings have differed somewhat from those of Koralnik’s laboratory. For example, in the several hundred nucleotide sequences we have looked at in PML brain tissue, we have found the Mad 1 genotype once. We consider Mad 1 to be a potential laboratory contamination, so if we find Mad 1 we resequence the sample. We never clone because cloning can introduce alterations; we sequence directly from the clinical tissue. We can identify Mad 1 because our assay is very sensitive. In normal individuals, CD34+ cells compose approximately 0.01% of the peripheral circulation; in individuals treated with natalizumab, however, their composition is 0.1% to 0.3%. So if there is a potential for latent infection, we have an opportunity to find it in those cells. Its presence does not necessarily mean that the individual is going to develop PML, however; there are other controlling factors.

Dr. Rudick: Have you found the virus in B cells in healthy people?

Dr. Major: Yes we have, in about one-third. It is higher than what we would expect to see in the normal population.

Dr. Rudick: How can that finding be turned into something that’s clinically useful?

Dr. Major: If you’re trying to identify persons who are more susceptible to PML given underlying risk factors—treatment with natalizumab or rituximab, presence of HIV infection, or some other immune-altering condition—looking at one parameter isn’t going to help. Based on the available data, rising antibody titers signals an active infection, and viremia of any kind means probable latent infection. Because this is a small event in very few cells, you will not have the numbers of cells needed to identify susceptibility in a normal population. For now, we monitor patients at risk and, if we find viremia, we assess the cell population to determine whether a molecular factor like Spi-B is upregulated. We hope to develop an assay in which we can obtain one test tube of blood and report T-cell responses, molecular factors, antibody titer, and presence or absence of viremia. Such an assay would provide the data necessary to make a clinical decision.

The neuropathology of progressive multifocal leukoencephalopathy (PML) was first reported in 1958 following examination of brain tissue from two cases of chronic lymphocytic leukemia and one case of Hodgkin lymphoma.¹ The classic triad of symptoms of PML—cognitive impairment, visual deficits, and motor dysfunction—had been observed previously but had not been formally described.²

Until PML was discovered in patients with autoimmune diseases treated with biologic therapies that do not directly suppress immunity, PML had been considered a very rare, virus-induced demyelinating disease of the white matter that occurred in immune-compromised patients. The incidence of PML rose sharply in the mid-1980s with the pandemic of human immunodeficiency virus (HIV)-1 infection and continues as an acquired immunodeficiency syndrome–defining illness at a rate of approximately 1% to 3% of HIV-1 seropositive individuals; more recently, it has been seen in approximately 1 in 850 natalizumab-treated individuals who have multiple sclerosis (MS). The incidence of PML in natalizumab-treated MS patients increases with dosing; among those who receive 24 or more doses, the incidence is 1 in 400.

The cause of PML was unknown until 1971, when viral particles were observed by electron microscopy in PML brain lesions and subsequently isolated at the University of Wisconsin, Madison, in cultures of human fetal brain tissue.³ The designation of JC virus (JCV) was derived from the initials of the patient whose brain tissue was used for culture and isolation. Variants in the noncoding region of the genome were then serially identified as Mad 1, Mad 2, and so on, representing the geographic location, Madison, Wisconsin, where the virus was identified.

The JCV, a polyomavirus, is a nonenveloped DNA virus with icosahedral structure containing double-stranded DNA genomes. The circular genome of JCV contains early and late transcription units, the latter of which encodes three virion structural proteins—VPl, VP2, and VP3. Humans generate antibodies directed against the amino terminal end of VP1 and perhaps VP2 and VP3.

JC VIRUS PATHOGENESIS

JCV pathogenesis is studied in cell cultures derived from human fetal brain tissue. In vitro, JCV robustly infects astrocytes, making it important to identify the culture’s cellular phenotypes. A cell line was developed that allows multiplication of JCV and, more recently, human multipotential progenitor cells were isolated and are being grown from the human developing brain at various gestational stages. The lineage pathways of these cells can be differentiated into astrocytes, oligodendrocytes, and neurons. Initiating infection in progenitor cells with JC virions made it possible to determine which cells were susceptible to infection. JCV susceptibility is evident in progenitor-derived astrocytes and glial cells, which reflects the pathologic process in PML brain tissue. Neuronal cells, by contrast, are not susceptible to infection.⁴

JC VIRUS CHARACTERISTICS: GLOBAL DISTRIBUTION, TRIAD OF SYMPTOMS

Subcortical multifocal white matter lesions are the classic feature of PML on neuroimaging. Seroepidemiology of JCV has revealed ubiquitous distribution, with 50% to 60% of adults aged 20 to 50 years demonstrating antibody to JCV.⁵ The percentage of the population with antibody increases with age, but may vary among geographic regions. Prevalence is lower among remote populations.

Although the initial site of JCV infection is not well characterized, we know that the primary infection is not in the brain. The JCV has a selective tropism for replication in glial cells in the human brain, but the absence of an animal model for PML has hindered our understanding of the JCV migration to the brain and the initiation and development of central nervous system infection.

Although humans carry JCV-specific antibodies, the clinical significance of these antibodies is unknown. Antibody levels rise during active infection, at times to very high titers, but offer no protection. T-cell–mediated immune responses directed to structural and nonstructural proteins are important in controlling infection.

A high index of suspicion for PML is warranted in individuals who demonstrate the classic triad of symptoms (cognitive impairment, visual deficits, and motor dysfunction) and in whom magnetic resonance imaging shows evidence of demyelinated plaque lesions; however, evidence of the presence of JCV DNA in pathologic tissue is necessary to confirm a diagnosis of PML.

The development of an in situ DNA hybridization assay using a biotinylated probe has facilitated identification of JCV DNA in the infected nuclei of the pathologic tissue. The presence of JCV DNA in cerebrospinal fluid (CSF) samples can be detected using a quantitative polymerase chain reaction assay, targeting the viral genome in the amino terminal end of the viral T protein.⁶ This T protein coding region was targeted because it does not crossreact, even with other human polyomaviruses, and it is intolerant of mutations. This assay is certified by the Clinical Laboratory Improvement Amendments, licensed by the National Institutes of Health; it is the most sensitive (to levels of 10 copies/mL sample) assay available.

JC VIRUS SUSCEPTIBILITY FACTORS

Despite the high prevalence of JCV infection, PML is rare, suggesting important barriers to its development. Although the receptor for JCV has been identified as alpha 2,6-linked sialic acid, the host range for productive infection is controlled by factors within the cell nucleus that bind to the viral promoter; this process initiates transcription of mRNA for the coordinated synthesis of viral proteins. Only certain cells have the necessary DNA binding proteins in high enough concentrations to allow lytic infection to take place, spreading by cell-to-cell contact. These cells include oligodendrocytes, the primary target for JCV, whose destruction leads to PML; astrocytes; and the CD34+ and CD19+ cells of the immune system. JCV can also be found in urine, at times in very high concentrations. It is present in the uroepithelial cells and multiplies without apparent pathologic consequences. Virus isolated from the urine has not been grown in cell culture systems in the laboratory setting.

Bone marrow CD34+ hematopoietic progenitor cells represent a potential pathway of JCV pathogenesis: in six people with PML, latent JCV DNA was demonstrated in pathologic tissue from lymph, spleen, or bone marrow biopsies taken months to years before the patient developed neurologic disease.⁷

Upon immunosuppression, reactivation of the virus occurs, with evidence of the virus found in CD10 and CD19/20 lymphocytes in the peripheral blood of some individuals. Blood-to-brain viral dissemination results in infection of oligodendrocytes, astrocytes, and progenitor cells.

Susceptibility to PML is associated with promoter/enhancer nucleotide sequences. The tandem repeat nucleotide structure has been found in the peripheral blood leukocytes and the CSF of patients with PML. Although the arrangement of nucleotide sequences in the viral regulatory region is highly variable among patients with PML, there are no alterations in the sequence within the origin of DNA replication. These highly conserved sequences contain regions for DNA-binding proteins that drive transcription, initiating the life cycle of the virus.

The nuclear transcription factor NF-1 is a cell-specific regulator of JCV promoter/enhancer activity. In humans, the NF-1 family of DNA-binding proteins is encoded by four discrete genes, one of which is NF-1 class X (NF-1X), a critical transcription factor that affects JCV cells. The human brain makes NF-1X in concentrations greater than the concentrations of other NF-1 transcription family members of DNA-binding proteins. NF-1X is located adjacent to and interacts with another family of transcription factors, activator protein-1, which has also been associated with JC viral activity.

Spi-B expression a factor in natalizumab-treated patients

Another transcription factor, Spi-B, binds to sequences present in the JCV promoter/enhancer. Spi-B is a regulator of JCV gene expression in susceptible cells and appears to play an important role in JCV activity. The expression of Spi-B is upregulated in patients with MS who are treated with the monoclonal antibody natalizumab, a population of patients in whom PML has been recently described.^11–15

Reprinted, with permission, from The New England Journal of Medicine (Major EO. Reemergence of PML in natalizumab-treated patients: new cases, same concerns. N Engl J Med 2009; 361:1041–1043). © 2009 Massachusetts Medical Society. All rights reserved.

Natalizumab binds to the alpha-4 integrin molecule, preventing hematopoietic stem cells and developing B cells from attaching to a vascular-cell adhesion molecule and forcing them to migrate from the bone marrow (Figure 2).¹⁶ An ideal environment is created for JCV when the natalizumab-induced increase in CD34+ cells in the circulation is combined with upregulation of gene cells involved in B-cell maturation. JCV can reside in the bone marrow in a latent state and can use B cells and their DNA-binding proteins to initiate viral multiplication, eventually gaining entry into the brain to cause PML.

In addition to natalizumab, PML has been described in patients treated with efalizumab, another biologic agent that binds alpha-4 integrin molecules on the surface of T and B cells, preventing their entry into the brain, gut, and skin, and forcing migration of bone marrow CD34+ into peripheral circulation for long periods.^9,17,18 Rituximab, another monoclonal antibody, binds the CD20 surface molecule on B cells, causing their depletion from the peripheral circulation through complement-mediated cytolysis.⁷

Risk factors for development of PML

Measurable risk factors for PML include:

• Rising antibody titers
• Evidence of viremia, especially persistent viremia associated with repeat sequences in the regulatory region of the viral genome
• Ineffective T-cell (CD4 and CD8) responses
• Molecular host factors (ie, Spi-B expression in B cells) that support JCV infection in potentially susceptible cells.

The presence of more than one of these risk factors is necessary for development of PML.

VIRAL LATENCY IN B LYMPHOCYTES IN BONE MARROW

A strong link between JCV infection in cells of the immune system and those of the nervous system points to the importance of the tissue origin of JCV latency. Bone marrow harbors CD34+ cells that migrate into the peripheral circulation and undergo differentiation to pre-B and mature B cells, augmenting JCV growth. The emergence of PML in patients treated with natalizumab, rituximab, efalizumab, and other immune-altering drugs underscores this observation.

As noted, the incidence of PML in natalizumab-treated patients with MS and Crohn disease rises as the number of doses increases. Analysis of blood samples collected from patients treated with natalizumab at baseline and again during treatment at months 1 to 12 and beyond 24 months demonstrates that the frequency of CD34+ cells in the peripheral circulation increases with the duration of therapy, adding credence to the theory that CD34+ cells act as a reservoir for latent virus. A higher frequency of CD34+ cells is associated with viremia.

The role of Spi-B in JC virus latency

Understanding the role of Spi-B during JCV latency and reactivation is increasingly important as the number of patients treated with immunomodulatory agents that can develop PML continues to rise. Spi-B is highly represented in the B cell and CD34+ cell fractions. Spi-B expression in B cells correlates with reactivation of JCV in immune cells in natalizumab-treated patients. In a sample of four patients with MS treated with natalizumab who developed PML, T-cell responses have been ineffective (absent or aberrant). Two patients had no detectable T-cell response to JCV; the other two demonstrated response, but their CD4 T-cell responses were dominated by interleukin-10–producing cells.

Longitudinal examination of CSF samples from 13 MS patients who were treated with natalizumab and subsequently developed PML revealed persistence of viral load even though all patients experienced immune reconstitution inflammatory syndrome and most had high levels of anti-JCV antibodies.¹⁹

Despite the prevalence of JCV in the population, the development of PML is rare. Levels of JCV antibody rise during the course of active JCV infection, but they do not protect against infection. T-cell responses directed to structural and nonstructural proteins play a role in controlling infection. Latency of JCV is associated with specific cells of the immune system, and its reactivation can follow alteration of normal immune cell function—either immunosuppression or immunomodulation. Risk factors for the development of PML include rising antibody titers and ineffective T-cell (CD4 and CD8) responses.

DISCUSSION

Dr. Berger: Does natalizumab upregulate Spi-B in glial cells?

Dr. Major: We never tested this directly. From human brain cultures, we know that Spi-B is made in glial cells, not in neurons. We are considering the idea that wherever JCV binds, it takes advantage of certain types of DNA-binding proteins in the molecular regulation. If the binding takes place in an immune system cell, for example, Spi-B plays an important role.

Dr. Berger: Koralnik et al demonstrated JCV excretion in urine in MS patients after 12 months of treatment with natalizumab, and at 18 months, viremia in 60% of the patients.²⁰ Yet, repeated studies of patients taking natalizumab have failed to demonstrate viremia or conversion of virus in the archetype. How do these findings correlate with your thoughts on the action of natalizumab in the pathogenesis of PML?

Dr. Major: We certainly know that natalizumab forces migration of hematopoietic stem cells and pre-B cells out of the marrow, but our findings have differed somewhat from those of Koralnik’s laboratory. For example, in the several hundred nucleotide sequences we have looked at in PML brain tissue, we have found the Mad 1 genotype once. We consider Mad 1 to be a potential laboratory contamination, so if we find Mad 1 we resequence the sample. We never clone because cloning can introduce alterations; we sequence directly from the clinical tissue. We can identify Mad 1 because our assay is very sensitive. In normal individuals, CD34+ cells compose approximately 0.01% of the peripheral circulation; in individuals treated with natalizumab, however, their composition is 0.1% to 0.3%. So if there is a potential for latent infection, we have an opportunity to find it in those cells. Its presence does not necessarily mean that the individual is going to develop PML, however; there are other controlling factors.

Dr. Rudick: Have you found the virus in B cells in healthy people?

Dr. Major: Yes we have, in about one-third. It is higher than what we would expect to see in the normal population.

Dr. Rudick: How can that finding be turned into something that’s clinically useful?

Dr. Major: If you’re trying to identify persons who are more susceptible to PML given underlying risk factors—treatment with natalizumab or rituximab, presence of HIV infection, or some other immune-altering condition—looking at one parameter isn’t going to help. Based on the available data, rising antibody titers signals an active infection, and viremia of any kind means probable latent infection. Because this is a small event in very few cells, you will not have the numbers of cells needed to identify susceptibility in a normal population. For now, we monitor patients at risk and, if we find viremia, we assess the cell population to determine whether a molecular factor like Spi-B is upregulated. We hope to develop an assay in which we can obtain one test tube of blood and report T-cell responses, molecular factors, antibody titer, and presence or absence of viremia. Such an assay would provide the data necessary to make a clinical decision.