ORLANDO – The use of nebivolol as part of a multidrug regimen to treat hypertension was associated with a significantly lower cardiovascular event risk than was combination antihypertensive therapy featuring either metoprolol or atenolol in a large observational study, Brent M. Egan, MD, reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/MDedge News

His study was supported by Allergan. He reported receiving research grants from Boehringer Ingelheim and serving as a consultant to Medtronic.

bjancin@mdedge.com

SOURCE: Egan BM et al. ACC 18, Abstract 1324M-11.

ORLANDO – The use of nebivolol as part of a multidrug regimen to treat hypertension was associated with a significantly lower cardiovascular event risk than was combination antihypertensive therapy featuring either metoprolol or atenolol in a large observational study, Brent M. Egan, MD, reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/MDedge News

His study was supported by Allergan. He reported receiving research grants from Boehringer Ingelheim and serving as a consultant to Medtronic.

bjancin@mdedge.com

SOURCE: Egan BM et al. ACC 18, Abstract 1324M-11.

ORLANDO – The use of nebivolol as part of a multidrug regimen to treat hypertension was associated with a significantly lower cardiovascular event risk than was combination antihypertensive therapy featuring either metoprolol or atenolol in a large observational study, Brent M. Egan, MD, reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/MDedge News

His study was supported by Allergan. He reported receiving research grants from Boehringer Ingelheim and serving as a consultant to Medtronic.

bjancin@mdedge.com

SOURCE: Egan BM et al. ACC 18, Abstract 1324M-11.

LOS ANGELES – A noninvasive peripheral nerve stimulation device has been shown to reduce symptoms of hand tremor among people with essential tremor, offering a possible alternative to invasive treatments such as deep-brain stimulation.

The neuromodulation device is worn on the wrist and uses electrodes to stimulate the radial and median nerves at a frequency that interrupts tremor. It contains sensors that measure tremor and adjust stimulation accordingly.

In two small, randomized, controlled studies presented at the annual meeting of the at the American Academy of Neurology, investigator Rajesh Pahwa, MD, of the University of Kansas in Kansas City, said that treatment with the device significantly reduced tremor symptoms, compared with sham treatment.

On April 26, the device’s manufacturer, Cala Health, announced in a news release that the U.S. Food and Drug Administration had granted marketing clearance for the device, based on this evidence.

For the first study, conducted in-clinic, 77 patients were randomized to either treatment (n = 40) or sham stimulation (n = 37) of the tremor-dominant hand. Tremor was measured before and immediately after a single 40-minute session of stimulation, and patients were asked to perform tasks in accordance with the Essential Tremor Rating Assessment Scale or TETRAS, a severity measure.

Subjects in the intervention group had about a 65% improvement in their upper-limb TETRAS scores, compared with those receiving sham treatment (P less than .01) and in total TETRAS performance (P less than .05).

Subjects also were tested in-clinic with props simulating common daily tasks such as unlocking a door with a key, holding a cup of tea, picking up loose change, or dialing a phone. Patients in the treatment group self-reported greater ease with all of these tasks after treatment, compared with the sham-treated group. Differences for some tasks reached statistical significance.

SOURCE: Pahwa R et al. AAN 2018, Abstract P4.474.

LOS ANGELES – A noninvasive peripheral nerve stimulation device has been shown to reduce symptoms of hand tremor among people with essential tremor, offering a possible alternative to invasive treatments such as deep-brain stimulation.

The neuromodulation device is worn on the wrist and uses electrodes to stimulate the radial and median nerves at a frequency that interrupts tremor. It contains sensors that measure tremor and adjust stimulation accordingly.

In two small, randomized, controlled studies presented at the annual meeting of the at the American Academy of Neurology, investigator Rajesh Pahwa, MD, of the University of Kansas in Kansas City, said that treatment with the device significantly reduced tremor symptoms, compared with sham treatment.

On April 26, the device’s manufacturer, Cala Health, announced in a news release that the U.S. Food and Drug Administration had granted marketing clearance for the device, based on this evidence.

For the first study, conducted in-clinic, 77 patients were randomized to either treatment (n = 40) or sham stimulation (n = 37) of the tremor-dominant hand. Tremor was measured before and immediately after a single 40-minute session of stimulation, and patients were asked to perform tasks in accordance with the Essential Tremor Rating Assessment Scale or TETRAS, a severity measure.

Subjects in the intervention group had about a 65% improvement in their upper-limb TETRAS scores, compared with those receiving sham treatment (P less than .01) and in total TETRAS performance (P less than .05).

Subjects also were tested in-clinic with props simulating common daily tasks such as unlocking a door with a key, holding a cup of tea, picking up loose change, or dialing a phone. Patients in the treatment group self-reported greater ease with all of these tasks after treatment, compared with the sham-treated group. Differences for some tasks reached statistical significance.

SOURCE: Pahwa R et al. AAN 2018, Abstract P4.474.

LOS ANGELES – A noninvasive peripheral nerve stimulation device has been shown to reduce symptoms of hand tremor among people with essential tremor, offering a possible alternative to invasive treatments such as deep-brain stimulation.

The neuromodulation device is worn on the wrist and uses electrodes to stimulate the radial and median nerves at a frequency that interrupts tremor. It contains sensors that measure tremor and adjust stimulation accordingly.

In two small, randomized, controlled studies presented at the annual meeting of the at the American Academy of Neurology, investigator Rajesh Pahwa, MD, of the University of Kansas in Kansas City, said that treatment with the device significantly reduced tremor symptoms, compared with sham treatment.

On April 26, the device’s manufacturer, Cala Health, announced in a news release that the U.S. Food and Drug Administration had granted marketing clearance for the device, based on this evidence.

For the first study, conducted in-clinic, 77 patients were randomized to either treatment (n = 40) or sham stimulation (n = 37) of the tremor-dominant hand. Tremor was measured before and immediately after a single 40-minute session of stimulation, and patients were asked to perform tasks in accordance with the Essential Tremor Rating Assessment Scale or TETRAS, a severity measure.

Subjects in the intervention group had about a 65% improvement in their upper-limb TETRAS scores, compared with those receiving sham treatment (P less than .01) and in total TETRAS performance (P less than .05).

Subjects also were tested in-clinic with props simulating common daily tasks such as unlocking a door with a key, holding a cup of tea, picking up loose change, or dialing a phone. Patients in the treatment group self-reported greater ease with all of these tasks after treatment, compared with the sham-treated group. Differences for some tasks reached statistical significance.

SOURCE: Pahwa R et al. AAN 2018, Abstract P4.474.

This is the ninth in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

There is growing awareness of the importance of supporting patient self-management as part of a comprehensive approach to caring for people with chronic conditions. This is in part the recognition that 15 minutes with a provider every few months contributes less to patient outcomes than what the patient does every day. This month’s article describes some elements of AHRQ’s Self-Management Support Resource Library, a collection of materials and tools produced by AHRQ and others.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is director of the National Center for Excellence in Primary Care Research at AHRQ.

This is the ninth in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

There is growing awareness of the importance of supporting patient self-management as part of a comprehensive approach to caring for people with chronic conditions. This is in part the recognition that 15 minutes with a provider every few months contributes less to patient outcomes than what the patient does every day. This month’s article describes some elements of AHRQ’s Self-Management Support Resource Library, a collection of materials and tools produced by AHRQ and others.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is director of the National Center for Excellence in Primary Care Research at AHRQ.

This is the ninth in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

There is growing awareness of the importance of supporting patient self-management as part of a comprehensive approach to caring for people with chronic conditions. This is in part the recognition that 15 minutes with a provider every few months contributes less to patient outcomes than what the patient does every day. This month’s article describes some elements of AHRQ’s Self-Management Support Resource Library, a collection of materials and tools produced by AHRQ and others.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is director of the National Center for Excellence in Primary Care Research at AHRQ.

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

 

 

Laboratory testing for phenocopies of HCM

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

 

 

Ambulatory electrocardiographic monitoring in all patients at diagnosis

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

 

 

Medical management: Beta-blockers, then calcium channel blockers

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

 

 

Septal reduction therapy

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

 

 

Laboratory testing for phenocopies of HCM

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

 

 

Ambulatory electrocardiographic monitoring in all patients at diagnosis

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

 

 

Medical management: Beta-blockers, then calcium channel blockers

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

 

 

Septal reduction therapy

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

 

 

Laboratory testing for phenocopies of HCM

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

 

 

Ambulatory electrocardiographic monitoring in all patients at diagnosis

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

 

 

Medical management: Beta-blockers, then calcium channel blockers

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

 

 

Septal reduction therapy

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Dermatologists are well suited to understand cosmeceutical science and the benefits of particular cosmeceutical products – especially if they are readers of this column. However, there is another critical thought process that must be undertaken when designing an efficacious skin care regimen for patients: Topical products should be applied in a particular order to maximize efficacy. This is because cosmeceutical ingredients interact with, change each other, and are affected by temperature, pH, humidity, and the microbiome in which they are in contact. This column focuses on the factors that should be considered when recommending skin care regimens to patients and in which order to apply topical products.

The chemistry of ingredients and how they interact is well understood by personal care product formulators. I think of formulators as chefs who are using ingredients and placing them in the formulation in a well-defined order under controlled circumstances that affect the final product. For example, ceramides are used in barrier repair moisturizers. The right form of ceramide must be chosen and used with the 1:1:1 ratio of ceramides, fatty acids, and cholesterol for the product to be effective at repairing the barrier.¹ However, the order of when the ceramides are added to the product formula also impacts efficacy. Waxy ceramides and cholesterol require heat to liquefy and form the proper mixture with the other ingredients. Too much heat can damage fatty acids. Also, heat can inactivate finicky active ingredients such as vitamins C and E. For this reason, the ceramides and cholesterol are often incorporated first, allowing the formula to cool before the active heat labile ingredients are added. The speed at which something is mixed can generate heat and affect the final preparations, so temperature is an important consideration at all steps in the formulation procedure.

PainterSaba/iStock/Getty Images

Efficacy and compliance in product layering

Improper choice and layering of skin care formulations reduces efficacy and increases the risk of side effects resulting in reduced patient compliance. Acne treatments are a good example. Patients are often prescribed a retinoid, benzoyl peroxide, topical antibiotic, and/or salicylic acid treatment product for acne. If the proper cleansers and moisturizers are not chosen, the patient will be more likely to develop redness and scaling and become noncompliant.

Compliance is a concerning issue to dermatologists because studies have shown that 95% of people underdose and one out of every three prescriptions is not even filled.² If patients develop side effects, they are more likely to underdose or stop the treatment. Prescribing the proper cleanser and moisturizer to accompany treatment products will ease side effects and increase compliance. Several studies have demonstrated that the best way to increase compliance is to provide patients with written instructions, so they understand the proper order in which to apply products.
 

The role of cleansers

Cleansers can alter the pH of the skin, loosen attachments between cells, remove lipids – and disrupt the bilayer protective membrane, desquamate layers from the stratum corneum, and influence the penetrability of the skin for the next topical product that is applied. Therefore, cleansers should be selected based on the products that will follow them in the regimen. In addition, cleansers should be chosen according to the patient’s Baumann Skin Type.³ For example, cleansers for use on oily skin should have the ability to remove excess sebum on the skin while cleansers designed for dry skin would not remove as many lipids from the skin. Washing skin with a foaming cleanser can disrupt the skin barrier, allowing increased penetration of the treatment product that follows it. Oleic acid, hyaluronic acid, stearic acid, and other lipids are among the ingredients that influence skin penetration. Cleansers should precede treatment products and should be designed to increase efficacy of the treatment product. For this reason, every ingredient and characteristic of the chosen cleanser is important.

The role of eye products

Eye products treat issues such as dryness, puffiness, fine lines, and dark circles. However, they also play an overlooked role of protecting the thin delicate eye area from the treatment product. Using an eye product, especially one with protective ingredients such as barrier repair lipids, will help the patient tolerate the potentially irritating treatment product that follows the eye product. At night, the treatment product ingredients can get on the pillowcase and transfer to the upper and lower eyelids. Use of a protective eye product before bedtime can prevent the accompanying irritation. For example, acne patients often develop redness at the corners of the eyes when using benzoyl peroxide or a retinoid at night. Applying these medications after an eye cream can reduce this side effect.

Improving efficacy of treatment products

Treatments products are defined as corrective products targeted to skin issues such as acne, rosacea, melasma, dryness, skin cancer, eczema, psoriasis, and photoaging. The entire skin care regimen should be designed to enhance efficacy and decrease side effects of the treatment products. Treatment products may be cosmeceuticals, OTC medications, or prescription medications. These products must be able to reach their target in the proper chemical structure to be effective. Each ingredient has various constraints and quirks that should be considered. One well known example is ascorbic acid (vitamin C). Ascorbic acid is a treatment product for skin pigmentation and skin aging that is well known to have specific needs to work properly. Sheldon Pinnell, MD, led multiple investigations demonstrating that the maximum absorption of ascorbic acid occurs at a pH of 2-2.5. He showed that ascorbic acid products should be formulated at a pH of 2-2.5.⁴ However, applying these on skin that has just been cleansed with a soap cleanser with a pH of 9 will raise the skin’s pH and decrease the absorption of ascorbic acid. Having the patient cleanse with a low pH cleanser such as salicylic or glycolic acid cleanser (usually a pH of 2.5-3.5) will lower the pH of the skin and promote absorption of vitamin C.

The role of moisturizers

Moisturizers have many duties, including hydrating the skin, protecting the skin, and delivering important ingredients to the skin. However, moisturizers have a less discussed role of improving the efficacy of the treatment product that is applied beforehand. Moisturizers often contain oleic acid, hyaluronic acid, or other fatty acids that can increase penetration of other skin care ingredients. In addition, many moisturizers provide an occlusive effect that helps increase penetration. They also help protect the underlying treatment product from getting wiped off on a pillowcase or into the environment. In other words, moisturizers “seal in” the treatment product. Some moisturizing ingredients such as heparan sulfate may affect how well the skin cells “hear” and respond to signals elicited by the treatment products. For this reason, moisturizers should also be chosen to improve the efficacy of the treatment product.

Retinoids

When using retinoids for the first time in a patient, applying them last on top of the moisturizer can reduce the incidence of side effects and increase compliance. Retinoids, unlike other ingredients, penetrate easily into the deeper layer of the epidermis. Layering them on top of a moisturizer can help titrate retinoid absorption. The moisturizer can be chosen to slow or increase penetration of retinoids. Retinoids should always be used at nighttime because many of them, especially retinol and tretinoin, are easily broken down by ultraviolet light exposure.

Selecting across brands and applying products in the right order

Manufacturers rarely perform research on a complete regimen, but rather on individual products. Dermatologists then are left to figure this out on their own. I recommend choosing the best technologies from each brand based on the patient’s Baumann Skin Type and combining them using the recommended layering technique. I choose the best “hero” products from the various brands and layer them in a sequence that increases efficacy of all of the products. I then test the entire regimen on patients to figure out what combinations have the best efficacy and fewest side effects. Once I solve this “regimen puzzle,” I program software to automatically generate the step-by-step regimen instructions by Baumann Skin Type so that I do not have to rethink this complicated subject matter with every patient. I have developed over 3,300 distinct regimens so I am certain that my patients will get the proper skin care regimen advice from me or any of my staff.

Conclusion

Dermatologists can make a significant difference in their patients’ long-term skin care health by assisting them in identifying the proper skin care formulations for their individual skin type and guiding them as to how much, and in which order, to apply the products in their personalized skin care regimen. Patients will not remember what you told them and will confuse the order in which products should be used. For this reason, providing a written step-by-step skin care regimen is paramount to ensuring patient compliance.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com.

References

1. Man MQ M et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol. 1996 May;106(5):1096-101.

2. Storm A et al. One in 3 prescriptions are never redeemed: Primary nonadherence in an outpatient clinic. J Am Acad Dermatol. 2008 Jul;59(1):27-33.

3. Baumann LS. The Baumann Skin Typing System, in Farage MA et al. “Textbook of Aging Skin.” Springer-Verlag Berlin Heidelberg, 2017, pp. 1579-94.

4. Pinnell SR et al. Topical L-ascorbic acid: Percutaneous absorption studies. Dermatol Surg. 2001 Feb; 27(2):137-42.

Dermatologists are well suited to understand cosmeceutical science and the benefits of particular cosmeceutical products – especially if they are readers of this column. However, there is another critical thought process that must be undertaken when designing an efficacious skin care regimen for patients: Topical products should be applied in a particular order to maximize efficacy. This is because cosmeceutical ingredients interact with, change each other, and are affected by temperature, pH, humidity, and the microbiome in which they are in contact. This column focuses on the factors that should be considered when recommending skin care regimens to patients and in which order to apply topical products.

The chemistry of ingredients and how they interact is well understood by personal care product formulators. I think of formulators as chefs who are using ingredients and placing them in the formulation in a well-defined order under controlled circumstances that affect the final product. For example, ceramides are used in barrier repair moisturizers. The right form of ceramide must be chosen and used with the 1:1:1 ratio of ceramides, fatty acids, and cholesterol for the product to be effective at repairing the barrier.¹ However, the order of when the ceramides are added to the product formula also impacts efficacy. Waxy ceramides and cholesterol require heat to liquefy and form the proper mixture with the other ingredients. Too much heat can damage fatty acids. Also, heat can inactivate finicky active ingredients such as vitamins C and E. For this reason, the ceramides and cholesterol are often incorporated first, allowing the formula to cool before the active heat labile ingredients are added. The speed at which something is mixed can generate heat and affect the final preparations, so temperature is an important consideration at all steps in the formulation procedure.

PainterSaba/iStock/Getty Images

Efficacy and compliance in product layering

Improper choice and layering of skin care formulations reduces efficacy and increases the risk of side effects resulting in reduced patient compliance. Acne treatments are a good example. Patients are often prescribed a retinoid, benzoyl peroxide, topical antibiotic, and/or salicylic acid treatment product for acne. If the proper cleansers and moisturizers are not chosen, the patient will be more likely to develop redness and scaling and become noncompliant.

Compliance is a concerning issue to dermatologists because studies have shown that 95% of people underdose and one out of every three prescriptions is not even filled.² If patients develop side effects, they are more likely to underdose or stop the treatment. Prescribing the proper cleanser and moisturizer to accompany treatment products will ease side effects and increase compliance. Several studies have demonstrated that the best way to increase compliance is to provide patients with written instructions, so they understand the proper order in which to apply products.
 

The role of cleansers

Cleansers can alter the pH of the skin, loosen attachments between cells, remove lipids – and disrupt the bilayer protective membrane, desquamate layers from the stratum corneum, and influence the penetrability of the skin for the next topical product that is applied. Therefore, cleansers should be selected based on the products that will follow them in the regimen. In addition, cleansers should be chosen according to the patient’s Baumann Skin Type.³ For example, cleansers for use on oily skin should have the ability to remove excess sebum on the skin while cleansers designed for dry skin would not remove as many lipids from the skin. Washing skin with a foaming cleanser can disrupt the skin barrier, allowing increased penetration of the treatment product that follows it. Oleic acid, hyaluronic acid, stearic acid, and other lipids are among the ingredients that influence skin penetration. Cleansers should precede treatment products and should be designed to increase efficacy of the treatment product. For this reason, every ingredient and characteristic of the chosen cleanser is important.

The role of eye products

Eye products treat issues such as dryness, puffiness, fine lines, and dark circles. However, they also play an overlooked role of protecting the thin delicate eye area from the treatment product. Using an eye product, especially one with protective ingredients such as barrier repair lipids, will help the patient tolerate the potentially irritating treatment product that follows the eye product. At night, the treatment product ingredients can get on the pillowcase and transfer to the upper and lower eyelids. Use of a protective eye product before bedtime can prevent the accompanying irritation. For example, acne patients often develop redness at the corners of the eyes when using benzoyl peroxide or a retinoid at night. Applying these medications after an eye cream can reduce this side effect.

Improving efficacy of treatment products

Treatments products are defined as corrective products targeted to skin issues such as acne, rosacea, melasma, dryness, skin cancer, eczema, psoriasis, and photoaging. The entire skin care regimen should be designed to enhance efficacy and decrease side effects of the treatment products. Treatment products may be cosmeceuticals, OTC medications, or prescription medications. These products must be able to reach their target in the proper chemical structure to be effective. Each ingredient has various constraints and quirks that should be considered. One well known example is ascorbic acid (vitamin C). Ascorbic acid is a treatment product for skin pigmentation and skin aging that is well known to have specific needs to work properly. Sheldon Pinnell, MD, led multiple investigations demonstrating that the maximum absorption of ascorbic acid occurs at a pH of 2-2.5. He showed that ascorbic acid products should be formulated at a pH of 2-2.5.⁴ However, applying these on skin that has just been cleansed with a soap cleanser with a pH of 9 will raise the skin’s pH and decrease the absorption of ascorbic acid. Having the patient cleanse with a low pH cleanser such as salicylic or glycolic acid cleanser (usually a pH of 2.5-3.5) will lower the pH of the skin and promote absorption of vitamin C.

The role of moisturizers

Moisturizers have many duties, including hydrating the skin, protecting the skin, and delivering important ingredients to the skin. However, moisturizers have a less discussed role of improving the efficacy of the treatment product that is applied beforehand. Moisturizers often contain oleic acid, hyaluronic acid, or other fatty acids that can increase penetration of other skin care ingredients. In addition, many moisturizers provide an occlusive effect that helps increase penetration. They also help protect the underlying treatment product from getting wiped off on a pillowcase or into the environment. In other words, moisturizers “seal in” the treatment product. Some moisturizing ingredients such as heparan sulfate may affect how well the skin cells “hear” and respond to signals elicited by the treatment products. For this reason, moisturizers should also be chosen to improve the efficacy of the treatment product.

Retinoids

When using retinoids for the first time in a patient, applying them last on top of the moisturizer can reduce the incidence of side effects and increase compliance. Retinoids, unlike other ingredients, penetrate easily into the deeper layer of the epidermis. Layering them on top of a moisturizer can help titrate retinoid absorption. The moisturizer can be chosen to slow or increase penetration of retinoids. Retinoids should always be used at nighttime because many of them, especially retinol and tretinoin, are easily broken down by ultraviolet light exposure.

Selecting across brands and applying products in the right order

Manufacturers rarely perform research on a complete regimen, but rather on individual products. Dermatologists then are left to figure this out on their own. I recommend choosing the best technologies from each brand based on the patient’s Baumann Skin Type and combining them using the recommended layering technique. I choose the best “hero” products from the various brands and layer them in a sequence that increases efficacy of all of the products. I then test the entire regimen on patients to figure out what combinations have the best efficacy and fewest side effects. Once I solve this “regimen puzzle,” I program software to automatically generate the step-by-step regimen instructions by Baumann Skin Type so that I do not have to rethink this complicated subject matter with every patient. I have developed over 3,300 distinct regimens so I am certain that my patients will get the proper skin care regimen advice from me or any of my staff.

Conclusion

Dermatologists can make a significant difference in their patients’ long-term skin care health by assisting them in identifying the proper skin care formulations for their individual skin type and guiding them as to how much, and in which order, to apply the products in their personalized skin care regimen. Patients will not remember what you told them and will confuse the order in which products should be used. For this reason, providing a written step-by-step skin care regimen is paramount to ensuring patient compliance.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com.

References

1. Man MQ M et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol. 1996 May;106(5):1096-101.

2. Storm A et al. One in 3 prescriptions are never redeemed: Primary nonadherence in an outpatient clinic. J Am Acad Dermatol. 2008 Jul;59(1):27-33.

3. Baumann LS. The Baumann Skin Typing System, in Farage MA et al. “Textbook of Aging Skin.” Springer-Verlag Berlin Heidelberg, 2017, pp. 1579-94.

4. Pinnell SR et al. Topical L-ascorbic acid: Percutaneous absorption studies. Dermatol Surg. 2001 Feb; 27(2):137-42.

Dermatologists are well suited to understand cosmeceutical science and the benefits of particular cosmeceutical products – especially if they are readers of this column. However, there is another critical thought process that must be undertaken when designing an efficacious skin care regimen for patients: Topical products should be applied in a particular order to maximize efficacy. This is because cosmeceutical ingredients interact with, change each other, and are affected by temperature, pH, humidity, and the microbiome in which they are in contact. This column focuses on the factors that should be considered when recommending skin care regimens to patients and in which order to apply topical products.

The chemistry of ingredients and how they interact is well understood by personal care product formulators. I think of formulators as chefs who are using ingredients and placing them in the formulation in a well-defined order under controlled circumstances that affect the final product. For example, ceramides are used in barrier repair moisturizers. The right form of ceramide must be chosen and used with the 1:1:1 ratio of ceramides, fatty acids, and cholesterol for the product to be effective at repairing the barrier.¹ However, the order of when the ceramides are added to the product formula also impacts efficacy. Waxy ceramides and cholesterol require heat to liquefy and form the proper mixture with the other ingredients. Too much heat can damage fatty acids. Also, heat can inactivate finicky active ingredients such as vitamins C and E. For this reason, the ceramides and cholesterol are often incorporated first, allowing the formula to cool before the active heat labile ingredients are added. The speed at which something is mixed can generate heat and affect the final preparations, so temperature is an important consideration at all steps in the formulation procedure.

PainterSaba/iStock/Getty Images

Efficacy and compliance in product layering

Improper choice and layering of skin care formulations reduces efficacy and increases the risk of side effects resulting in reduced patient compliance. Acne treatments are a good example. Patients are often prescribed a retinoid, benzoyl peroxide, topical antibiotic, and/or salicylic acid treatment product for acne. If the proper cleansers and moisturizers are not chosen, the patient will be more likely to develop redness and scaling and become noncompliant.

Compliance is a concerning issue to dermatologists because studies have shown that 95% of people underdose and one out of every three prescriptions is not even filled.² If patients develop side effects, they are more likely to underdose or stop the treatment. Prescribing the proper cleanser and moisturizer to accompany treatment products will ease side effects and increase compliance. Several studies have demonstrated that the best way to increase compliance is to provide patients with written instructions, so they understand the proper order in which to apply products.
 

The role of cleansers

Cleansers can alter the pH of the skin, loosen attachments between cells, remove lipids – and disrupt the bilayer protective membrane, desquamate layers from the stratum corneum, and influence the penetrability of the skin for the next topical product that is applied. Therefore, cleansers should be selected based on the products that will follow them in the regimen. In addition, cleansers should be chosen according to the patient’s Baumann Skin Type.³ For example, cleansers for use on oily skin should have the ability to remove excess sebum on the skin while cleansers designed for dry skin would not remove as many lipids from the skin. Washing skin with a foaming cleanser can disrupt the skin barrier, allowing increased penetration of the treatment product that follows it. Oleic acid, hyaluronic acid, stearic acid, and other lipids are among the ingredients that influence skin penetration. Cleansers should precede treatment products and should be designed to increase efficacy of the treatment product. For this reason, every ingredient and characteristic of the chosen cleanser is important.

The role of eye products

Eye products treat issues such as dryness, puffiness, fine lines, and dark circles. However, they also play an overlooked role of protecting the thin delicate eye area from the treatment product. Using an eye product, especially one with protective ingredients such as barrier repair lipids, will help the patient tolerate the potentially irritating treatment product that follows the eye product. At night, the treatment product ingredients can get on the pillowcase and transfer to the upper and lower eyelids. Use of a protective eye product before bedtime can prevent the accompanying irritation. For example, acne patients often develop redness at the corners of the eyes when using benzoyl peroxide or a retinoid at night. Applying these medications after an eye cream can reduce this side effect.

Improving efficacy of treatment products

Treatments products are defined as corrective products targeted to skin issues such as acne, rosacea, melasma, dryness, skin cancer, eczema, psoriasis, and photoaging. The entire skin care regimen should be designed to enhance efficacy and decrease side effects of the treatment products. Treatment products may be cosmeceuticals, OTC medications, or prescription medications. These products must be able to reach their target in the proper chemical structure to be effective. Each ingredient has various constraints and quirks that should be considered. One well known example is ascorbic acid (vitamin C). Ascorbic acid is a treatment product for skin pigmentation and skin aging that is well known to have specific needs to work properly. Sheldon Pinnell, MD, led multiple investigations demonstrating that the maximum absorption of ascorbic acid occurs at a pH of 2-2.5. He showed that ascorbic acid products should be formulated at a pH of 2-2.5.⁴ However, applying these on skin that has just been cleansed with a soap cleanser with a pH of 9 will raise the skin’s pH and decrease the absorption of ascorbic acid. Having the patient cleanse with a low pH cleanser such as salicylic or glycolic acid cleanser (usually a pH of 2.5-3.5) will lower the pH of the skin and promote absorption of vitamin C.

The role of moisturizers

Moisturizers have many duties, including hydrating the skin, protecting the skin, and delivering important ingredients to the skin. However, moisturizers have a less discussed role of improving the efficacy of the treatment product that is applied beforehand. Moisturizers often contain oleic acid, hyaluronic acid, or other fatty acids that can increase penetration of other skin care ingredients. In addition, many moisturizers provide an occlusive effect that helps increase penetration. They also help protect the underlying treatment product from getting wiped off on a pillowcase or into the environment. In other words, moisturizers “seal in” the treatment product. Some moisturizing ingredients such as heparan sulfate may affect how well the skin cells “hear” and respond to signals elicited by the treatment products. For this reason, moisturizers should also be chosen to improve the efficacy of the treatment product.

Retinoids

When using retinoids for the first time in a patient, applying them last on top of the moisturizer can reduce the incidence of side effects and increase compliance. Retinoids, unlike other ingredients, penetrate easily into the deeper layer of the epidermis. Layering them on top of a moisturizer can help titrate retinoid absorption. The moisturizer can be chosen to slow or increase penetration of retinoids. Retinoids should always be used at nighttime because many of them, especially retinol and tretinoin, are easily broken down by ultraviolet light exposure.

Selecting across brands and applying products in the right order

Manufacturers rarely perform research on a complete regimen, but rather on individual products. Dermatologists then are left to figure this out on their own. I recommend choosing the best technologies from each brand based on the patient’s Baumann Skin Type and combining them using the recommended layering technique. I choose the best “hero” products from the various brands and layer them in a sequence that increases efficacy of all of the products. I then test the entire regimen on patients to figure out what combinations have the best efficacy and fewest side effects. Once I solve this “regimen puzzle,” I program software to automatically generate the step-by-step regimen instructions by Baumann Skin Type so that I do not have to rethink this complicated subject matter with every patient. I have developed over 3,300 distinct regimens so I am certain that my patients will get the proper skin care regimen advice from me or any of my staff.

Conclusion

Dermatologists can make a significant difference in their patients’ long-term skin care health by assisting them in identifying the proper skin care formulations for their individual skin type and guiding them as to how much, and in which order, to apply the products in their personalized skin care regimen. Patients will not remember what you told them and will confuse the order in which products should be used. For this reason, providing a written step-by-step skin care regimen is paramount to ensuring patient compliance.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com.

References

1. Man MQ M et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol. 1996 May;106(5):1096-101.

2. Storm A et al. One in 3 prescriptions are never redeemed: Primary nonadherence in an outpatient clinic. J Am Acad Dermatol. 2008 Jul;59(1):27-33.

3. Baumann LS. The Baumann Skin Typing System, in Farage MA et al. “Textbook of Aging Skin.” Springer-Verlag Berlin Heidelberg, 2017, pp. 1579-94.

4. Pinnell SR et al. Topical L-ascorbic acid: Percutaneous absorption studies. Dermatol Surg. 2001 Feb; 27(2):137-42.

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal lung disease that generally affects older adults. It is characterized by a radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) that has no other known etiology.

See related editorial

Accurate diagnosis of IPF is crucial. We recommend early referral to a center specializing in interstitial lung disease to confirm the diagnosis, start appropriate therapy, advise the patient on prognosis and enrollment in disease registries and clinical trials, and determine candidacy for lung transplant.

Primary care physicians are uniquely positioned to encounter patients with IPF, whether because of a patient complaint or as an incidental finding on computed tomography. The goal of this article is to delineate the features of IPF so that it may be recognized early and thus expedite referral to a center with expertise in interstitial lung disease for a thorough evaluation and appropriate management.

WHAT IS IDIOPATHIC PULMONARY FIBROSIS?

MORE COMMON THAN ONCE THOUGHT

The true incidence and prevalence of IPF are difficult to assess. IPF is generally considered a rare disease, but it is more common than once thought. In 2011, Raghu et al³ estimated the prevalence in Medicare beneficiaries to be 495 cases per 100,000. Based on this estimate and the current US population, up to 160,000 Americans could have IPF.⁴ Raghu et al also showed that IPF more often affects adults over age 65, which suggests that as the US population ages, the incidence of IPF may rise. Studies have also reported an increased incidence of IPF worldwide.⁵

Further, with the rising use of low-dose computed tomography to screen for lung cancer, more incidental cases of IPF will likely be found.^6–8

Older data showed a lag from symptom onset to accurate diagnosis of 1 to 2 years.⁹ A more recent study found a lag in referral of patients with IPF to tertiary care centers, and this delay was associated with a higher rate of death independent of disease severity.¹⁰

TYPICALLY PROGRESSIVE, OFTEN FATAL

IPF is typically progressive and limited to the lungs, and it portends a poor prognosis. The median survival is commonly cited as 2 to 5 years from diagnosis, although this is based on older observations that may not reflect current best practice and newer therapies. More recent studies suggest higher survival rates if patients have preserved lung function.¹¹

As the name indicates, the etiology of IPF is unknown, but studies have indicated genetic underpinnings in a notable proportion of cases.¹² Regardless of the cause, the pathogenesis and progression of IPF are thought to be the result of an abnormal and persistent wound-repair response. The progressive deposition of scar tissue disrupts normal lung architecture and function, eventually causing clinical disease.¹³

SYMPTOMS AND KEY FEATURES

Patients with IPF typically present with the insidious onset of dyspnea on exertion, with or without chronic cough. Risk factors include male sex, increasing age, and a history of smoking. Patients with undiagnosed IPF who present with dyspnea and a history of smoking are often treated empirically for chronic obstructive pulmonary disease (COPD).

Rales are a common finding on auscultation in IPF, and this can lead to an exhaustive cardiac evaluation and empiric treatment for heart failure. Digital clubbing is also relatively common.¹⁴ Hypoxemia with exertion is another common feature that also often correlates with disease severity and prognosis. Resting hypoxemia is more common in advanced disease.

On spirometry, patients with IPF typically demonstrate restrictive physiology, suggested by a normal or elevated ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁/FVC) (> 70% predicted or above the lower limit of normal) combined with a lower than normal FVC. Restrictive physiology is definitively demonstrated by a decreased total lung capacity (< 80% predicted or below the lower limit of normal) on plethysmography. Impaired gas exchange, manifested by a decreased diffusing capacity of the lungs for carbon monoxide (DLCO) on pulmonary function testing, is also common. Because pulmonary perfusion is higher in the lung bases, where IPF is also predominant, the DLCO is often reduced to a greater extent than the FVC.

PROGNOSTIC INDICATORS

Clinicians typically view IPF as a relentless and progressive process, but its course is variable and can be uncertain in an individual patient (Figure 1).^15,16 Nevertheless, over time, most patients have a decline in lung function leading to respiratory failure. Respiratory failure, often preceded by a subacute deterioration (over weeks to months) or an acute deterioration (< 4 weeks), is the most common cause of death, but comorbid diseases such as lung cancer, infection, and heart failure are also common causes of death in these patients.^17,18

Predictors of mortality include worsening FVC, DLCO, symptoms, and physiologic impairment, manifested by a decline in the 6-minute walking test or worsening exertional hypoxemia.^19–22 Other common comorbidities linked with impaired quality of life and poor prognosis include obstructive sleep apnea, gastroesophageal reflux disease, and depression.^16,23 Retrospective studies suggest that most IPF patients die 2 to 5 years after symptom onset. With the lag from symptom onset to final diagnosis, the average life expectancy is as little as 2 years from the time of diagnosis.^9,18,24,25

Two staging systems have been developed to predict short-term and long-term mortality risk based on sex, age, and physiologic parameters.^23,24 The GAP (gender, age, physiology) index provides an estimate of the risk of death for a cohort of patients: a score of 0 to 8 is calculated, and the score is then categorized as stage I, II, or III. Each stage is associated with 1-, 2-, and 3-year mortality rates, with stage III having the highest rates. The GAP calculator (www.acponline.org/journals/annals/extras/gap) provides an estimate of the risk of death for an individual patient. The application of these tools for the management of IPF is evolving; however, they may be helpful for counseling patients about disease prognosis.

CLUES TO DIAGNOSIS

Histologic patterns

UIP on histologic study is also seen in fibrotic lung diseases other than IPF, including connective tissue disease-associated interstitial lung disease, inhalational or occupational interstitial lung disease, and chronic hypersensitivity pneumonitis.^26–29 Consequently, the diagnosis of IPF requires exclusion of other known causes of UIP.

According to the 2011 guidelines,¹⁶ the histology of interstitial lung disease can be categorized as definite UIP, probable UIP, or possible UIP, or as an atypical pattern suggesting another diagnosis. If no definite cause of the interstitial lung abnormality is found, the level of certainty of the histopathologic pattern of UIP helps formulate the clinical diagnosis and management plan.

Clues on computed tomography

The UIP nomenclature also describes patterns on high-resolution computed tomography (HRCT). HRCT is done without contrast and produces thin-sliced images (usually < 1.5 mm) in inspiratory, expiratory, and prone views; this allows detection of air trapping, which may indicate an airway-centric alternative diagnosis.

On HRCT, UIP appears as reticular opacities, often with traction bronchiectasis or bronchiolectasis, usually with a basilar and peripheral predominance. Honeycombing is a key feature and appears as clustered cystic spaces with well-defined walls in the periphery of the lung parenchyma. Ground-glass opacities are not a prominent feature of UIP, and although they do not exclude a UIP pattern, they should spur consideration of other diagnoses.¹⁶ Reactive mediastinal and hilar lymphadenopathy is another common feature of UIP.

When evaluating results of HRCT for UIP, the radiologist categorizes the pattern as definite UIP, possible UIP, or inconsistent. The definite pattern meets all the above features and has none of the features suggesting an alternative diagnosis (Figure 3). The possible pattern includes all the above features with the exception of honeycombing. If the predominant features on HRCT include any atypical finding listed above, then the study is considered inconsistent with UIP. If the pattern on HRCT is considered definite, evaluation of pathology is not necessary. If the pattern is categorized as possible or is inconsistent, then surgical lung biopsy-confirmed UIP is necessary for the definitive diagnosis of IPF.

However, evidence is emerging that in the correct clinical scenario, possible UIP behaves similarly to definite UIP and may be sufficient to make the clinical diagnosis of IPF even without surgical biopsy confirmation.³⁰

A DIAGNOSTIC ALGORITHM FOR IPF

Given the multitude of interstitial lung diseases, their complexities, and the lack of a gold standard definitive diagnostic test, the diagnosis of IPF can be difficult, requiring the integration of clinical, radiologic, and, if necessary, pathologic findings.

Demographic features

The patient’s demographic features and risk factors dictate the initial clinical suspicion of IPF compared with other interstitial lung diseases. The incidence of IPF increases with age, and IPF is more common in men. A history of smoking is another risk factor.³¹ A 45-year-old never-smoker is much less likely to have IPF than a 70-year-old former smoker, and a 70-year-old man is more likely to have IPF than a woman of the same age. Thus, the finding of interstitial lung disease in a patient with a demographic profile that is not typical (ie, a younger woman who never smoked) should prompt an exhaustive investigation for another diagnosis such as hypersensitivity pneumonitis or connective tissue disease.

Key elements of the history

After considering the demographic profile and risk factors, the next step in the evaluation is a thorough and accurate medical history. This should include assessment of the severity of dyspnea and cough, signs and symptoms of connective tissue disease (eg, arthralgias, sicca symptoms, Raynaud phenomenon, difficulty swallowing), and gastroesophageal reflux disease, which can be associated with connective tissue disease and, independently, with IPF.

It is also important to identify any environmental exposures that suggest pneumoconiosis or chronic hypersensitivity pneumonitis. The most common risk factors for hypersensitivity pneumonitis are birds and bird feathers, molds, fungi, hot tub use, and some industrial chemicals.³²

A medication history is important. Many medications are associated with interstitial lung disease, but amiodarone, bleomycin, methotrexate, and nitrofurantoin are among the common offenders.³³

A thorough family history is necessary, as there are familial forms of IPF.

Focus of the physical examination

The physical examination must include careful auscultation for rales. While rales are not specific for IPF, they are the most common pulmonary abnormality. Detailed skin, musculoskeletal, and cardiovascular examinations are also important to evaluate for rheumatologic signs, clubbing, or evidence of heart failure or pulmonary hypertension.

Laboratory tests

Laboratory testing should include a serologic autoantibody panel to evaluate for connective tissue diseases that can manifest as interstitial lung disease, including rheumatoid arthritis, dermatopolymyositis, scleroderma, Sjögren syndrome, and undifferentiated or mixed connective tissue disease. Typical preliminary laboratory tests are antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. Others may include anticyclic citrullinated peptide (anti-CCP), anti-Scl-70, anti-RNP, anti-SS-A, anti-SS-B, and anti-Jo-1.¹⁶ The breadth of the panel should depend on patient demographics and findings in the history or physical examination that increase or decrease the likelihood of a connective tissue disease.

Lung function testing

Assessing the patient’s pulmonary physiology should include spirometry, DLCO, and body plethysmography (lung volumes). In most cases, IPF manifests with restrictive physiology. Once restrictive physiology is confirmed with a low total lung capacity, FVC testing can be used as a longitudinal surrogate, as it is less expensive and easier for the patient to perform. In general, a lower total lung capacity or FVC indicates more severe impairment.

The DLCO serves as another marker of severity but is less reliable due to baseline variability and difficulties performing the maneuver.

A 6-minute walk test is another crucial physiologic assessment tool that can quantify exertional hypoxemia and functional status (ie, distance walked), and can assist in prognosis.

Imaging

Most patients undergo chest radiography in the workup for undiagnosed dyspnea. However, chest radiography is not adequate to formulate an accurate diagnosis in suspected interstitial lung disease, and a normal radiograph cannot exclude changes that might reflect early phases of the disease. As the disease progresses, the plain radiograph can show reticulonodular opacities and honeycombing in the peripheral and lower lung zones (Figure 3).³⁴

The decision whether to order HRCT in the workup for a patient who has dyspnea and a normal chest radiograph is challenging. We recommend cross-sectional imaging when physiologic testing shows restriction or low DLCO, or when there is a high index of suspicion for underlying lung disease as the cause of symptoms.

Expert consultation can aid with this decision, especially when the underlying cause of dyspnea remains unclear after initial studies have been completed. Otherwise, HRCT is an essential test in the evaluation of interstitial lung disease.

Bronchoscopy’s role controversial

If the pattern on HRCT is nondiagnostic, then surgical biopsy is necessary, and the diagnosis of IPF requires a histologic pattern of UIP as described above.^16,35

Although bronchoscopy can be valuable if an alternative diagnosis such as sarcoidosis or chronic hypersensitivity pneumonitis is suspected, the role of bronchoscopic biopsy in the workup of IPF is controversial. The patchy nature of UIP does not lend itself to the relatively small biopsy samples obtained through bronchoscopy.^36,37

Surgical biopsy options

The favored biopsy approach is surgical, using either an open or a video-assisted thoracoscopic technique. The latter is preferred as it is less invasive, requires a shorter length of hospital stay, and allows a faster recovery.³⁸ Bronchoscopic cryobiopsy, currently under investigation, is a potentially valuable tool whose role in diagnosing IPF is evolving.

Frequently, neither HRCT nor surgical lung biopsy demonstrates UIP, making the definitive diagnosis of IPF difficult. Moreover, some patients with nondiagnostic HRCT results are unable to tolerate surgical lung biopsy because of severely impaired lung function or other comorbidities.

The role of multidisciplinary discussions

When surgical lung biopsy is not possible, current practice at leading centers uses a multidisciplinary approach to allow for a confident diagnosis.^30,39 Discussions take place between pulmonologists, pathologists, radiologists, and other specialists to collectively consider all aspects of a case before rendering a consensus opinion on the diagnosis and the management plan. If the discussion leads to a consensus diagnosis of IPF, then the patient’s clinician can move forward with treatment options. If not, the group can recommend further workup or alternative diagnoses and treatment regimens. The multidisciplinary group is also well positioned to consider the relative risks and benefits of moving forward with surgical lung biopsy for individual patients.

This approach illustrates the importance of referring these patients to centers of excellence in diagnosing and managing complex cases of interstitial lung disease, including IPF.⁴⁰

TREATMENT OF IPF

Antifibrotic therapy

Antifibrotic therapy is a choice between pirfenidone and nintedanib.

Pirfenidone, which has an undefined molecular target, was approved based on the results of 3 trials.^41,42 Pooled analyses from these trials showed a reduction in the decline from baseline in FVC percent predicted and improved progression-free survival.⁴³ Pooled and meta-analyses of pirfenidone clinical trials have shown a mortality benefit, although no individual study has shown such an effect on mortality rates.⁴⁴

The major adverse effects of pirfenidone are gastrointestinal distress and photosensitivity rash.

Nintedanib is a triple tyrosine kinase inhibitor that broadly targets fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptors. Combined analysis of 2 concurrent trials⁴⁵ showed that nintedanib reduced the decline in FVC, similarly to pirfenidone. The major adverse event associated with nintedanib was diarrhea. Since it inhibits vascular endothelial growth factor, there is a risk of hematologic complications such as bleeding or clotting events.

Because pirfenidone and nintedanib can increase aminotransferase levels, regular monitoring is recommended.

To date, no trial has compared pirfenidone and nintedanib in terms of their efficacy and tolerability. Therefore, the choice of agent is based on the patient’s preference after a discussion of potential risks and expected benefits, a review of each drug’s side effects, and consideration of comorbid conditions and physician experience.

Patients need to understand that these drugs slow the rate of decline in FVC but have not been shown to improve symptoms or functional status.

Corticosteroids are not routine

Corticosteroids should not be used routinely in the treatment of IPF. Although steroids, alone or in combination with other immunosuppressive medications, were commonly used for IPF in the past, such use was not based on results of randomized controlled trials.⁴⁶ Retrospective controlled studies have failed to show that corticosteroids improve mortality rates in IPF; indeed, they have shown that corticosteroids confer substantial morbidity.^47,48 In addition, a randomized controlled trial combining corticosteroids with N-acetylcysteine and azathioprine was stopped early due to an increased risk of death and hospitalization.⁴⁹ Collectively, these data suggest that corticosteroids confer no benefit and are potentially harmful. Their use in IPF is discouraged, and the joint international guidelines recommend against immunosuppression to treat IPF.¹⁶

Other treatments

The guidelines offer additional suggestions for the management of IPF.

Preliminary evidence suggests that microaspiration associated with abnormal gastroesophageal acid reflux is a risk factor for IPF. As such, there is a weak recommendation for aggressive treatment of reflux disease.⁵⁰ However, because evidence suggests that proton-pump inhibitor therapy may be associated with adverse renal or central nervous system effects, this recommendation bears caution. It is hoped that ongoing studies will provide further insight into the role of acid-suppression in the management of IPF.^51,52

Further treatment recommendations include best supportive management such as supplemental oxygen, pulmonary rehabilitation, and vaccinations.

Prompt referral for lung transplant is imperative. IPF is now the most common indication for lung transplant, and given the poor overall prognosis of advanced IPF, transplant confers a survival benefit in appropriately selected patients.^53,54  Table 2 provides an evidence-based checklist for the workup and management of IPF.

ACUTE EXACERBATIONS OF IPF

The unpredictable nature of IPF can manifest in the form of acute exacerbations without an identifiable cause. The loosely defined diagnostic criteria for the diagnosis of acute exacerbations are a previous or new diagnosis of IPF, worsening or development of dyspnea in the last 30 days, and new bilateral ground-glass or consolidative changes with a background of UIP on HRCT.¹⁶

A new definition has been proposed⁵⁵ to facilitate research in the characterization and treatment of acute exacerbations of IPF. The new definition includes all causes of respiratory deterioration except for heart failure and volume overload. It is less strict about the 30-day time frame. This newer definition is based on the lack of evidence differentiating outcomes when an acute deterioration is associated with known or unknown etiologies.⁵⁵

The incidence of acute exacerbations is variable, with a 1- and 3-year incidence ranging between 8.6% and 23.9% depending on the criteria used.⁵⁶ In general, acute exacerbations carry a grim prognosis, with a median life expectancy of 2.2 months.⁵⁷

There is no approved therapy for exacerbations of IPF. Rather, treatment is mainly supportive with supplemental oxygen and mechanical ventilation. Current guidelines have a weak recommendation for the use of corticosteroids, but there are no recommendations regarding dose, route, or duration of therapy. Other treatments, primarily immunomodulatory agents, have been suggested but lack evidence of benefit.

Acknowledgments: Pathology images were provided by Carol Farver, MD, Pathology Institute, Cleveland Clinic. Radiology images were provided by Ruchi Yadav, MD, Imaging Institute, Cleveland Clinic.

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal lung disease that generally affects older adults. It is characterized by a radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) that has no other known etiology.

See related editorial

Accurate diagnosis of IPF is crucial. We recommend early referral to a center specializing in interstitial lung disease to confirm the diagnosis, start appropriate therapy, advise the patient on prognosis and enrollment in disease registries and clinical trials, and determine candidacy for lung transplant.

Primary care physicians are uniquely positioned to encounter patients with IPF, whether because of a patient complaint or as an incidental finding on computed tomography. The goal of this article is to delineate the features of IPF so that it may be recognized early and thus expedite referral to a center with expertise in interstitial lung disease for a thorough evaluation and appropriate management.

WHAT IS IDIOPATHIC PULMONARY FIBROSIS?

MORE COMMON THAN ONCE THOUGHT

The true incidence and prevalence of IPF are difficult to assess. IPF is generally considered a rare disease, but it is more common than once thought. In 2011, Raghu et al³ estimated the prevalence in Medicare beneficiaries to be 495 cases per 100,000. Based on this estimate and the current US population, up to 160,000 Americans could have IPF.⁴ Raghu et al also showed that IPF more often affects adults over age 65, which suggests that as the US population ages, the incidence of IPF may rise. Studies have also reported an increased incidence of IPF worldwide.⁵

Further, with the rising use of low-dose computed tomography to screen for lung cancer, more incidental cases of IPF will likely be found.^6–8

Older data showed a lag from symptom onset to accurate diagnosis of 1 to 2 years.⁹ A more recent study found a lag in referral of patients with IPF to tertiary care centers, and this delay was associated with a higher rate of death independent of disease severity.¹⁰

TYPICALLY PROGRESSIVE, OFTEN FATAL

IPF is typically progressive and limited to the lungs, and it portends a poor prognosis. The median survival is commonly cited as 2 to 5 years from diagnosis, although this is based on older observations that may not reflect current best practice and newer therapies. More recent studies suggest higher survival rates if patients have preserved lung function.¹¹

As the name indicates, the etiology of IPF is unknown, but studies have indicated genetic underpinnings in a notable proportion of cases.¹² Regardless of the cause, the pathogenesis and progression of IPF are thought to be the result of an abnormal and persistent wound-repair response. The progressive deposition of scar tissue disrupts normal lung architecture and function, eventually causing clinical disease.¹³

SYMPTOMS AND KEY FEATURES

Patients with IPF typically present with the insidious onset of dyspnea on exertion, with or without chronic cough. Risk factors include male sex, increasing age, and a history of smoking. Patients with undiagnosed IPF who present with dyspnea and a history of smoking are often treated empirically for chronic obstructive pulmonary disease (COPD).

Rales are a common finding on auscultation in IPF, and this can lead to an exhaustive cardiac evaluation and empiric treatment for heart failure. Digital clubbing is also relatively common.¹⁴ Hypoxemia with exertion is another common feature that also often correlates with disease severity and prognosis. Resting hypoxemia is more common in advanced disease.

On spirometry, patients with IPF typically demonstrate restrictive physiology, suggested by a normal or elevated ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁/FVC) (> 70% predicted or above the lower limit of normal) combined with a lower than normal FVC. Restrictive physiology is definitively demonstrated by a decreased total lung capacity (< 80% predicted or below the lower limit of normal) on plethysmography. Impaired gas exchange, manifested by a decreased diffusing capacity of the lungs for carbon monoxide (DLCO) on pulmonary function testing, is also common. Because pulmonary perfusion is higher in the lung bases, where IPF is also predominant, the DLCO is often reduced to a greater extent than the FVC.

PROGNOSTIC INDICATORS

Clinicians typically view IPF as a relentless and progressive process, but its course is variable and can be uncertain in an individual patient (Figure 1).^15,16 Nevertheless, over time, most patients have a decline in lung function leading to respiratory failure. Respiratory failure, often preceded by a subacute deterioration (over weeks to months) or an acute deterioration (< 4 weeks), is the most common cause of death, but comorbid diseases such as lung cancer, infection, and heart failure are also common causes of death in these patients.^17,18

Predictors of mortality include worsening FVC, DLCO, symptoms, and physiologic impairment, manifested by a decline in the 6-minute walking test or worsening exertional hypoxemia.^19–22 Other common comorbidities linked with impaired quality of life and poor prognosis include obstructive sleep apnea, gastroesophageal reflux disease, and depression.^16,23 Retrospective studies suggest that most IPF patients die 2 to 5 years after symptom onset. With the lag from symptom onset to final diagnosis, the average life expectancy is as little as 2 years from the time of diagnosis.^9,18,24,25

Two staging systems have been developed to predict short-term and long-term mortality risk based on sex, age, and physiologic parameters.^23,24 The GAP (gender, age, physiology) index provides an estimate of the risk of death for a cohort of patients: a score of 0 to 8 is calculated, and the score is then categorized as stage I, II, or III. Each stage is associated with 1-, 2-, and 3-year mortality rates, with stage III having the highest rates. The GAP calculator (www.acponline.org/journals/annals/extras/gap) provides an estimate of the risk of death for an individual patient. The application of these tools for the management of IPF is evolving; however, they may be helpful for counseling patients about disease prognosis.

CLUES TO DIAGNOSIS

Histologic patterns

UIP on histologic study is also seen in fibrotic lung diseases other than IPF, including connective tissue disease-associated interstitial lung disease, inhalational or occupational interstitial lung disease, and chronic hypersensitivity pneumonitis.^26–29 Consequently, the diagnosis of IPF requires exclusion of other known causes of UIP.

According to the 2011 guidelines,¹⁶ the histology of interstitial lung disease can be categorized as definite UIP, probable UIP, or possible UIP, or as an atypical pattern suggesting another diagnosis. If no definite cause of the interstitial lung abnormality is found, the level of certainty of the histopathologic pattern of UIP helps formulate the clinical diagnosis and management plan.

Clues on computed tomography

The UIP nomenclature also describes patterns on high-resolution computed tomography (HRCT). HRCT is done without contrast and produces thin-sliced images (usually < 1.5 mm) in inspiratory, expiratory, and prone views; this allows detection of air trapping, which may indicate an airway-centric alternative diagnosis.

On HRCT, UIP appears as reticular opacities, often with traction bronchiectasis or bronchiolectasis, usually with a basilar and peripheral predominance. Honeycombing is a key feature and appears as clustered cystic spaces with well-defined walls in the periphery of the lung parenchyma. Ground-glass opacities are not a prominent feature of UIP, and although they do not exclude a UIP pattern, they should spur consideration of other diagnoses.¹⁶ Reactive mediastinal and hilar lymphadenopathy is another common feature of UIP.

When evaluating results of HRCT for UIP, the radiologist categorizes the pattern as definite UIP, possible UIP, or inconsistent. The definite pattern meets all the above features and has none of the features suggesting an alternative diagnosis (Figure 3). The possible pattern includes all the above features with the exception of honeycombing. If the predominant features on HRCT include any atypical finding listed above, then the study is considered inconsistent with UIP. If the pattern on HRCT is considered definite, evaluation of pathology is not necessary. If the pattern is categorized as possible or is inconsistent, then surgical lung biopsy-confirmed UIP is necessary for the definitive diagnosis of IPF.

However, evidence is emerging that in the correct clinical scenario, possible UIP behaves similarly to definite UIP and may be sufficient to make the clinical diagnosis of IPF even without surgical biopsy confirmation.³⁰

A DIAGNOSTIC ALGORITHM FOR IPF

Given the multitude of interstitial lung diseases, their complexities, and the lack of a gold standard definitive diagnostic test, the diagnosis of IPF can be difficult, requiring the integration of clinical, radiologic, and, if necessary, pathologic findings.

Demographic features

The patient’s demographic features and risk factors dictate the initial clinical suspicion of IPF compared with other interstitial lung diseases. The incidence of IPF increases with age, and IPF is more common in men. A history of smoking is another risk factor.³¹ A 45-year-old never-smoker is much less likely to have IPF than a 70-year-old former smoker, and a 70-year-old man is more likely to have IPF than a woman of the same age. Thus, the finding of interstitial lung disease in a patient with a demographic profile that is not typical (ie, a younger woman who never smoked) should prompt an exhaustive investigation for another diagnosis such as hypersensitivity pneumonitis or connective tissue disease.

Key elements of the history

After considering the demographic profile and risk factors, the next step in the evaluation is a thorough and accurate medical history. This should include assessment of the severity of dyspnea and cough, signs and symptoms of connective tissue disease (eg, arthralgias, sicca symptoms, Raynaud phenomenon, difficulty swallowing), and gastroesophageal reflux disease, which can be associated with connective tissue disease and, independently, with IPF.

It is also important to identify any environmental exposures that suggest pneumoconiosis or chronic hypersensitivity pneumonitis. The most common risk factors for hypersensitivity pneumonitis are birds and bird feathers, molds, fungi, hot tub use, and some industrial chemicals.³²

A medication history is important. Many medications are associated with interstitial lung disease, but amiodarone, bleomycin, methotrexate, and nitrofurantoin are among the common offenders.³³

A thorough family history is necessary, as there are familial forms of IPF.

Focus of the physical examination

The physical examination must include careful auscultation for rales. While rales are not specific for IPF, they are the most common pulmonary abnormality. Detailed skin, musculoskeletal, and cardiovascular examinations are also important to evaluate for rheumatologic signs, clubbing, or evidence of heart failure or pulmonary hypertension.

Laboratory tests

Laboratory testing should include a serologic autoantibody panel to evaluate for connective tissue diseases that can manifest as interstitial lung disease, including rheumatoid arthritis, dermatopolymyositis, scleroderma, Sjögren syndrome, and undifferentiated or mixed connective tissue disease. Typical preliminary laboratory tests are antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. Others may include anticyclic citrullinated peptide (anti-CCP), anti-Scl-70, anti-RNP, anti-SS-A, anti-SS-B, and anti-Jo-1.¹⁶ The breadth of the panel should depend on patient demographics and findings in the history or physical examination that increase or decrease the likelihood of a connective tissue disease.

Lung function testing

Assessing the patient’s pulmonary physiology should include spirometry, DLCO, and body plethysmography (lung volumes). In most cases, IPF manifests with restrictive physiology. Once restrictive physiology is confirmed with a low total lung capacity, FVC testing can be used as a longitudinal surrogate, as it is less expensive and easier for the patient to perform. In general, a lower total lung capacity or FVC indicates more severe impairment.

The DLCO serves as another marker of severity but is less reliable due to baseline variability and difficulties performing the maneuver.

A 6-minute walk test is another crucial physiologic assessment tool that can quantify exertional hypoxemia and functional status (ie, distance walked), and can assist in prognosis.

Imaging

Most patients undergo chest radiography in the workup for undiagnosed dyspnea. However, chest radiography is not adequate to formulate an accurate diagnosis in suspected interstitial lung disease, and a normal radiograph cannot exclude changes that might reflect early phases of the disease. As the disease progresses, the plain radiograph can show reticulonodular opacities and honeycombing in the peripheral and lower lung zones (Figure 3).³⁴

The decision whether to order HRCT in the workup for a patient who has dyspnea and a normal chest radiograph is challenging. We recommend cross-sectional imaging when physiologic testing shows restriction or low DLCO, or when there is a high index of suspicion for underlying lung disease as the cause of symptoms.

Expert consultation can aid with this decision, especially when the underlying cause of dyspnea remains unclear after initial studies have been completed. Otherwise, HRCT is an essential test in the evaluation of interstitial lung disease.

Bronchoscopy’s role controversial

If the pattern on HRCT is nondiagnostic, then surgical biopsy is necessary, and the diagnosis of IPF requires a histologic pattern of UIP as described above.^16,35

Although bronchoscopy can be valuable if an alternative diagnosis such as sarcoidosis or chronic hypersensitivity pneumonitis is suspected, the role of bronchoscopic biopsy in the workup of IPF is controversial. The patchy nature of UIP does not lend itself to the relatively small biopsy samples obtained through bronchoscopy.^36,37

Surgical biopsy options

The favored biopsy approach is surgical, using either an open or a video-assisted thoracoscopic technique. The latter is preferred as it is less invasive, requires a shorter length of hospital stay, and allows a faster recovery.³⁸ Bronchoscopic cryobiopsy, currently under investigation, is a potentially valuable tool whose role in diagnosing IPF is evolving.

Frequently, neither HRCT nor surgical lung biopsy demonstrates UIP, making the definitive diagnosis of IPF difficult. Moreover, some patients with nondiagnostic HRCT results are unable to tolerate surgical lung biopsy because of severely impaired lung function or other comorbidities.

The role of multidisciplinary discussions

When surgical lung biopsy is not possible, current practice at leading centers uses a multidisciplinary approach to allow for a confident diagnosis.^30,39 Discussions take place between pulmonologists, pathologists, radiologists, and other specialists to collectively consider all aspects of a case before rendering a consensus opinion on the diagnosis and the management plan. If the discussion leads to a consensus diagnosis of IPF, then the patient’s clinician can move forward with treatment options. If not, the group can recommend further workup or alternative diagnoses and treatment regimens. The multidisciplinary group is also well positioned to consider the relative risks and benefits of moving forward with surgical lung biopsy for individual patients.

This approach illustrates the importance of referring these patients to centers of excellence in diagnosing and managing complex cases of interstitial lung disease, including IPF.⁴⁰

TREATMENT OF IPF

Antifibrotic therapy

Antifibrotic therapy is a choice between pirfenidone and nintedanib.

Pirfenidone, which has an undefined molecular target, was approved based on the results of 3 trials.^41,42 Pooled analyses from these trials showed a reduction in the decline from baseline in FVC percent predicted and improved progression-free survival.⁴³ Pooled and meta-analyses of pirfenidone clinical trials have shown a mortality benefit, although no individual study has shown such an effect on mortality rates.⁴⁴

The major adverse effects of pirfenidone are gastrointestinal distress and photosensitivity rash.

Nintedanib is a triple tyrosine kinase inhibitor that broadly targets fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptors. Combined analysis of 2 concurrent trials⁴⁵ showed that nintedanib reduced the decline in FVC, similarly to pirfenidone. The major adverse event associated with nintedanib was diarrhea. Since it inhibits vascular endothelial growth factor, there is a risk of hematologic complications such as bleeding or clotting events.

Because pirfenidone and nintedanib can increase aminotransferase levels, regular monitoring is recommended.

To date, no trial has compared pirfenidone and nintedanib in terms of their efficacy and tolerability. Therefore, the choice of agent is based on the patient’s preference after a discussion of potential risks and expected benefits, a review of each drug’s side effects, and consideration of comorbid conditions and physician experience.

Patients need to understand that these drugs slow the rate of decline in FVC but have not been shown to improve symptoms or functional status.

Corticosteroids are not routine

Corticosteroids should not be used routinely in the treatment of IPF. Although steroids, alone or in combination with other immunosuppressive medications, were commonly used for IPF in the past, such use was not based on results of randomized controlled trials.⁴⁶ Retrospective controlled studies have failed to show that corticosteroids improve mortality rates in IPF; indeed, they have shown that corticosteroids confer substantial morbidity.^47,48 In addition, a randomized controlled trial combining corticosteroids with N-acetylcysteine and azathioprine was stopped early due to an increased risk of death and hospitalization.⁴⁹ Collectively, these data suggest that corticosteroids confer no benefit and are potentially harmful. Their use in IPF is discouraged, and the joint international guidelines recommend against immunosuppression to treat IPF.¹⁶

Other treatments

The guidelines offer additional suggestions for the management of IPF.

Preliminary evidence suggests that microaspiration associated with abnormal gastroesophageal acid reflux is a risk factor for IPF. As such, there is a weak recommendation for aggressive treatment of reflux disease.⁵⁰ However, because evidence suggests that proton-pump inhibitor therapy may be associated with adverse renal or central nervous system effects, this recommendation bears caution. It is hoped that ongoing studies will provide further insight into the role of acid-suppression in the management of IPF.^51,52

Further treatment recommendations include best supportive management such as supplemental oxygen, pulmonary rehabilitation, and vaccinations.

Prompt referral for lung transplant is imperative. IPF is now the most common indication for lung transplant, and given the poor overall prognosis of advanced IPF, transplant confers a survival benefit in appropriately selected patients.^53,54  Table 2 provides an evidence-based checklist for the workup and management of IPF.

ACUTE EXACERBATIONS OF IPF

The unpredictable nature of IPF can manifest in the form of acute exacerbations without an identifiable cause. The loosely defined diagnostic criteria for the diagnosis of acute exacerbations are a previous or new diagnosis of IPF, worsening or development of dyspnea in the last 30 days, and new bilateral ground-glass or consolidative changes with a background of UIP on HRCT.¹⁶

A new definition has been proposed⁵⁵ to facilitate research in the characterization and treatment of acute exacerbations of IPF. The new definition includes all causes of respiratory deterioration except for heart failure and volume overload. It is less strict about the 30-day time frame. This newer definition is based on the lack of evidence differentiating outcomes when an acute deterioration is associated with known or unknown etiologies.⁵⁵

The incidence of acute exacerbations is variable, with a 1- and 3-year incidence ranging between 8.6% and 23.9% depending on the criteria used.⁵⁶ In general, acute exacerbations carry a grim prognosis, with a median life expectancy of 2.2 months.⁵⁷

There is no approved therapy for exacerbations of IPF. Rather, treatment is mainly supportive with supplemental oxygen and mechanical ventilation. Current guidelines have a weak recommendation for the use of corticosteroids, but there are no recommendations regarding dose, route, or duration of therapy. Other treatments, primarily immunomodulatory agents, have been suggested but lack evidence of benefit.

Acknowledgments: Pathology images were provided by Carol Farver, MD, Pathology Institute, Cleveland Clinic. Radiology images were provided by Ruchi Yadav, MD, Imaging Institute, Cleveland Clinic.

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal lung disease that generally affects older adults. It is characterized by a radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) that has no other known etiology.

See related editorial

Accurate diagnosis of IPF is crucial. We recommend early referral to a center specializing in interstitial lung disease to confirm the diagnosis, start appropriate therapy, advise the patient on prognosis and enrollment in disease registries and clinical trials, and determine candidacy for lung transplant.

Primary care physicians are uniquely positioned to encounter patients with IPF, whether because of a patient complaint or as an incidental finding on computed tomography. The goal of this article is to delineate the features of IPF so that it may be recognized early and thus expedite referral to a center with expertise in interstitial lung disease for a thorough evaluation and appropriate management.

WHAT IS IDIOPATHIC PULMONARY FIBROSIS?

MORE COMMON THAN ONCE THOUGHT

The true incidence and prevalence of IPF are difficult to assess. IPF is generally considered a rare disease, but it is more common than once thought. In 2011, Raghu et al³ estimated the prevalence in Medicare beneficiaries to be 495 cases per 100,000. Based on this estimate and the current US population, up to 160,000 Americans could have IPF.⁴ Raghu et al also showed that IPF more often affects adults over age 65, which suggests that as the US population ages, the incidence of IPF may rise. Studies have also reported an increased incidence of IPF worldwide.⁵

Further, with the rising use of low-dose computed tomography to screen for lung cancer, more incidental cases of IPF will likely be found.^6–8

Older data showed a lag from symptom onset to accurate diagnosis of 1 to 2 years.⁹ A more recent study found a lag in referral of patients with IPF to tertiary care centers, and this delay was associated with a higher rate of death independent of disease severity.¹⁰

TYPICALLY PROGRESSIVE, OFTEN FATAL

IPF is typically progressive and limited to the lungs, and it portends a poor prognosis. The median survival is commonly cited as 2 to 5 years from diagnosis, although this is based on older observations that may not reflect current best practice and newer therapies. More recent studies suggest higher survival rates if patients have preserved lung function.¹¹

As the name indicates, the etiology of IPF is unknown, but studies have indicated genetic underpinnings in a notable proportion of cases.¹² Regardless of the cause, the pathogenesis and progression of IPF are thought to be the result of an abnormal and persistent wound-repair response. The progressive deposition of scar tissue disrupts normal lung architecture and function, eventually causing clinical disease.¹³

SYMPTOMS AND KEY FEATURES

Patients with IPF typically present with the insidious onset of dyspnea on exertion, with or without chronic cough. Risk factors include male sex, increasing age, and a history of smoking. Patients with undiagnosed IPF who present with dyspnea and a history of smoking are often treated empirically for chronic obstructive pulmonary disease (COPD).

Rales are a common finding on auscultation in IPF, and this can lead to an exhaustive cardiac evaluation and empiric treatment for heart failure. Digital clubbing is also relatively common.¹⁴ Hypoxemia with exertion is another common feature that also often correlates with disease severity and prognosis. Resting hypoxemia is more common in advanced disease.

On spirometry, patients with IPF typically demonstrate restrictive physiology, suggested by a normal or elevated ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁/FVC) (> 70% predicted or above the lower limit of normal) combined with a lower than normal FVC. Restrictive physiology is definitively demonstrated by a decreased total lung capacity (< 80% predicted or below the lower limit of normal) on plethysmography. Impaired gas exchange, manifested by a decreased diffusing capacity of the lungs for carbon monoxide (DLCO) on pulmonary function testing, is also common. Because pulmonary perfusion is higher in the lung bases, where IPF is also predominant, the DLCO is often reduced to a greater extent than the FVC.

PROGNOSTIC INDICATORS

Clinicians typically view IPF as a relentless and progressive process, but its course is variable and can be uncertain in an individual patient (Figure 1).^15,16 Nevertheless, over time, most patients have a decline in lung function leading to respiratory failure. Respiratory failure, often preceded by a subacute deterioration (over weeks to months) or an acute deterioration (< 4 weeks), is the most common cause of death, but comorbid diseases such as lung cancer, infection, and heart failure are also common causes of death in these patients.^17,18

Predictors of mortality include worsening FVC, DLCO, symptoms, and physiologic impairment, manifested by a decline in the 6-minute walking test or worsening exertional hypoxemia.^19–22 Other common comorbidities linked with impaired quality of life and poor prognosis include obstructive sleep apnea, gastroesophageal reflux disease, and depression.^16,23 Retrospective studies suggest that most IPF patients die 2 to 5 years after symptom onset. With the lag from symptom onset to final diagnosis, the average life expectancy is as little as 2 years from the time of diagnosis.^9,18,24,25

Two staging systems have been developed to predict short-term and long-term mortality risk based on sex, age, and physiologic parameters.^23,24 The GAP (gender, age, physiology) index provides an estimate of the risk of death for a cohort of patients: a score of 0 to 8 is calculated, and the score is then categorized as stage I, II, or III. Each stage is associated with 1-, 2-, and 3-year mortality rates, with stage III having the highest rates. The GAP calculator (www.acponline.org/journals/annals/extras/gap) provides an estimate of the risk of death for an individual patient. The application of these tools for the management of IPF is evolving; however, they may be helpful for counseling patients about disease prognosis.

CLUES TO DIAGNOSIS

Histologic patterns

UIP on histologic study is also seen in fibrotic lung diseases other than IPF, including connective tissue disease-associated interstitial lung disease, inhalational or occupational interstitial lung disease, and chronic hypersensitivity pneumonitis.^26–29 Consequently, the diagnosis of IPF requires exclusion of other known causes of UIP.

According to the 2011 guidelines,¹⁶ the histology of interstitial lung disease can be categorized as definite UIP, probable UIP, or possible UIP, or as an atypical pattern suggesting another diagnosis. If no definite cause of the interstitial lung abnormality is found, the level of certainty of the histopathologic pattern of UIP helps formulate the clinical diagnosis and management plan.

Clues on computed tomography

The UIP nomenclature also describes patterns on high-resolution computed tomography (HRCT). HRCT is done without contrast and produces thin-sliced images (usually < 1.5 mm) in inspiratory, expiratory, and prone views; this allows detection of air trapping, which may indicate an airway-centric alternative diagnosis.

On HRCT, UIP appears as reticular opacities, often with traction bronchiectasis or bronchiolectasis, usually with a basilar and peripheral predominance. Honeycombing is a key feature and appears as clustered cystic spaces with well-defined walls in the periphery of the lung parenchyma. Ground-glass opacities are not a prominent feature of UIP, and although they do not exclude a UIP pattern, they should spur consideration of other diagnoses.¹⁶ Reactive mediastinal and hilar lymphadenopathy is another common feature of UIP.

When evaluating results of HRCT for UIP, the radiologist categorizes the pattern as definite UIP, possible UIP, or inconsistent. The definite pattern meets all the above features and has none of the features suggesting an alternative diagnosis (Figure 3). The possible pattern includes all the above features with the exception of honeycombing. If the predominant features on HRCT include any atypical finding listed above, then the study is considered inconsistent with UIP. If the pattern on HRCT is considered definite, evaluation of pathology is not necessary. If the pattern is categorized as possible or is inconsistent, then surgical lung biopsy-confirmed UIP is necessary for the definitive diagnosis of IPF.

However, evidence is emerging that in the correct clinical scenario, possible UIP behaves similarly to definite UIP and may be sufficient to make the clinical diagnosis of IPF even without surgical biopsy confirmation.³⁰

A DIAGNOSTIC ALGORITHM FOR IPF

Given the multitude of interstitial lung diseases, their complexities, and the lack of a gold standard definitive diagnostic test, the diagnosis of IPF can be difficult, requiring the integration of clinical, radiologic, and, if necessary, pathologic findings.

Demographic features

The patient’s demographic features and risk factors dictate the initial clinical suspicion of IPF compared with other interstitial lung diseases. The incidence of IPF increases with age, and IPF is more common in men. A history of smoking is another risk factor.³¹ A 45-year-old never-smoker is much less likely to have IPF than a 70-year-old former smoker, and a 70-year-old man is more likely to have IPF than a woman of the same age. Thus, the finding of interstitial lung disease in a patient with a demographic profile that is not typical (ie, a younger woman who never smoked) should prompt an exhaustive investigation for another diagnosis such as hypersensitivity pneumonitis or connective tissue disease.

Key elements of the history

After considering the demographic profile and risk factors, the next step in the evaluation is a thorough and accurate medical history. This should include assessment of the severity of dyspnea and cough, signs and symptoms of connective tissue disease (eg, arthralgias, sicca symptoms, Raynaud phenomenon, difficulty swallowing), and gastroesophageal reflux disease, which can be associated with connective tissue disease and, independently, with IPF.

It is also important to identify any environmental exposures that suggest pneumoconiosis or chronic hypersensitivity pneumonitis. The most common risk factors for hypersensitivity pneumonitis are birds and bird feathers, molds, fungi, hot tub use, and some industrial chemicals.³²

A medication history is important. Many medications are associated with interstitial lung disease, but amiodarone, bleomycin, methotrexate, and nitrofurantoin are among the common offenders.³³

A thorough family history is necessary, as there are familial forms of IPF.

Focus of the physical examination

The physical examination must include careful auscultation for rales. While rales are not specific for IPF, they are the most common pulmonary abnormality. Detailed skin, musculoskeletal, and cardiovascular examinations are also important to evaluate for rheumatologic signs, clubbing, or evidence of heart failure or pulmonary hypertension.

Laboratory tests

Laboratory testing should include a serologic autoantibody panel to evaluate for connective tissue diseases that can manifest as interstitial lung disease, including rheumatoid arthritis, dermatopolymyositis, scleroderma, Sjögren syndrome, and undifferentiated or mixed connective tissue disease. Typical preliminary laboratory tests are antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. Others may include anticyclic citrullinated peptide (anti-CCP), anti-Scl-70, anti-RNP, anti-SS-A, anti-SS-B, and anti-Jo-1.¹⁶ The breadth of the panel should depend on patient demographics and findings in the history or physical examination that increase or decrease the likelihood of a connective tissue disease.

Lung function testing

Assessing the patient’s pulmonary physiology should include spirometry, DLCO, and body plethysmography (lung volumes). In most cases, IPF manifests with restrictive physiology. Once restrictive physiology is confirmed with a low total lung capacity, FVC testing can be used as a longitudinal surrogate, as it is less expensive and easier for the patient to perform. In general, a lower total lung capacity or FVC indicates more severe impairment.

The DLCO serves as another marker of severity but is less reliable due to baseline variability and difficulties performing the maneuver.

A 6-minute walk test is another crucial physiologic assessment tool that can quantify exertional hypoxemia and functional status (ie, distance walked), and can assist in prognosis.

Imaging

Most patients undergo chest radiography in the workup for undiagnosed dyspnea. However, chest radiography is not adequate to formulate an accurate diagnosis in suspected interstitial lung disease, and a normal radiograph cannot exclude changes that might reflect early phases of the disease. As the disease progresses, the plain radiograph can show reticulonodular opacities and honeycombing in the peripheral and lower lung zones (Figure 3).³⁴

The decision whether to order HRCT in the workup for a patient who has dyspnea and a normal chest radiograph is challenging. We recommend cross-sectional imaging when physiologic testing shows restriction or low DLCO, or when there is a high index of suspicion for underlying lung disease as the cause of symptoms.

Expert consultation can aid with this decision, especially when the underlying cause of dyspnea remains unclear after initial studies have been completed. Otherwise, HRCT is an essential test in the evaluation of interstitial lung disease.

Bronchoscopy’s role controversial

If the pattern on HRCT is nondiagnostic, then surgical biopsy is necessary, and the diagnosis of IPF requires a histologic pattern of UIP as described above.^16,35

Although bronchoscopy can be valuable if an alternative diagnosis such as sarcoidosis or chronic hypersensitivity pneumonitis is suspected, the role of bronchoscopic biopsy in the workup of IPF is controversial. The patchy nature of UIP does not lend itself to the relatively small biopsy samples obtained through bronchoscopy.^36,37

Surgical biopsy options

The favored biopsy approach is surgical, using either an open or a video-assisted thoracoscopic technique. The latter is preferred as it is less invasive, requires a shorter length of hospital stay, and allows a faster recovery.³⁸ Bronchoscopic cryobiopsy, currently under investigation, is a potentially valuable tool whose role in diagnosing IPF is evolving.

Frequently, neither HRCT nor surgical lung biopsy demonstrates UIP, making the definitive diagnosis of IPF difficult. Moreover, some patients with nondiagnostic HRCT results are unable to tolerate surgical lung biopsy because of severely impaired lung function or other comorbidities.

The role of multidisciplinary discussions

When surgical lung biopsy is not possible, current practice at leading centers uses a multidisciplinary approach to allow for a confident diagnosis.^30,39 Discussions take place between pulmonologists, pathologists, radiologists, and other specialists to collectively consider all aspects of a case before rendering a consensus opinion on the diagnosis and the management plan. If the discussion leads to a consensus diagnosis of IPF, then the patient’s clinician can move forward with treatment options. If not, the group can recommend further workup or alternative diagnoses and treatment regimens. The multidisciplinary group is also well positioned to consider the relative risks and benefits of moving forward with surgical lung biopsy for individual patients.

This approach illustrates the importance of referring these patients to centers of excellence in diagnosing and managing complex cases of interstitial lung disease, including IPF.⁴⁰

TREATMENT OF IPF

Antifibrotic therapy

Antifibrotic therapy is a choice between pirfenidone and nintedanib.

Pirfenidone, which has an undefined molecular target, was approved based on the results of 3 trials.^41,42 Pooled analyses from these trials showed a reduction in the decline from baseline in FVC percent predicted and improved progression-free survival.⁴³ Pooled and meta-analyses of pirfenidone clinical trials have shown a mortality benefit, although no individual study has shown such an effect on mortality rates.⁴⁴

The major adverse effects of pirfenidone are gastrointestinal distress and photosensitivity rash.

Nintedanib is a triple tyrosine kinase inhibitor that broadly targets fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptors. Combined analysis of 2 concurrent trials⁴⁵ showed that nintedanib reduced the decline in FVC, similarly to pirfenidone. The major adverse event associated with nintedanib was diarrhea. Since it inhibits vascular endothelial growth factor, there is a risk of hematologic complications such as bleeding or clotting events.

Because pirfenidone and nintedanib can increase aminotransferase levels, regular monitoring is recommended.

To date, no trial has compared pirfenidone and nintedanib in terms of their efficacy and tolerability. Therefore, the choice of agent is based on the patient’s preference after a discussion of potential risks and expected benefits, a review of each drug’s side effects, and consideration of comorbid conditions and physician experience.

Patients need to understand that these drugs slow the rate of decline in FVC but have not been shown to improve symptoms or functional status.

Corticosteroids are not routine

Corticosteroids should not be used routinely in the treatment of IPF. Although steroids, alone or in combination with other immunosuppressive medications, were commonly used for IPF in the past, such use was not based on results of randomized controlled trials.⁴⁶ Retrospective controlled studies have failed to show that corticosteroids improve mortality rates in IPF; indeed, they have shown that corticosteroids confer substantial morbidity.^47,48 In addition, a randomized controlled trial combining corticosteroids with N-acetylcysteine and azathioprine was stopped early due to an increased risk of death and hospitalization.⁴⁹ Collectively, these data suggest that corticosteroids confer no benefit and are potentially harmful. Their use in IPF is discouraged, and the joint international guidelines recommend against immunosuppression to treat IPF.¹⁶

Other treatments

The guidelines offer additional suggestions for the management of IPF.

Preliminary evidence suggests that microaspiration associated with abnormal gastroesophageal acid reflux is a risk factor for IPF. As such, there is a weak recommendation for aggressive treatment of reflux disease.⁵⁰ However, because evidence suggests that proton-pump inhibitor therapy may be associated with adverse renal or central nervous system effects, this recommendation bears caution. It is hoped that ongoing studies will provide further insight into the role of acid-suppression in the management of IPF.^51,52

Further treatment recommendations include best supportive management such as supplemental oxygen, pulmonary rehabilitation, and vaccinations.

Prompt referral for lung transplant is imperative. IPF is now the most common indication for lung transplant, and given the poor overall prognosis of advanced IPF, transplant confers a survival benefit in appropriately selected patients.^53,54  Table 2 provides an evidence-based checklist for the workup and management of IPF.

ACUTE EXACERBATIONS OF IPF

The unpredictable nature of IPF can manifest in the form of acute exacerbations without an identifiable cause. The loosely defined diagnostic criteria for the diagnosis of acute exacerbations are a previous or new diagnosis of IPF, worsening or development of dyspnea in the last 30 days, and new bilateral ground-glass or consolidative changes with a background of UIP on HRCT.¹⁶

A new definition has been proposed⁵⁵ to facilitate research in the characterization and treatment of acute exacerbations of IPF. The new definition includes all causes of respiratory deterioration except for heart failure and volume overload. It is less strict about the 30-day time frame. This newer definition is based on the lack of evidence differentiating outcomes when an acute deterioration is associated with known or unknown etiologies.⁵⁵

The incidence of acute exacerbations is variable, with a 1- and 3-year incidence ranging between 8.6% and 23.9% depending on the criteria used.⁵⁶ In general, acute exacerbations carry a grim prognosis, with a median life expectancy of 2.2 months.⁵⁷

There is no approved therapy for exacerbations of IPF. Rather, treatment is mainly supportive with supplemental oxygen and mechanical ventilation. Current guidelines have a weak recommendation for the use of corticosteroids, but there are no recommendations regarding dose, route, or duration of therapy. Other treatments, primarily immunomodulatory agents, have been suggested but lack evidence of benefit.

Acknowledgments: Pathology images were provided by Carol Farver, MD, Pathology Institute, Cleveland Clinic. Radiology images were provided by Ruchi Yadav, MD, Imaging Institute, Cleveland Clinic.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrosing interstitial lung disease associated with a high burden of morbidity and death.¹ A clinical diagnosis of IPF is made only after careful interpretation of integrated clinical, radiologic, and often histopathologic data.

See related article

Interstitial lung disease encompasses a broad spectrum of parenchymal lung diseases, and a classification of IPF is restricted to a lung injury pattern of usual interstitial pneumonia (UIP) based on high-resolution computed tomography or surgical lung biopsy, after all known causes of UIP have been excluded.¹

However, a lung injury pattern of UIP is not synonymous with IPF, as UIP can be seen with connective tissue disease, chronic hypersensitivity pneumonitis, drug toxicity, and sarcoidosis.¹ As such, rendering a diagnosis of IPF requires a thorough evaluation to exclude such diverse potential etiologies.

In this issue of the Cleveland Clinic Journal of Medicine, Tolle and colleagues² provide an up-to-date, broad overview of IPF focused on what the primary care provider needs to know about the disease. Their review is timely and serves as a useful primer for the practicing clinician.

The field of IPF is actively evolving, as this era has been witness to a recent paradigm shift in pharmacologic management. Immunosuppression is no longer recommended³ and may even be harmful.⁴ And the US Food and Drug Administration has approved 2 antifibrotic drugs—pirfenidone and nintedanib—that have been shown to delay progression of IPF.^5,6

Primary care providers have a unique opportunity to play an integral role in the evaluation and care of patients with IPF, in particular with earlier disease recognition, initial disease assessment, and timely specialty consultative referral—as well as implementing a comprehensive longitudinal care plan.

EARLIER DISEASE RECOGNITION

IPF is a rare disease primarily affecting men over the age of 65.¹ It is reasonable to presume that many or most of these individuals ultimately diagnosed with IPF are already seeking routine care for existing common medical conditions such as hypertension or dyslipidemia—or at least having periodic routine health maintenance assessments. Such evaluations may offer an opportunity for earlier recognition of an underlying fibrotic lung disease that may be subclinical in nature.

IPF has a lower-lung zone predominance. The importance of chest auscultation, particularly listening carefully to the lung bases, is poignantly highlighted in a recent editorial: “It is time that the stethoscope draped around the neck of physicians, which tends to be used for identification purposes rather than for medical diagnosis, be also the (presently only) genuine tool for an earlier diagnosis of IPF.”⁷

Advances in imaging also provide an opportunity for earlier diagnosis. Many patients undergo screening computed tomography for coronary calcium scoring or lung cancer surveillance, and these studies may incidentally identify subtle interstitial lung abnormalities. These incidental findings should lead to further investigation, as they have been shown to be functionally important and carry risk of progression to clinical interstitial lung disease.⁸

 

 

INITIAL ASSESSMENT, TIMELY REFERRAL

But whether evidence of interstitial lung disease is detected incidentally or during testing for respiratory symptoms, further evaluation is necessary. Primary care providers are uniquely positioned to initiate the assessment and to expedite and guide further evaluation and specialty referral consultation to ensure an accurate diagnosis. They can also help grade the severity of the disease with pulmonary function testing, oxygen assessments at rest and with ambulation, and ordering thoracic high-resolution computed tomography to provide valuable information about disease extent and interstitial lung disease pattern.

General practitioners may assess for features suggesting connective tissue disease that would warrant specific serologic testing and dedicated rheumatologic consultation.

Finally, given the rarity, complexity, and challenges of interstitial lung disease, an effective multidisciplinary team consisting of clinicians, radiologists, and pathologists enhances diagnostic accuracy.⁹ This may also help general practitioners deviate from normal patterns of referral to general pulmonary providers, and instead refer patients to specialized centers with dedicated clinical and research expertise in interstitial lung disease.

IMPLEMENTING A COMPREHENSIVE, LONGITUDINAL CARE PLAN

The primary care practitioner often has developed long-term relationships with patients ultimately diagnosed with IPF, and because of this is particularly well positioned to help implement a collaborative and comprehensive care plan. Logistical realities such as distance to a specialty center, limited insurance coverage for specialty visits, and limited specialty availability all reinforce the central role that primary care practitioners play in ensuring that patients adhere to a comprehensive treatment program.

Primary providers may be very experienced and more inclined to manage a number of the common and often important comorbid conditions seen in patients with IPF, such as gastroesophageal reflux disease, obstructive sleep apnea, and depression. Reinforcing to the patient the need to adhere to adjunctive therapies such as supplemental oxygen and pulmonary rehabilitation is another key opportunity to actively engage in the management of patients with IPF.

Primary providers may also play a central role in IPF care through prevention strategies such as smoking cessation and ensuring appropriate immunization against seasonal influenza, pneumococcal pneumonia, and pertussis, among other age-appropriate vaccinations.

With the introduction and expansion of use of nintedanib and pirfenidone for IPF over the past few years, general practitioners may be called on to help manage common gastrointestinal side effects associated with pirfenidone (primarily nausea) and nintedanib (primarily diarrhea), and to be aware of potential drug-drug interactions and other medication-related toxicities.

Finally, as IPF remains a progressive disease, primary care practitioners are often well positioned to help implement palliative care, hospice care, and end-of-life care.

Despite recent advances in treatment, IPF remains a devastating lung disease with a high degree of morbidity and mortality. It takes a village to help care for the IPF patient. And as key members of the healthcare team, primary care providers have unique and important opportunities to help in the early recognition, thorough assessment, and comprehensive management of patients with IPF.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrosing interstitial lung disease associated with a high burden of morbidity and death.¹ A clinical diagnosis of IPF is made only after careful interpretation of integrated clinical, radiologic, and often histopathologic data.

See related article

Interstitial lung disease encompasses a broad spectrum of parenchymal lung diseases, and a classification of IPF is restricted to a lung injury pattern of usual interstitial pneumonia (UIP) based on high-resolution computed tomography or surgical lung biopsy, after all known causes of UIP have been excluded.¹

However, a lung injury pattern of UIP is not synonymous with IPF, as UIP can be seen with connective tissue disease, chronic hypersensitivity pneumonitis, drug toxicity, and sarcoidosis.¹ As such, rendering a diagnosis of IPF requires a thorough evaluation to exclude such diverse potential etiologies.

In this issue of the Cleveland Clinic Journal of Medicine, Tolle and colleagues² provide an up-to-date, broad overview of IPF focused on what the primary care provider needs to know about the disease. Their review is timely and serves as a useful primer for the practicing clinician.

The field of IPF is actively evolving, as this era has been witness to a recent paradigm shift in pharmacologic management. Immunosuppression is no longer recommended³ and may even be harmful.⁴ And the US Food and Drug Administration has approved 2 antifibrotic drugs—pirfenidone and nintedanib—that have been shown to delay progression of IPF.^5,6

Primary care providers have a unique opportunity to play an integral role in the evaluation and care of patients with IPF, in particular with earlier disease recognition, initial disease assessment, and timely specialty consultative referral—as well as implementing a comprehensive longitudinal care plan.

EARLIER DISEASE RECOGNITION

IPF is a rare disease primarily affecting men over the age of 65.¹ It is reasonable to presume that many or most of these individuals ultimately diagnosed with IPF are already seeking routine care for existing common medical conditions such as hypertension or dyslipidemia—or at least having periodic routine health maintenance assessments. Such evaluations may offer an opportunity for earlier recognition of an underlying fibrotic lung disease that may be subclinical in nature.

IPF has a lower-lung zone predominance. The importance of chest auscultation, particularly listening carefully to the lung bases, is poignantly highlighted in a recent editorial: “It is time that the stethoscope draped around the neck of physicians, which tends to be used for identification purposes rather than for medical diagnosis, be also the (presently only) genuine tool for an earlier diagnosis of IPF.”⁷

Advances in imaging also provide an opportunity for earlier diagnosis. Many patients undergo screening computed tomography for coronary calcium scoring or lung cancer surveillance, and these studies may incidentally identify subtle interstitial lung abnormalities. These incidental findings should lead to further investigation, as they have been shown to be functionally important and carry risk of progression to clinical interstitial lung disease.⁸

 

 

INITIAL ASSESSMENT, TIMELY REFERRAL

But whether evidence of interstitial lung disease is detected incidentally or during testing for respiratory symptoms, further evaluation is necessary. Primary care providers are uniquely positioned to initiate the assessment and to expedite and guide further evaluation and specialty referral consultation to ensure an accurate diagnosis. They can also help grade the severity of the disease with pulmonary function testing, oxygen assessments at rest and with ambulation, and ordering thoracic high-resolution computed tomography to provide valuable information about disease extent and interstitial lung disease pattern.

General practitioners may assess for features suggesting connective tissue disease that would warrant specific serologic testing and dedicated rheumatologic consultation.

Finally, given the rarity, complexity, and challenges of interstitial lung disease, an effective multidisciplinary team consisting of clinicians, radiologists, and pathologists enhances diagnostic accuracy.⁹ This may also help general practitioners deviate from normal patterns of referral to general pulmonary providers, and instead refer patients to specialized centers with dedicated clinical and research expertise in interstitial lung disease.

IMPLEMENTING A COMPREHENSIVE, LONGITUDINAL CARE PLAN

The primary care practitioner often has developed long-term relationships with patients ultimately diagnosed with IPF, and because of this is particularly well positioned to help implement a collaborative and comprehensive care plan. Logistical realities such as distance to a specialty center, limited insurance coverage for specialty visits, and limited specialty availability all reinforce the central role that primary care practitioners play in ensuring that patients adhere to a comprehensive treatment program.

Primary providers may be very experienced and more inclined to manage a number of the common and often important comorbid conditions seen in patients with IPF, such as gastroesophageal reflux disease, obstructive sleep apnea, and depression. Reinforcing to the patient the need to adhere to adjunctive therapies such as supplemental oxygen and pulmonary rehabilitation is another key opportunity to actively engage in the management of patients with IPF.

Primary providers may also play a central role in IPF care through prevention strategies such as smoking cessation and ensuring appropriate immunization against seasonal influenza, pneumococcal pneumonia, and pertussis, among other age-appropriate vaccinations.

With the introduction and expansion of use of nintedanib and pirfenidone for IPF over the past few years, general practitioners may be called on to help manage common gastrointestinal side effects associated with pirfenidone (primarily nausea) and nintedanib (primarily diarrhea), and to be aware of potential drug-drug interactions and other medication-related toxicities.

Finally, as IPF remains a progressive disease, primary care practitioners are often well positioned to help implement palliative care, hospice care, and end-of-life care.

Despite recent advances in treatment, IPF remains a devastating lung disease with a high degree of morbidity and mortality. It takes a village to help care for the IPF patient. And as key members of the healthcare team, primary care providers have unique and important opportunities to help in the early recognition, thorough assessment, and comprehensive management of patients with IPF.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrosing interstitial lung disease associated with a high burden of morbidity and death.¹ A clinical diagnosis of IPF is made only after careful interpretation of integrated clinical, radiologic, and often histopathologic data.

See related article

Interstitial lung disease encompasses a broad spectrum of parenchymal lung diseases, and a classification of IPF is restricted to a lung injury pattern of usual interstitial pneumonia (UIP) based on high-resolution computed tomography or surgical lung biopsy, after all known causes of UIP have been excluded.¹

However, a lung injury pattern of UIP is not synonymous with IPF, as UIP can be seen with connective tissue disease, chronic hypersensitivity pneumonitis, drug toxicity, and sarcoidosis.¹ As such, rendering a diagnosis of IPF requires a thorough evaluation to exclude such diverse potential etiologies.

In this issue of the Cleveland Clinic Journal of Medicine, Tolle and colleagues² provide an up-to-date, broad overview of IPF focused on what the primary care provider needs to know about the disease. Their review is timely and serves as a useful primer for the practicing clinician.

The field of IPF is actively evolving, as this era has been witness to a recent paradigm shift in pharmacologic management. Immunosuppression is no longer recommended³ and may even be harmful.⁴ And the US Food and Drug Administration has approved 2 antifibrotic drugs—pirfenidone and nintedanib—that have been shown to delay progression of IPF.^5,6

Primary care providers have a unique opportunity to play an integral role in the evaluation and care of patients with IPF, in particular with earlier disease recognition, initial disease assessment, and timely specialty consultative referral—as well as implementing a comprehensive longitudinal care plan.

EARLIER DISEASE RECOGNITION

IPF is a rare disease primarily affecting men over the age of 65.¹ It is reasonable to presume that many or most of these individuals ultimately diagnosed with IPF are already seeking routine care for existing common medical conditions such as hypertension or dyslipidemia—or at least having periodic routine health maintenance assessments. Such evaluations may offer an opportunity for earlier recognition of an underlying fibrotic lung disease that may be subclinical in nature.

IPF has a lower-lung zone predominance. The importance of chest auscultation, particularly listening carefully to the lung bases, is poignantly highlighted in a recent editorial: “It is time that the stethoscope draped around the neck of physicians, which tends to be used for identification purposes rather than for medical diagnosis, be also the (presently only) genuine tool for an earlier diagnosis of IPF.”⁷

Advances in imaging also provide an opportunity for earlier diagnosis. Many patients undergo screening computed tomography for coronary calcium scoring or lung cancer surveillance, and these studies may incidentally identify subtle interstitial lung abnormalities. These incidental findings should lead to further investigation, as they have been shown to be functionally important and carry risk of progression to clinical interstitial lung disease.⁸

 

 

INITIAL ASSESSMENT, TIMELY REFERRAL

But whether evidence of interstitial lung disease is detected incidentally or during testing for respiratory symptoms, further evaluation is necessary. Primary care providers are uniquely positioned to initiate the assessment and to expedite and guide further evaluation and specialty referral consultation to ensure an accurate diagnosis. They can also help grade the severity of the disease with pulmonary function testing, oxygen assessments at rest and with ambulation, and ordering thoracic high-resolution computed tomography to provide valuable information about disease extent and interstitial lung disease pattern.

General practitioners may assess for features suggesting connective tissue disease that would warrant specific serologic testing and dedicated rheumatologic consultation.

Finally, given the rarity, complexity, and challenges of interstitial lung disease, an effective multidisciplinary team consisting of clinicians, radiologists, and pathologists enhances diagnostic accuracy.⁹ This may also help general practitioners deviate from normal patterns of referral to general pulmonary providers, and instead refer patients to specialized centers with dedicated clinical and research expertise in interstitial lung disease.

IMPLEMENTING A COMPREHENSIVE, LONGITUDINAL CARE PLAN

The primary care practitioner often has developed long-term relationships with patients ultimately diagnosed with IPF, and because of this is particularly well positioned to help implement a collaborative and comprehensive care plan. Logistical realities such as distance to a specialty center, limited insurance coverage for specialty visits, and limited specialty availability all reinforce the central role that primary care practitioners play in ensuring that patients adhere to a comprehensive treatment program.

Primary providers may be very experienced and more inclined to manage a number of the common and often important comorbid conditions seen in patients with IPF, such as gastroesophageal reflux disease, obstructive sleep apnea, and depression. Reinforcing to the patient the need to adhere to adjunctive therapies such as supplemental oxygen and pulmonary rehabilitation is another key opportunity to actively engage in the management of patients with IPF.

Primary providers may also play a central role in IPF care through prevention strategies such as smoking cessation and ensuring appropriate immunization against seasonal influenza, pneumococcal pneumonia, and pertussis, among other age-appropriate vaccinations.

With the introduction and expansion of use of nintedanib and pirfenidone for IPF over the past few years, general practitioners may be called on to help manage common gastrointestinal side effects associated with pirfenidone (primarily nausea) and nintedanib (primarily diarrhea), and to be aware of potential drug-drug interactions and other medication-related toxicities.

Finally, as IPF remains a progressive disease, primary care practitioners are often well positioned to help implement palliative care, hospice care, and end-of-life care.

Despite recent advances in treatment, IPF remains a devastating lung disease with a high degree of morbidity and mortality. It takes a village to help care for the IPF patient. And as key members of the healthcare team, primary care providers have unique and important opportunities to help in the early recognition, thorough assessment, and comprehensive management of patients with IPF.

Lumbar puncture study revealed 34 nucleated cells/µL (94% lymphocytes), protein 58 mg/dL, and glucose 62 mg/dL. Cerebrospinal fluid Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption tests were reactive, confirming a diagnosis of ocular syphilis.

The patient was admitted to the hospital for treatment with intravenous penicillin G. After 5 days, he was discharged with instructions to complete a 10-day course of intravenous ceftriaxone (chosen for its ease of administration), for a total of 14 days of antibiotic therapy. His vision improved with treatment.

He continued to follow up with ophthalmology and infectious disease. Subsequent dilated fundus examinations showed resolution of pathology in the left eye, resolution of Roth spots in the right eye, and resolution of the subhyaloid hemorrhage. Repeat cerebrospinal fluid study examination was planned if the serum rapid plasma reagin had not become nonreactive 24 months after treatment.

RECOGNIZING AND MANAGING OCULAR SYPHILIS AND NEUROSYPHILIS

In addition to ocular syphilis and neurosyphilis, the differential diagnosis for Roth spots and disc edema on dilated funduscopy includes endocarditis, viral retinitis, and autoimmune or inflammatory conditions such as sarcoidosis and vasculitis.

In our patient, infectious endocarditis was considered, given his history of intermittent fevers and rigors, but it was ultimately ruled out by negative blood cultures and the absence of valvular vegetations on echocardiography.

The large subhyaloid hemorrhage raised suspicion of leukemia, but this was ruled out by the normal total white blood cell count and differential. HIV, herpetic retinitis, and toxoplasmosis were also considered, but laboratory tests for these infections were negative.

Typically, retinal precipitates are more characteristic of syphilitic retinitis and distinguish it from other infectious causes such as herpetic retinitis and toxoplasmosis.¹ Additionally, ocular syphilis more commonly manifests as uveitis or panuveitis.^1,2 Our patient’s ocular syphilis presented with white-centered retinal hemorrhages, subhyaloid hemorrhage, and optic disc edema.

Who is at highest risk?

About 90% of syphilis cases occur in men, and 81% occur in men who have sex with men. The US Centers for Disease Control and Prevention (CDC) thus recommends annual syphilis testing for men who have sex with men.³

Classically, syphilis was called “the great imitator” because it mimicked manifestations of other diseases. Patients with ocular manifestations of syphilis may not have other neurologic symptoms.^4,5 Nevertheless, cerebrospinal fluid examination should be done in all instances of ocular syphilis, as many patients with ocular syphilis have evidence of neurosyphilis on testing.² The CDC also recommends follow-up cerebrospinal fluid analysis to assess treatment response.² This was planned in our patient.

Lumbar puncture study revealed 34 nucleated cells/µL (94% lymphocytes), protein 58 mg/dL, and glucose 62 mg/dL. Cerebrospinal fluid Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption tests were reactive, confirming a diagnosis of ocular syphilis.

The patient was admitted to the hospital for treatment with intravenous penicillin G. After 5 days, he was discharged with instructions to complete a 10-day course of intravenous ceftriaxone (chosen for its ease of administration), for a total of 14 days of antibiotic therapy. His vision improved with treatment.

He continued to follow up with ophthalmology and infectious disease. Subsequent dilated fundus examinations showed resolution of pathology in the left eye, resolution of Roth spots in the right eye, and resolution of the subhyaloid hemorrhage. Repeat cerebrospinal fluid study examination was planned if the serum rapid plasma reagin had not become nonreactive 24 months after treatment.

RECOGNIZING AND MANAGING OCULAR SYPHILIS AND NEUROSYPHILIS

In addition to ocular syphilis and neurosyphilis, the differential diagnosis for Roth spots and disc edema on dilated funduscopy includes endocarditis, viral retinitis, and autoimmune or inflammatory conditions such as sarcoidosis and vasculitis.

In our patient, infectious endocarditis was considered, given his history of intermittent fevers and rigors, but it was ultimately ruled out by negative blood cultures and the absence of valvular vegetations on echocardiography.

The large subhyaloid hemorrhage raised suspicion of leukemia, but this was ruled out by the normal total white blood cell count and differential. HIV, herpetic retinitis, and toxoplasmosis were also considered, but laboratory tests for these infections were negative.

Typically, retinal precipitates are more characteristic of syphilitic retinitis and distinguish it from other infectious causes such as herpetic retinitis and toxoplasmosis.¹ Additionally, ocular syphilis more commonly manifests as uveitis or panuveitis.^1,2 Our patient’s ocular syphilis presented with white-centered retinal hemorrhages, subhyaloid hemorrhage, and optic disc edema.

Who is at highest risk?

About 90% of syphilis cases occur in men, and 81% occur in men who have sex with men. The US Centers for Disease Control and Prevention (CDC) thus recommends annual syphilis testing for men who have sex with men.³

Classically, syphilis was called “the great imitator” because it mimicked manifestations of other diseases. Patients with ocular manifestations of syphilis may not have other neurologic symptoms.^4,5 Nevertheless, cerebrospinal fluid examination should be done in all instances of ocular syphilis, as many patients with ocular syphilis have evidence of neurosyphilis on testing.² The CDC also recommends follow-up cerebrospinal fluid analysis to assess treatment response.² This was planned in our patient.

Lumbar puncture study revealed 34 nucleated cells/µL (94% lymphocytes), protein 58 mg/dL, and glucose 62 mg/dL. Cerebrospinal fluid Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption tests were reactive, confirming a diagnosis of ocular syphilis.

The patient was admitted to the hospital for treatment with intravenous penicillin G. After 5 days, he was discharged with instructions to complete a 10-day course of intravenous ceftriaxone (chosen for its ease of administration), for a total of 14 days of antibiotic therapy. His vision improved with treatment.

He continued to follow up with ophthalmology and infectious disease. Subsequent dilated fundus examinations showed resolution of pathology in the left eye, resolution of Roth spots in the right eye, and resolution of the subhyaloid hemorrhage. Repeat cerebrospinal fluid study examination was planned if the serum rapid plasma reagin had not become nonreactive 24 months after treatment.

RECOGNIZING AND MANAGING OCULAR SYPHILIS AND NEUROSYPHILIS

In addition to ocular syphilis and neurosyphilis, the differential diagnosis for Roth spots and disc edema on dilated funduscopy includes endocarditis, viral retinitis, and autoimmune or inflammatory conditions such as sarcoidosis and vasculitis.

In our patient, infectious endocarditis was considered, given his history of intermittent fevers and rigors, but it was ultimately ruled out by negative blood cultures and the absence of valvular vegetations on echocardiography.

The large subhyaloid hemorrhage raised suspicion of leukemia, but this was ruled out by the normal total white blood cell count and differential. HIV, herpetic retinitis, and toxoplasmosis were also considered, but laboratory tests for these infections were negative.

Typically, retinal precipitates are more characteristic of syphilitic retinitis and distinguish it from other infectious causes such as herpetic retinitis and toxoplasmosis.¹ Additionally, ocular syphilis more commonly manifests as uveitis or panuveitis.^1,2 Our patient’s ocular syphilis presented with white-centered retinal hemorrhages, subhyaloid hemorrhage, and optic disc edema.

Who is at highest risk?

About 90% of syphilis cases occur in men, and 81% occur in men who have sex with men. The US Centers for Disease Control and Prevention (CDC) thus recommends annual syphilis testing for men who have sex with men.³

Classically, syphilis was called “the great imitator” because it mimicked manifestations of other diseases. Patients with ocular manifestations of syphilis may not have other neurologic symptoms.^4,5 Nevertheless, cerebrospinal fluid examination should be done in all instances of ocular syphilis, as many patients with ocular syphilis have evidence of neurosyphilis on testing.² The CDC also recommends follow-up cerebrospinal fluid analysis to assess treatment response.² This was planned in our patient.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

For many women, the postmenopausal loss of estrogen is associated with uncomfortable genitourinary symptoms, collectively referred to as the genitourinary syndrome of menopause (GSM). But despite the prevalence of GSM and the availability of treatments, most women do not seek relief.

This article reviews the syndrome and offers advice on how to talk about it with patients and what treatment options to consider.

A SYNDROME RECENTLY DEFINED

The term GSM and its definition were approved by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health in 2014.¹ It replaces older terms such as vulvovaginal atrophy, urogenital atrophy, and atrophic vaginitis.

GSM refers collectively to the symptoms associated with estrogen loss after menopause that adversely affect the vulvovaginal area and lower urinary tract. The most common symptoms are vulvovaginal dryness, burning, or irritation; sexual pain from inadequate lubrication; and urinary urgency, dysuria, or recurrent urinary tract infection.^1,2

The definition notes that symptoms are self-reported as bothersome and are not the result of another disorder. Symptoms may be chronic and progressive, are not likely to resolve without treatment (pharmacologic or nonpharmacologic), and can have a significant negative impact on a woman’s quality of life and sexual health.^1,2

COMMON BUT UNDERTREATED

From 40% to 60% of postmenopausal women experience GSM, but few seek treatment.³ Nevertheless, most postmenopausal women remain sexually active. In a 2008 survey of 94,000 postmenopausal women ages 50 to 79, 52% reported that they had been sexually active with a partner in the past year.⁴ However, 45% of postmenopausal women experienced unpleasant vaginal symptoms, according to a 2012 international survey of 3,520 postmenopausal women ages 55 to 65.⁵ In this survey, most respondents (75%) felt that vaginal symptoms had a negative impact on their life, but only 4% connected their symptoms to the vulvovaginal atrophy that resulted from loss of estrogen after menopause. Moreover, almost half were unaware of management options.⁵ 

These findings were supported by a 2013 survey of more than 3,000 US women who reported unpleasant vulvar and vaginal symptoms.⁶ From 60% to 85% noted negative sexual consequences from vulvovaginal symptoms, 47% felt their relationship suffered, and 27% felt it had a negative impact on their general enjoyment of life. In this study, 24% attributed their symptoms to menopause and 12% to hormonal changes. Although 56% had discussed GSM symptoms with a healthcare provider, only 40% were using GSM-specific topical treatments, mostly over-the-counter preparations.

Male partners of symptomatic women also note adverse emotional and physical effects.⁷ In an online survey of 4,100 men and 4,100 women ages 55 to 65, 52% to 78% of men and 58% to 64% of women expressed the negative effects of vulvovaginal symptoms on intimacy, libido, and sexual pain.

GSM is a progressive disorder. Women may note symptoms many years before menopause or have no symptoms until several years after menopause. One study found the prevalence of GSM to be 4% during perimenopause, rising after menopause to 25% after 1 year and to 47% after 3 years.⁸

Although distressing symptoms occur mostly after menopause, they may be seen in women of any age who experience a hypo­estrogenic state, even if it is transient. Causes of this include premature ovarian failure, hypothalamic amenorrhea, and hyperprolactinemia. In addition, some treatments such as gonadotropin-releasing hormone agonists and aromatase inhibitors may cause vulvovaginal and lower urinary tract symptoms. Chemotherapy, radiation, and surgical removal of ovaries may also precipitate symptoms. The abrupt onset of menopause that may occur with these treatments is often associated with significantly greater sexual dysfunction and negative impact on quality of life. Cigarette smoking also leads to lower estrogen levels, which may contribute to GSM.

WHAT CAUSES GSM?

The genitourinary system develops from common embryologic tissue, the basis for the functional and clinical connection. Estrogen maintains the epithelium of the vagina, vulva, urethra, and bladder trigone via estrogen receptors present throughout these tissues.⁹

Premenopausal changes

Histologically, the estrogen-exposed vagina of a premenopausal woman is lined by glycogen-rich, stratified squamous epithelium, with underlying supportive fibromuscular layers. The epithelium is composed of superficial, intermediate, and parabasal cellular layers. In the presence of estrogen, the superficial and intermediate cellular levels predominate, with few parabasal cells.

Glycogen acts as a substrate for lactobacilli, producing organic acids, primarily lactate, that help maintain an acidic pH of 2.8 to 4.0. The low pH helps protect against pathologic shifts in the microbiome. Estrogen also maintains the collagen content of the epithelium, maintains acid mucopolysaccharides and hyaluronic acid, and optimizes vaginal blood flow. These effects result in optimal epithelial thickness and elasticity, moisture, vaginal secretions, and lubrication.¹⁰

Postmenopausal changes

Low levels of estrogen after menopause result in adverse anatomic, physiologic, and clinical changes in vaginal tissue. Effects of hypoestrogenism include the loss of collagen and adipose, leading to decreased elasticity and vaginal mucosal thinning. Vascular flow is decreased. The epithelial cytology transitions to a predominance of parabasal cells and a decrease in superficial and intermediate cells. Eccrine and apocrine glands become attenuated. These changes result in decreased vaginal secretions, diminished or delayed lubrication with sexual stimulation, friability of the vaginal vault, and vaginal dryness.¹¹

Additionally, without estrogen, glycogen content is diminished, leading to decreased lactic acid production and a rise in vaginal pH to greater than 5. As the pH rises, Lactobacillus colonization decreases, leading to a further decrease in glycogen metabolism and to propagation of an elevated vaginal pH. The loss of vaginal acidity makes the vagina more susceptible to pathologic bacteria, including those found in the bowel and skin, sexually transmitted infections, and bacterial vaginosis.¹²

Other affected tissues. Anatomic effects of estrogen loss are not limited to the vagina. The epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone are also affected. The labia minora become thinner and regress, the introitus retracts, and narrowing and stricture of the vaginal canal and introitus may result. In some women, the urethral meatus becomes prominent relative to the introitus and more vulnerable to physical irritation, infection, and trauma.

Clinically, estrogen-related changes are usually responsible for vaginal dryness, irritation, burning, and superficial or deep dyspareunia. Urinary frequency, urgency, and incontinence also may develop.

 

 

THE DIAGNOSIS IS CLINICAL

The diagnosis of GSM is based on the history and physical examination. Standardized diagnostic tools for GSM are lacking, but some tools are available.

In 2006, the US Food and Drug Administration (FDA) published guidelines for industry to better define patient-reported outcome measures in clinical trials.¹³ The most significant addition was having the patient define the symptoms and rate how “bothersome” the symptoms are. Although this measure does not help diagnose GSM, it can be used effectively to follow response to treatment.

The Vaginal Symptom Questionnaire¹⁴ can be useful for assessing symptoms. It is a validated 21-item questionnaire that measures the quality-of-life impact of genital, but not urinary, symptoms of menopause.

Ask patients about symptoms

Healthcare providers should ask about GSM symptoms (Table 1) during routine clinical visits with women who are peri- or postmenopausal or who have hypoestrogenism from other causes, as many women are reluctant to initiate this discussion. Conversely, in women who present with sexual problems, such as difficulty with arousal or dyspareunia, GSM should be considered as a possible cause.

Specifically, ask women if they have any of the following symptoms:

• Vaginal itching, burning, discomfort, or irritation
• Malodorous or irritating vaginal discharge
• Urinary frequency, urgency, dysuria, urethral discomfort, or recurrent urinary tract infections
• Sexual symptoms of entry dyspareunia, vaginal pain, or irritation with sexual activity, which may be complicated by postcoital bleeding, spotting, or fissuring.

Vulvovaginal pain or irritation may be constant or may be present in the absence of sexual activity, such as with exercise, wearing tight clothing, or sitting for long periods.

Physical examination

Characteristic physical findings of GSM include scarce pubic hair, thinning of the labia from loss of labial fat, resorption of the labia minora, or fusion of the labia minora and majora (Table 2).^15,16 The vulvar skin is pale and thin. The clitoral hood may retract, exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. The vagina is pale, dry, smooth, and shiny with loss of rugae; shortening or stricturing may be present. Vaginal elasticity decreases. Inflammation and petechiae (pinpoint, nonraised, round purple-red spots) may be present. The cervix may be flush with the vaginal fornices.

Prolonged atrophy may result in introital narrowing and friability, which may cause tearing with sexual activity or insertion of a speculum during pelvic examination. In addition, the epithelium of the lower urinary tract thins, and the muscular and fibrous layers atrophy—changes that may not be obvious during examination. A urethral caruncle may form, presenting as proliferative red tissue at the entrance of the urethra. Prolapse may become more prominent.

In women with severe genitourinary atrophy, pelvic examination may cause significant discomfort. Reassuring the patient that she can ask the clinician to stop at any time due to extreme discomfort is the first step in a successful pelvic examination.

In some situations, initial examination of the pelvic area may not include insertion of a speculum. Use of a hand-held mirror so the patient can observe the examination may help her relax during the examination.

Vaginal pH and cultures, if indicated, may be obtained by gently inserting a cotton-tipped swab into the vagina without a speculum and before applying lubricant. Lubricant should be used generously; in some instances, topical lidocaine gel (diluted, as it may burn) may be placed against the perineum on a gauze pad for 3 to 5 minutes before insertion of the speculum.

When an internal pelvic examination is necessary in a timely manner, such as with postmenopausal bleeding or a history of an abnormal Papanicolaou smear, but is too painful for the patient, the examination should be done under anesthesia.

Additional considerations

The history should review current medical conditions, medication use, nongenital skin disorders (eg, eczema), and systemic menopausal symptoms, such as hot flashes.

Also, consider other potential causes of GSM during the evaluation (Table 3).^17,18 Review the use of detergents, soaps, douches, or over-the-counter topical products that could cause genitourinary symptoms secondary to contact irritation or allergy.

Any isolated, ulcerated, or nonhealing lesion should be biopsied. Reevaluate patients who have not responded to previous topical therapy or consider referral to a specialist.

Assess the personal, interpersonal, social, and sexual impact of the symptoms: if they do not cause distress, GSM does not require treatment. Nevertheless, potential treatment options should be discussed as symptoms may progress, making intervention necessary.

Laboratory tests: Helpful, not essential

Laboratory tests are unnecessary for the diagnosis of GSM. However, office-based objective evaluations such as vaginal pH testing and the maturation index can support the diagnosis.

The pH of the estrogenized vagina ranges from 3.8 to 4.2, whereas in women with GSM, the pH may reach 5.5 or higher. The pH can be obtained by placing a pH-sensitive paper against the lateral vaginal wall, avoiding any discharge or cervical mucus. A vaginal pH of 5 or greater in the absence of blood, semen, or infection suggests vulvovaginal atrophy.¹⁹

The vaginal maturation index is determined by a vaginal smear using Rakoff staining, in which 100 cells are counted and the number of parabasal, intermediate, and superficial cells is determined. In general, a well-estrogenized vagina has mostly superficial and intermediate cells, which shifts to a predominance of parabasal cells as estrogen levels decline.²⁰

A recent review of vaginal atrophy suggests that after a diagnosis of GSM, healthcare providers can consider the most bothersome symptom along with the vaginal pH to assess the response to treatment.²¹ In general, schedule a follow-up appointment at 8 to 12 weeks to review treatment response. If treatment has not resulted in adequate symptom relief, consider a pelvic examination and further testing.

 

 

SELECTING A TREATMENT

Symptomatic women with GSM who desire intervention should be offered over-the-counter nonhormonal products as the first line of therapy.

If nonhormonal products are ineffective and there are no contraindications, locally applied estrogen in cream, tablet, or a ring delivery system may be offered. Local dehydro­epiandrosterone (DHEA) inserts or ospemifene, an oral selective estrogen-receptor modulator, are FDA-approved for moderate to severe dyspareunia secondary to GSM.

Oral estrogen therapy is not indicated for vulvovaginal symptoms, but some women taking systemic estrogen for vasomotor symptoms may need additional local estrogen application to relieve vaginal symptoms.

Nonhormonal treatments

Nonhormonal over-the-counter therapies provide sufficient relief for most women with mild symptoms. There is a plethora of products, so practitioners need to offer guidance to help women with their individual choices.

Vaginal lubricants are intended for use with sexual or penetrative activity (including pelvic examination). They provide short-term relief of symptoms, but there is no evidence of any impact on histologic changes of atrophy. They are meant to relieve friction. Lubricants may be water-based, oil-based, silicone-based, or a combination. Individual products have different effects on condom integrity. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially in small amounts.

Vaginal moisturizers are intended to treat GSM. They are applied regularly, not just with vaginal activity, usually once or twice a week. Some vaginal lubricants can maintain an acidic pH in the vagina and may reverse the histologic changes of atrophy. Symptomatic improvement over placebo or estrogen has been shown in clinical trials.^22–24

Women should be advised that trial and error in choosing products may be necessary to establish a successful regimen. Products should be tried in succession, not simultaneously, with a “wash-out” period between, to be able to evaluate response.

Vaginal dilators and pelvic floor physical therapy

Sexual activity, either by self-stimulation or with a partner, helps maintain vaginal health by contributing to increased vascularity and elasticity of tissue. Women who resume sexual activity after a long period of inactivity may benefit from the use of vaginal dilators, which aid both in mechanical distention and progressive relaxation of the vaginal musculature.

In some women, long-term dyspareunia may result in vaginismus, an involuntary contraction of the vaginal musculature. For these women, dilators may be effective. Additional options focus on pelvic floor physical therapy, which can isolate trigger points, using biofeedback to teach relaxation and home exercises such as vaginal massage.

HORMONAL THERAPIES

If nonhormonal lubricants and moisturizers do not achieve satisfactory symptomatic relief, FDA-approved hormonal therapies (Table 4) include estrogen-containing vaginal creams, rings, and a tablet; a vaginal tablet containing DHEA; and an oral tablet containing ospemifene.

Estrogen products

For patients whose symptoms do not respond to nonhormonal therapies, low-dose, locally applied estrogen therapy is the first treatment recommended.² Locally applied estrogens can reverse the atrophic changes of estrogen deprivation, resulting in an increase in blood flow, elasticity, and vaginal wall thickness. This therapy also can normalize pH levels with subsequent restoration of a healthy lactobacilli-based flora. Locally applied estrogens also have been shown to decrease the frequency of recurrent urinary tract infection.²⁵

Estrogen-containing vaginal creams, rings, and a tablet are available, and each has been shown to be effective for GSM. Locally applied estrogens at recommended dosages tend to have fewer adverse events and risks than systemic estrogens.²⁶ Estradiol levels generally do not exceed levels found in the untreated menopausal population, although a dose- and duration-dependent increase in systemic levels may occur.²⁷

Dosing considerations

The vaginal ring and the vaginal tablet provide the lowest prefixed daily dose of estradiol (7.5 and 10 µg daily, respectively). Estrogen creams (estradiol, conjugated equine estrogens) are more readily absorbed, and dosing should be tapered to the lowest, most effective dose for symptom relief.

The FDA-approved doses for vaginal creams containing 17-beta estradiol are higher than the dose found to be effective in clinical practice (0.5 g twice a week). Most practitioners start with the lower dose, reserving the FDA-approved higher doses for patients who do not obtain adequate relief over 6 to 8 weeks of treatment. The conjugated-estrogen vaginal cream Premarin is the only locally applied estrogen approved by the FDA to treat dyspareunia. It is dosed at 0.5 g intravaginally for 21 days and is then either withdrawn for 7 days or, more commonly, administered at 0.5 g twice a week.

Initial treatment with vaginal cream may require more frequent vulvovaginal application, such as daily for 1 to 2 weeks. Women with vaginal fissures or tearing will benefit from externally applied creams in addition to internal applications. Response to therapy is usually seen within 4 to 6 weeks from onset of treatment. Once symptom relief is obtained, treatment should continue indefinitely. Although long-term safety studies are lacking, risks are believed to be minimal.

Endometrial impact. Women with contraindications to systemic estrogen should be counseled about possible small increases in serum levels of estradiol associated with locally applied estrogens and the potential risks and benefits those increases incur. Endometrial surveillance with either transvaginal ultrasonography or endometrial sampling is not required, even with long-term use, but it should be considered with higher doses or more frequent applications.

Similarly, progesterone replacement for endometrial protection is not recommended but can be considered in women with an intact uterus at high risk of endometrial cancer, such as obese patients. If a systemic progestational agent is considered, the risks and benefits should be weighed carefully. Even in women at high risk, endometrial surveillance may be the most appropriate option.²⁸ Uterine bleeding that occurs should be considered abnormal and should be investigated.

DHEA (prasterone)

In 2016, the FDA approved intravaginal prasterone, a DHEA-containing product for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy caused by menopause. DHEA is an endogenous steroid that is converted by aromatase activity into testosterone and estradiol.

Clinical trials have found that 12 weeks of vaginal DHEA supplementation (0.25%, 0.5%, and 1% DHEA ovules) was more effective than placebo in improving vaginal dryness and dyspareunia in women with GSM.^29–31 In these studies, locally applied DHEA decreased parabasal cells, decreased vaginal pH, increased vaginal secretions, and improved epithelial surface thickness and integrity without any significant impact on serum levels of DHEA, DHEA-sulfate, estradiol, testosterone, or their metabolites. Importantly, transvaginal DHEA had negligible endometrial effect.

The breast cancer risk associated with vaginal DHEA has not been fully evaluated. However, labeling lists breast cancer as a warning, not a contraindication.

 

 

Selective estrogen-receptor modulator

In 2013, the FDA approved ospemifene for the treatment of dyspareunia caused by GSM. Ospemifene, an estrogen agonist in the vagina, is taken daily as a 60-mg oral dose. Long-term safety studies suggested no adverse effects on the endometrium or breast for at least 52 weeks.³²

These studies also noted that ospemifene improved the vaginal maturation index (decreased parabasal cells and increased superficial cells) and decreased vaginal pH. It has further been shown to decrease severity of the self-identified most bothersome symptom—dyspareunia or vaginal dryness—compared with placebo.³³

Potential increases in hot flashes, which may occur in up to 7% of patients, and the risk of blood clots should be considered. Additionally, the safety of ospemifene in women with a history of breast cancer has not been established. Although early studies suggest it either has no effect or possibly a protective effect on breast tissue, the FDA does not recommend its use in women at risk for breast cancer. Long-term effects on bone are unknown.

The labeling for ospemifene includes a boxed warning about the risk of stroke, blood clots, and cancer of the lining of the uterus. Patients should be counseled about worrisome signs or symptoms that require medical attention.

ALTERNATIVE THERAPIES

Treatments for GSM not approved by the FDA include laser and radiofrequency therapies, testosterone, isoflavones, and bioidentical hormones.

Laser and radiofrequency therapies

Both of these therapies aim to promote tissue remodeling with increased collagen and elastin production and increased vascularity. This, in turn, increases muscle support and tone.

Laser therapies act by ablating and coagulating vaginal tissues; radiofrequency therapies directly heat the tissue. Both treatments are office-based, require up to 3 initial treatments, and are followed by retreatment at approximately 1-year intervals.

Studies have reported high patient satisfaction rates (91% to 100%), improved sexual functioning, and decreased GSM symptoms of vaginal dryness, burning, itching, and dyspareunia.^34–36 Data, however, are from observational studies, not placebo-controlled trials.

Although laser and radiofrequency therapies are FDA-approved for several indications, laser treatment for symptoms of vulvovaginal atrophy is not currently an approved indication. Patients should be advised of this.

Testosterone

Locally applied testosterone was shown in a small study to improve dyspareunia and vaginal dryness associated with aromatase inhibitor use in breast cancer patients.³⁷ However, due to the lack of safety and efficacy data from larger, controlled trials, testosterone therapy is not currently recommended.

Isoflavones

Isoflavones are phytoestrogens found in soy. In a 12-week, double-blind placebo-controlled study of vaginally applied 4% soy isoflavone gel, improvements in vaginal atrophy symptoms, maturation values, and vaginal pH were found in 60 postmenopausal women.³⁸ Additional data on efficacy and safety are needed before isoflavones should be considered as a treatment for GSM.

Bioidentical hormones

Bioidentical hormones are plant-derived hormones that are chemically similar or identical to those produced by the body. Although there are FDA-approved bioidentical hormones (eg, micronized progesterone, estradiol, DHEA), the term bioidentical usually refers to non-FDA-approved, commercially available hormones produced and compounded by specialty pharmacies.

Patients often view these substances as being better, safer, and more acceptable for use, and healthcare practitioners need to be prepared to address these beliefs. The FDA and the American College of Obstetricians and Gynecologists consider bioidentical hormones to be a marketing term and not an alternative treatment based on scientific evidence.³⁹ Patients should be informed that bioidentical hormones have the same risks as any similar hormone preparation along with additional risks related to potential lack of purity and potency. Further, they have not been adequately studied in controlled clinical trials.

FOLLOW-UP CARE

Healthcare providers caring for women should assume a proactive role in diagnosing and treating the symptoms of GSM. And once diagnosis of GSM is established and treatment is under way, practitioners can use symptom questionnaires and vaginal pH testing as easy and reliable means of measuring clinical response to therapy.

For many women, the postmenopausal loss of estrogen is associated with uncomfortable genitourinary symptoms, collectively referred to as the genitourinary syndrome of menopause (GSM). But despite the prevalence of GSM and the availability of treatments, most women do not seek relief.

This article reviews the syndrome and offers advice on how to talk about it with patients and what treatment options to consider.

A SYNDROME RECENTLY DEFINED

The term GSM and its definition were approved by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health in 2014.¹ It replaces older terms such as vulvovaginal atrophy, urogenital atrophy, and atrophic vaginitis.

GSM refers collectively to the symptoms associated with estrogen loss after menopause that adversely affect the vulvovaginal area and lower urinary tract. The most common symptoms are vulvovaginal dryness, burning, or irritation; sexual pain from inadequate lubrication; and urinary urgency, dysuria, or recurrent urinary tract infection.^1,2

The definition notes that symptoms are self-reported as bothersome and are not the result of another disorder. Symptoms may be chronic and progressive, are not likely to resolve without treatment (pharmacologic or nonpharmacologic), and can have a significant negative impact on a woman’s quality of life and sexual health.^1,2

COMMON BUT UNDERTREATED

From 40% to 60% of postmenopausal women experience GSM, but few seek treatment.³ Nevertheless, most postmenopausal women remain sexually active. In a 2008 survey of 94,000 postmenopausal women ages 50 to 79, 52% reported that they had been sexually active with a partner in the past year.⁴ However, 45% of postmenopausal women experienced unpleasant vaginal symptoms, according to a 2012 international survey of 3,520 postmenopausal women ages 55 to 65.⁵ In this survey, most respondents (75%) felt that vaginal symptoms had a negative impact on their life, but only 4% connected their symptoms to the vulvovaginal atrophy that resulted from loss of estrogen after menopause. Moreover, almost half were unaware of management options.⁵ 

These findings were supported by a 2013 survey of more than 3,000 US women who reported unpleasant vulvar and vaginal symptoms.⁶ From 60% to 85% noted negative sexual consequences from vulvovaginal symptoms, 47% felt their relationship suffered, and 27% felt it had a negative impact on their general enjoyment of life. In this study, 24% attributed their symptoms to menopause and 12% to hormonal changes. Although 56% had discussed GSM symptoms with a healthcare provider, only 40% were using GSM-specific topical treatments, mostly over-the-counter preparations.

Male partners of symptomatic women also note adverse emotional and physical effects.⁷ In an online survey of 4,100 men and 4,100 women ages 55 to 65, 52% to 78% of men and 58% to 64% of women expressed the negative effects of vulvovaginal symptoms on intimacy, libido, and sexual pain.

GSM is a progressive disorder. Women may note symptoms many years before menopause or have no symptoms until several years after menopause. One study found the prevalence of GSM to be 4% during perimenopause, rising after menopause to 25% after 1 year and to 47% after 3 years.⁸

Although distressing symptoms occur mostly after menopause, they may be seen in women of any age who experience a hypo­estrogenic state, even if it is transient. Causes of this include premature ovarian failure, hypothalamic amenorrhea, and hyperprolactinemia. In addition, some treatments such as gonadotropin-releasing hormone agonists and aromatase inhibitors may cause vulvovaginal and lower urinary tract symptoms. Chemotherapy, radiation, and surgical removal of ovaries may also precipitate symptoms. The abrupt onset of menopause that may occur with these treatments is often associated with significantly greater sexual dysfunction and negative impact on quality of life. Cigarette smoking also leads to lower estrogen levels, which may contribute to GSM.

WHAT CAUSES GSM?

The genitourinary system develops from common embryologic tissue, the basis for the functional and clinical connection. Estrogen maintains the epithelium of the vagina, vulva, urethra, and bladder trigone via estrogen receptors present throughout these tissues.⁹

Premenopausal changes

Histologically, the estrogen-exposed vagina of a premenopausal woman is lined by glycogen-rich, stratified squamous epithelium, with underlying supportive fibromuscular layers. The epithelium is composed of superficial, intermediate, and parabasal cellular layers. In the presence of estrogen, the superficial and intermediate cellular levels predominate, with few parabasal cells.

Glycogen acts as a substrate for lactobacilli, producing organic acids, primarily lactate, that help maintain an acidic pH of 2.8 to 4.0. The low pH helps protect against pathologic shifts in the microbiome. Estrogen also maintains the collagen content of the epithelium, maintains acid mucopolysaccharides and hyaluronic acid, and optimizes vaginal blood flow. These effects result in optimal epithelial thickness and elasticity, moisture, vaginal secretions, and lubrication.¹⁰

Postmenopausal changes

Low levels of estrogen after menopause result in adverse anatomic, physiologic, and clinical changes in vaginal tissue. Effects of hypoestrogenism include the loss of collagen and adipose, leading to decreased elasticity and vaginal mucosal thinning. Vascular flow is decreased. The epithelial cytology transitions to a predominance of parabasal cells and a decrease in superficial and intermediate cells. Eccrine and apocrine glands become attenuated. These changes result in decreased vaginal secretions, diminished or delayed lubrication with sexual stimulation, friability of the vaginal vault, and vaginal dryness.¹¹

Additionally, without estrogen, glycogen content is diminished, leading to decreased lactic acid production and a rise in vaginal pH to greater than 5. As the pH rises, Lactobacillus colonization decreases, leading to a further decrease in glycogen metabolism and to propagation of an elevated vaginal pH. The loss of vaginal acidity makes the vagina more susceptible to pathologic bacteria, including those found in the bowel and skin, sexually transmitted infections, and bacterial vaginosis.¹²

Other affected tissues. Anatomic effects of estrogen loss are not limited to the vagina. The epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone are also affected. The labia minora become thinner and regress, the introitus retracts, and narrowing and stricture of the vaginal canal and introitus may result. In some women, the urethral meatus becomes prominent relative to the introitus and more vulnerable to physical irritation, infection, and trauma.

Clinically, estrogen-related changes are usually responsible for vaginal dryness, irritation, burning, and superficial or deep dyspareunia. Urinary frequency, urgency, and incontinence also may develop.

 

 

THE DIAGNOSIS IS CLINICAL

The diagnosis of GSM is based on the history and physical examination. Standardized diagnostic tools for GSM are lacking, but some tools are available.

In 2006, the US Food and Drug Administration (FDA) published guidelines for industry to better define patient-reported outcome measures in clinical trials.¹³ The most significant addition was having the patient define the symptoms and rate how “bothersome” the symptoms are. Although this measure does not help diagnose GSM, it can be used effectively to follow response to treatment.

The Vaginal Symptom Questionnaire¹⁴ can be useful for assessing symptoms. It is a validated 21-item questionnaire that measures the quality-of-life impact of genital, but not urinary, symptoms of menopause.

Ask patients about symptoms

Healthcare providers should ask about GSM symptoms (Table 1) during routine clinical visits with women who are peri- or postmenopausal or who have hypoestrogenism from other causes, as many women are reluctant to initiate this discussion. Conversely, in women who present with sexual problems, such as difficulty with arousal or dyspareunia, GSM should be considered as a possible cause.

Specifically, ask women if they have any of the following symptoms:

• Vaginal itching, burning, discomfort, or irritation
• Malodorous or irritating vaginal discharge
• Urinary frequency, urgency, dysuria, urethral discomfort, or recurrent urinary tract infections
• Sexual symptoms of entry dyspareunia, vaginal pain, or irritation with sexual activity, which may be complicated by postcoital bleeding, spotting, or fissuring.

Vulvovaginal pain or irritation may be constant or may be present in the absence of sexual activity, such as with exercise, wearing tight clothing, or sitting for long periods.

Physical examination

Characteristic physical findings of GSM include scarce pubic hair, thinning of the labia from loss of labial fat, resorption of the labia minora, or fusion of the labia minora and majora (Table 2).^15,16 The vulvar skin is pale and thin. The clitoral hood may retract, exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. The vagina is pale, dry, smooth, and shiny with loss of rugae; shortening or stricturing may be present. Vaginal elasticity decreases. Inflammation and petechiae (pinpoint, nonraised, round purple-red spots) may be present. The cervix may be flush with the vaginal fornices.

Prolonged atrophy may result in introital narrowing and friability, which may cause tearing with sexual activity or insertion of a speculum during pelvic examination. In addition, the epithelium of the lower urinary tract thins, and the muscular and fibrous layers atrophy—changes that may not be obvious during examination. A urethral caruncle may form, presenting as proliferative red tissue at the entrance of the urethra. Prolapse may become more prominent.

In women with severe genitourinary atrophy, pelvic examination may cause significant discomfort. Reassuring the patient that she can ask the clinician to stop at any time due to extreme discomfort is the first step in a successful pelvic examination.

In some situations, initial examination of the pelvic area may not include insertion of a speculum. Use of a hand-held mirror so the patient can observe the examination may help her relax during the examination.

Vaginal pH and cultures, if indicated, may be obtained by gently inserting a cotton-tipped swab into the vagina without a speculum and before applying lubricant. Lubricant should be used generously; in some instances, topical lidocaine gel (diluted, as it may burn) may be placed against the perineum on a gauze pad for 3 to 5 minutes before insertion of the speculum.

When an internal pelvic examination is necessary in a timely manner, such as with postmenopausal bleeding or a history of an abnormal Papanicolaou smear, but is too painful for the patient, the examination should be done under anesthesia.

Additional considerations

The history should review current medical conditions, medication use, nongenital skin disorders (eg, eczema), and systemic menopausal symptoms, such as hot flashes.

Also, consider other potential causes of GSM during the evaluation (Table 3).^17,18 Review the use of detergents, soaps, douches, or over-the-counter topical products that could cause genitourinary symptoms secondary to contact irritation or allergy.

Any isolated, ulcerated, or nonhealing lesion should be biopsied. Reevaluate patients who have not responded to previous topical therapy or consider referral to a specialist.

Assess the personal, interpersonal, social, and sexual impact of the symptoms: if they do not cause distress, GSM does not require treatment. Nevertheless, potential treatment options should be discussed as symptoms may progress, making intervention necessary.

Laboratory tests: Helpful, not essential

Laboratory tests are unnecessary for the diagnosis of GSM. However, office-based objective evaluations such as vaginal pH testing and the maturation index can support the diagnosis.

The pH of the estrogenized vagina ranges from 3.8 to 4.2, whereas in women with GSM, the pH may reach 5.5 or higher. The pH can be obtained by placing a pH-sensitive paper against the lateral vaginal wall, avoiding any discharge or cervical mucus. A vaginal pH of 5 or greater in the absence of blood, semen, or infection suggests vulvovaginal atrophy.¹⁹

The vaginal maturation index is determined by a vaginal smear using Rakoff staining, in which 100 cells are counted and the number of parabasal, intermediate, and superficial cells is determined. In general, a well-estrogenized vagina has mostly superficial and intermediate cells, which shifts to a predominance of parabasal cells as estrogen levels decline.²⁰

A recent review of vaginal atrophy suggests that after a diagnosis of GSM, healthcare providers can consider the most bothersome symptom along with the vaginal pH to assess the response to treatment.²¹ In general, schedule a follow-up appointment at 8 to 12 weeks to review treatment response. If treatment has not resulted in adequate symptom relief, consider a pelvic examination and further testing.

 

 

SELECTING A TREATMENT

Symptomatic women with GSM who desire intervention should be offered over-the-counter nonhormonal products as the first line of therapy.

If nonhormonal products are ineffective and there are no contraindications, locally applied estrogen in cream, tablet, or a ring delivery system may be offered. Local dehydro­epiandrosterone (DHEA) inserts or ospemifene, an oral selective estrogen-receptor modulator, are FDA-approved for moderate to severe dyspareunia secondary to GSM.

Oral estrogen therapy is not indicated for vulvovaginal symptoms, but some women taking systemic estrogen for vasomotor symptoms may need additional local estrogen application to relieve vaginal symptoms.

Nonhormonal treatments

Nonhormonal over-the-counter therapies provide sufficient relief for most women with mild symptoms. There is a plethora of products, so practitioners need to offer guidance to help women with their individual choices.

Vaginal lubricants are intended for use with sexual or penetrative activity (including pelvic examination). They provide short-term relief of symptoms, but there is no evidence of any impact on histologic changes of atrophy. They are meant to relieve friction. Lubricants may be water-based, oil-based, silicone-based, or a combination. Individual products have different effects on condom integrity. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially in small amounts.

Vaginal moisturizers are intended to treat GSM. They are applied regularly, not just with vaginal activity, usually once or twice a week. Some vaginal lubricants can maintain an acidic pH in the vagina and may reverse the histologic changes of atrophy. Symptomatic improvement over placebo or estrogen has been shown in clinical trials.^22–24

Women should be advised that trial and error in choosing products may be necessary to establish a successful regimen. Products should be tried in succession, not simultaneously, with a “wash-out” period between, to be able to evaluate response.

Vaginal dilators and pelvic floor physical therapy

Sexual activity, either by self-stimulation or with a partner, helps maintain vaginal health by contributing to increased vascularity and elasticity of tissue. Women who resume sexual activity after a long period of inactivity may benefit from the use of vaginal dilators, which aid both in mechanical distention and progressive relaxation of the vaginal musculature.

In some women, long-term dyspareunia may result in vaginismus, an involuntary contraction of the vaginal musculature. For these women, dilators may be effective. Additional options focus on pelvic floor physical therapy, which can isolate trigger points, using biofeedback to teach relaxation and home exercises such as vaginal massage.

HORMONAL THERAPIES

If nonhormonal lubricants and moisturizers do not achieve satisfactory symptomatic relief, FDA-approved hormonal therapies (Table 4) include estrogen-containing vaginal creams, rings, and a tablet; a vaginal tablet containing DHEA; and an oral tablet containing ospemifene.

Estrogen products

For patients whose symptoms do not respond to nonhormonal therapies, low-dose, locally applied estrogen therapy is the first treatment recommended.² Locally applied estrogens can reverse the atrophic changes of estrogen deprivation, resulting in an increase in blood flow, elasticity, and vaginal wall thickness. This therapy also can normalize pH levels with subsequent restoration of a healthy lactobacilli-based flora. Locally applied estrogens also have been shown to decrease the frequency of recurrent urinary tract infection.²⁵

Estrogen-containing vaginal creams, rings, and a tablet are available, and each has been shown to be effective for GSM. Locally applied estrogens at recommended dosages tend to have fewer adverse events and risks than systemic estrogens.²⁶ Estradiol levels generally do not exceed levels found in the untreated menopausal population, although a dose- and duration-dependent increase in systemic levels may occur.²⁷

Dosing considerations

The vaginal ring and the vaginal tablet provide the lowest prefixed daily dose of estradiol (7.5 and 10 µg daily, respectively). Estrogen creams (estradiol, conjugated equine estrogens) are more readily absorbed, and dosing should be tapered to the lowest, most effective dose for symptom relief.

The FDA-approved doses for vaginal creams containing 17-beta estradiol are higher than the dose found to be effective in clinical practice (0.5 g twice a week). Most practitioners start with the lower dose, reserving the FDA-approved higher doses for patients who do not obtain adequate relief over 6 to 8 weeks of treatment. The conjugated-estrogen vaginal cream Premarin is the only locally applied estrogen approved by the FDA to treat dyspareunia. It is dosed at 0.5 g intravaginally for 21 days and is then either withdrawn for 7 days or, more commonly, administered at 0.5 g twice a week.

Initial treatment with vaginal cream may require more frequent vulvovaginal application, such as daily for 1 to 2 weeks. Women with vaginal fissures or tearing will benefit from externally applied creams in addition to internal applications. Response to therapy is usually seen within 4 to 6 weeks from onset of treatment. Once symptom relief is obtained, treatment should continue indefinitely. Although long-term safety studies are lacking, risks are believed to be minimal.

Endometrial impact. Women with contraindications to systemic estrogen should be counseled about possible small increases in serum levels of estradiol associated with locally applied estrogens and the potential risks and benefits those increases incur. Endometrial surveillance with either transvaginal ultrasonography or endometrial sampling is not required, even with long-term use, but it should be considered with higher doses or more frequent applications.

Similarly, progesterone replacement for endometrial protection is not recommended but can be considered in women with an intact uterus at high risk of endometrial cancer, such as obese patients. If a systemic progestational agent is considered, the risks and benefits should be weighed carefully. Even in women at high risk, endometrial surveillance may be the most appropriate option.²⁸ Uterine bleeding that occurs should be considered abnormal and should be investigated.

DHEA (prasterone)

In 2016, the FDA approved intravaginal prasterone, a DHEA-containing product for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy caused by menopause. DHEA is an endogenous steroid that is converted by aromatase activity into testosterone and estradiol.

Clinical trials have found that 12 weeks of vaginal DHEA supplementation (0.25%, 0.5%, and 1% DHEA ovules) was more effective than placebo in improving vaginal dryness and dyspareunia in women with GSM.^29–31 In these studies, locally applied DHEA decreased parabasal cells, decreased vaginal pH, increased vaginal secretions, and improved epithelial surface thickness and integrity without any significant impact on serum levels of DHEA, DHEA-sulfate, estradiol, testosterone, or their metabolites. Importantly, transvaginal DHEA had negligible endometrial effect.

The breast cancer risk associated with vaginal DHEA has not been fully evaluated. However, labeling lists breast cancer as a warning, not a contraindication.

 

 

Selective estrogen-receptor modulator

In 2013, the FDA approved ospemifene for the treatment of dyspareunia caused by GSM. Ospemifene, an estrogen agonist in the vagina, is taken daily as a 60-mg oral dose. Long-term safety studies suggested no adverse effects on the endometrium or breast for at least 52 weeks.³²

These studies also noted that ospemifene improved the vaginal maturation index (decreased parabasal cells and increased superficial cells) and decreased vaginal pH. It has further been shown to decrease severity of the self-identified most bothersome symptom—dyspareunia or vaginal dryness—compared with placebo.³³

Potential increases in hot flashes, which may occur in up to 7% of patients, and the risk of blood clots should be considered. Additionally, the safety of ospemifene in women with a history of breast cancer has not been established. Although early studies suggest it either has no effect or possibly a protective effect on breast tissue, the FDA does not recommend its use in women at risk for breast cancer. Long-term effects on bone are unknown.

The labeling for ospemifene includes a boxed warning about the risk of stroke, blood clots, and cancer of the lining of the uterus. Patients should be counseled about worrisome signs or symptoms that require medical attention.

ALTERNATIVE THERAPIES

Treatments for GSM not approved by the FDA include laser and radiofrequency therapies, testosterone, isoflavones, and bioidentical hormones.

Laser and radiofrequency therapies

Both of these therapies aim to promote tissue remodeling with increased collagen and elastin production and increased vascularity. This, in turn, increases muscle support and tone.

Laser therapies act by ablating and coagulating vaginal tissues; radiofrequency therapies directly heat the tissue. Both treatments are office-based, require up to 3 initial treatments, and are followed by retreatment at approximately 1-year intervals.

Studies have reported high patient satisfaction rates (91% to 100%), improved sexual functioning, and decreased GSM symptoms of vaginal dryness, burning, itching, and dyspareunia.^34–36 Data, however, are from observational studies, not placebo-controlled trials.

Although laser and radiofrequency therapies are FDA-approved for several indications, laser treatment for symptoms of vulvovaginal atrophy is not currently an approved indication. Patients should be advised of this.

Testosterone

Locally applied testosterone was shown in a small study to improve dyspareunia and vaginal dryness associated with aromatase inhibitor use in breast cancer patients.³⁷ However, due to the lack of safety and efficacy data from larger, controlled trials, testosterone therapy is not currently recommended.

Isoflavones

Isoflavones are phytoestrogens found in soy. In a 12-week, double-blind placebo-controlled study of vaginally applied 4% soy isoflavone gel, improvements in vaginal atrophy symptoms, maturation values, and vaginal pH were found in 60 postmenopausal women.³⁸ Additional data on efficacy and safety are needed before isoflavones should be considered as a treatment for GSM.

Bioidentical hormones

Bioidentical hormones are plant-derived hormones that are chemically similar or identical to those produced by the body. Although there are FDA-approved bioidentical hormones (eg, micronized progesterone, estradiol, DHEA), the term bioidentical usually refers to non-FDA-approved, commercially available hormones produced and compounded by specialty pharmacies.

Patients often view these substances as being better, safer, and more acceptable for use, and healthcare practitioners need to be prepared to address these beliefs. The FDA and the American College of Obstetricians and Gynecologists consider bioidentical hormones to be a marketing term and not an alternative treatment based on scientific evidence.³⁹ Patients should be informed that bioidentical hormones have the same risks as any similar hormone preparation along with additional risks related to potential lack of purity and potency. Further, they have not been adequately studied in controlled clinical trials.

FOLLOW-UP CARE

Healthcare providers caring for women should assume a proactive role in diagnosing and treating the symptoms of GSM. And once diagnosis of GSM is established and treatment is under way, practitioners can use symptom questionnaires and vaginal pH testing as easy and reliable means of measuring clinical response to therapy.

For many women, the postmenopausal loss of estrogen is associated with uncomfortable genitourinary symptoms, collectively referred to as the genitourinary syndrome of menopause (GSM). But despite the prevalence of GSM and the availability of treatments, most women do not seek relief.

This article reviews the syndrome and offers advice on how to talk about it with patients and what treatment options to consider.

A SYNDROME RECENTLY DEFINED

The term GSM and its definition were approved by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health in 2014.¹ It replaces older terms such as vulvovaginal atrophy, urogenital atrophy, and atrophic vaginitis.

GSM refers collectively to the symptoms associated with estrogen loss after menopause that adversely affect the vulvovaginal area and lower urinary tract. The most common symptoms are vulvovaginal dryness, burning, or irritation; sexual pain from inadequate lubrication; and urinary urgency, dysuria, or recurrent urinary tract infection.^1,2

The definition notes that symptoms are self-reported as bothersome and are not the result of another disorder. Symptoms may be chronic and progressive, are not likely to resolve without treatment (pharmacologic or nonpharmacologic), and can have a significant negative impact on a woman’s quality of life and sexual health.^1,2

COMMON BUT UNDERTREATED

From 40% to 60% of postmenopausal women experience GSM, but few seek treatment.³ Nevertheless, most postmenopausal women remain sexually active. In a 2008 survey of 94,000 postmenopausal women ages 50 to 79, 52% reported that they had been sexually active with a partner in the past year.⁴ However, 45% of postmenopausal women experienced unpleasant vaginal symptoms, according to a 2012 international survey of 3,520 postmenopausal women ages 55 to 65.⁵ In this survey, most respondents (75%) felt that vaginal symptoms had a negative impact on their life, but only 4% connected their symptoms to the vulvovaginal atrophy that resulted from loss of estrogen after menopause. Moreover, almost half were unaware of management options.⁵ 

These findings were supported by a 2013 survey of more than 3,000 US women who reported unpleasant vulvar and vaginal symptoms.⁶ From 60% to 85% noted negative sexual consequences from vulvovaginal symptoms, 47% felt their relationship suffered, and 27% felt it had a negative impact on their general enjoyment of life. In this study, 24% attributed their symptoms to menopause and 12% to hormonal changes. Although 56% had discussed GSM symptoms with a healthcare provider, only 40% were using GSM-specific topical treatments, mostly over-the-counter preparations.

Male partners of symptomatic women also note adverse emotional and physical effects.⁷ In an online survey of 4,100 men and 4,100 women ages 55 to 65, 52% to 78% of men and 58% to 64% of women expressed the negative effects of vulvovaginal symptoms on intimacy, libido, and sexual pain.

GSM is a progressive disorder. Women may note symptoms many years before menopause or have no symptoms until several years after menopause. One study found the prevalence of GSM to be 4% during perimenopause, rising after menopause to 25% after 1 year and to 47% after 3 years.⁸

Although distressing symptoms occur mostly after menopause, they may be seen in women of any age who experience a hypo­estrogenic state, even if it is transient. Causes of this include premature ovarian failure, hypothalamic amenorrhea, and hyperprolactinemia. In addition, some treatments such as gonadotropin-releasing hormone agonists and aromatase inhibitors may cause vulvovaginal and lower urinary tract symptoms. Chemotherapy, radiation, and surgical removal of ovaries may also precipitate symptoms. The abrupt onset of menopause that may occur with these treatments is often associated with significantly greater sexual dysfunction and negative impact on quality of life. Cigarette smoking also leads to lower estrogen levels, which may contribute to GSM.

WHAT CAUSES GSM?

The genitourinary system develops from common embryologic tissue, the basis for the functional and clinical connection. Estrogen maintains the epithelium of the vagina, vulva, urethra, and bladder trigone via estrogen receptors present throughout these tissues.⁹

Premenopausal changes

Histologically, the estrogen-exposed vagina of a premenopausal woman is lined by glycogen-rich, stratified squamous epithelium, with underlying supportive fibromuscular layers. The epithelium is composed of superficial, intermediate, and parabasal cellular layers. In the presence of estrogen, the superficial and intermediate cellular levels predominate, with few parabasal cells.

Glycogen acts as a substrate for lactobacilli, producing organic acids, primarily lactate, that help maintain an acidic pH of 2.8 to 4.0. The low pH helps protect against pathologic shifts in the microbiome. Estrogen also maintains the collagen content of the epithelium, maintains acid mucopolysaccharides and hyaluronic acid, and optimizes vaginal blood flow. These effects result in optimal epithelial thickness and elasticity, moisture, vaginal secretions, and lubrication.¹⁰

Postmenopausal changes

Low levels of estrogen after menopause result in adverse anatomic, physiologic, and clinical changes in vaginal tissue. Effects of hypoestrogenism include the loss of collagen and adipose, leading to decreased elasticity and vaginal mucosal thinning. Vascular flow is decreased. The epithelial cytology transitions to a predominance of parabasal cells and a decrease in superficial and intermediate cells. Eccrine and apocrine glands become attenuated. These changes result in decreased vaginal secretions, diminished or delayed lubrication with sexual stimulation, friability of the vaginal vault, and vaginal dryness.¹¹

Additionally, without estrogen, glycogen content is diminished, leading to decreased lactic acid production and a rise in vaginal pH to greater than 5. As the pH rises, Lactobacillus colonization decreases, leading to a further decrease in glycogen metabolism and to propagation of an elevated vaginal pH. The loss of vaginal acidity makes the vagina more susceptible to pathologic bacteria, including those found in the bowel and skin, sexually transmitted infections, and bacterial vaginosis.¹²

Other affected tissues. Anatomic effects of estrogen loss are not limited to the vagina. The epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone are also affected. The labia minora become thinner and regress, the introitus retracts, and narrowing and stricture of the vaginal canal and introitus may result. In some women, the urethral meatus becomes prominent relative to the introitus and more vulnerable to physical irritation, infection, and trauma.

Clinically, estrogen-related changes are usually responsible for vaginal dryness, irritation, burning, and superficial or deep dyspareunia. Urinary frequency, urgency, and incontinence also may develop.

 

 

THE DIAGNOSIS IS CLINICAL

The diagnosis of GSM is based on the history and physical examination. Standardized diagnostic tools for GSM are lacking, but some tools are available.

In 2006, the US Food and Drug Administration (FDA) published guidelines for industry to better define patient-reported outcome measures in clinical trials.¹³ The most significant addition was having the patient define the symptoms and rate how “bothersome” the symptoms are. Although this measure does not help diagnose GSM, it can be used effectively to follow response to treatment.

The Vaginal Symptom Questionnaire¹⁴ can be useful for assessing symptoms. It is a validated 21-item questionnaire that measures the quality-of-life impact of genital, but not urinary, symptoms of menopause.

Ask patients about symptoms

Healthcare providers should ask about GSM symptoms (Table 1) during routine clinical visits with women who are peri- or postmenopausal or who have hypoestrogenism from other causes, as many women are reluctant to initiate this discussion. Conversely, in women who present with sexual problems, such as difficulty with arousal or dyspareunia, GSM should be considered as a possible cause.

Specifically, ask women if they have any of the following symptoms:

• Vaginal itching, burning, discomfort, or irritation
• Malodorous or irritating vaginal discharge
• Urinary frequency, urgency, dysuria, urethral discomfort, or recurrent urinary tract infections
• Sexual symptoms of entry dyspareunia, vaginal pain, or irritation with sexual activity, which may be complicated by postcoital bleeding, spotting, or fissuring.

Vulvovaginal pain or irritation may be constant or may be present in the absence of sexual activity, such as with exercise, wearing tight clothing, or sitting for long periods.

Physical examination

Characteristic physical findings of GSM include scarce pubic hair, thinning of the labia from loss of labial fat, resorption of the labia minora, or fusion of the labia minora and majora (Table 2).^15,16 The vulvar skin is pale and thin. The clitoral hood may retract, exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. The vagina is pale, dry, smooth, and shiny with loss of rugae; shortening or stricturing may be present. Vaginal elasticity decreases. Inflammation and petechiae (pinpoint, nonraised, round purple-red spots) may be present. The cervix may be flush with the vaginal fornices.

Prolonged atrophy may result in introital narrowing and friability, which may cause tearing with sexual activity or insertion of a speculum during pelvic examination. In addition, the epithelium of the lower urinary tract thins, and the muscular and fibrous layers atrophy—changes that may not be obvious during examination. A urethral caruncle may form, presenting as proliferative red tissue at the entrance of the urethra. Prolapse may become more prominent.

In women with severe genitourinary atrophy, pelvic examination may cause significant discomfort. Reassuring the patient that she can ask the clinician to stop at any time due to extreme discomfort is the first step in a successful pelvic examination.

In some situations, initial examination of the pelvic area may not include insertion of a speculum. Use of a hand-held mirror so the patient can observe the examination may help her relax during the examination.

Vaginal pH and cultures, if indicated, may be obtained by gently inserting a cotton-tipped swab into the vagina without a speculum and before applying lubricant. Lubricant should be used generously; in some instances, topical lidocaine gel (diluted, as it may burn) may be placed against the perineum on a gauze pad for 3 to 5 minutes before insertion of the speculum.

When an internal pelvic examination is necessary in a timely manner, such as with postmenopausal bleeding or a history of an abnormal Papanicolaou smear, but is too painful for the patient, the examination should be done under anesthesia.

Additional considerations

The history should review current medical conditions, medication use, nongenital skin disorders (eg, eczema), and systemic menopausal symptoms, such as hot flashes.

Also, consider other potential causes of GSM during the evaluation (Table 3).^17,18 Review the use of detergents, soaps, douches, or over-the-counter topical products that could cause genitourinary symptoms secondary to contact irritation or allergy.

Any isolated, ulcerated, or nonhealing lesion should be biopsied. Reevaluate patients who have not responded to previous topical therapy or consider referral to a specialist.

Assess the personal, interpersonal, social, and sexual impact of the symptoms: if they do not cause distress, GSM does not require treatment. Nevertheless, potential treatment options should be discussed as symptoms may progress, making intervention necessary.

Laboratory tests: Helpful, not essential

Laboratory tests are unnecessary for the diagnosis of GSM. However, office-based objective evaluations such as vaginal pH testing and the maturation index can support the diagnosis.

The pH of the estrogenized vagina ranges from 3.8 to 4.2, whereas in women with GSM, the pH may reach 5.5 or higher. The pH can be obtained by placing a pH-sensitive paper against the lateral vaginal wall, avoiding any discharge or cervical mucus. A vaginal pH of 5 or greater in the absence of blood, semen, or infection suggests vulvovaginal atrophy.¹⁹

The vaginal maturation index is determined by a vaginal smear using Rakoff staining, in which 100 cells are counted and the number of parabasal, intermediate, and superficial cells is determined. In general, a well-estrogenized vagina has mostly superficial and intermediate cells, which shifts to a predominance of parabasal cells as estrogen levels decline.²⁰

A recent review of vaginal atrophy suggests that after a diagnosis of GSM, healthcare providers can consider the most bothersome symptom along with the vaginal pH to assess the response to treatment.²¹ In general, schedule a follow-up appointment at 8 to 12 weeks to review treatment response. If treatment has not resulted in adequate symptom relief, consider a pelvic examination and further testing.

 

 

SELECTING A TREATMENT

Symptomatic women with GSM who desire intervention should be offered over-the-counter nonhormonal products as the first line of therapy.

If nonhormonal products are ineffective and there are no contraindications, locally applied estrogen in cream, tablet, or a ring delivery system may be offered. Local dehydro­epiandrosterone (DHEA) inserts or ospemifene, an oral selective estrogen-receptor modulator, are FDA-approved for moderate to severe dyspareunia secondary to GSM.

Oral estrogen therapy is not indicated for vulvovaginal symptoms, but some women taking systemic estrogen for vasomotor symptoms may need additional local estrogen application to relieve vaginal symptoms.

Nonhormonal treatments

Nonhormonal over-the-counter therapies provide sufficient relief for most women with mild symptoms. There is a plethora of products, so practitioners need to offer guidance to help women with their individual choices.

Vaginal lubricants are intended for use with sexual or penetrative activity (including pelvic examination). They provide short-term relief of symptoms, but there is no evidence of any impact on histologic changes of atrophy. They are meant to relieve friction. Lubricants may be water-based, oil-based, silicone-based, or a combination. Individual products have different effects on condom integrity. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially in small amounts.

Vaginal moisturizers are intended to treat GSM. They are applied regularly, not just with vaginal activity, usually once or twice a week. Some vaginal lubricants can maintain an acidic pH in the vagina and may reverse the histologic changes of atrophy. Symptomatic improvement over placebo or estrogen has been shown in clinical trials.^22–24

Women should be advised that trial and error in choosing products may be necessary to establish a successful regimen. Products should be tried in succession, not simultaneously, with a “wash-out” period between, to be able to evaluate response.

Vaginal dilators and pelvic floor physical therapy

Sexual activity, either by self-stimulation or with a partner, helps maintain vaginal health by contributing to increased vascularity and elasticity of tissue. Women who resume sexual activity after a long period of inactivity may benefit from the use of vaginal dilators, which aid both in mechanical distention and progressive relaxation of the vaginal musculature.

In some women, long-term dyspareunia may result in vaginismus, an involuntary contraction of the vaginal musculature. For these women, dilators may be effective. Additional options focus on pelvic floor physical therapy, which can isolate trigger points, using biofeedback to teach relaxation and home exercises such as vaginal massage.

HORMONAL THERAPIES

If nonhormonal lubricants and moisturizers do not achieve satisfactory symptomatic relief, FDA-approved hormonal therapies (Table 4) include estrogen-containing vaginal creams, rings, and a tablet; a vaginal tablet containing DHEA; and an oral tablet containing ospemifene.

Estrogen products

For patients whose symptoms do not respond to nonhormonal therapies, low-dose, locally applied estrogen therapy is the first treatment recommended.² Locally applied estrogens can reverse the atrophic changes of estrogen deprivation, resulting in an increase in blood flow, elasticity, and vaginal wall thickness. This therapy also can normalize pH levels with subsequent restoration of a healthy lactobacilli-based flora. Locally applied estrogens also have been shown to decrease the frequency of recurrent urinary tract infection.²⁵

Estrogen-containing vaginal creams, rings, and a tablet are available, and each has been shown to be effective for GSM. Locally applied estrogens at recommended dosages tend to have fewer adverse events and risks than systemic estrogens.²⁶ Estradiol levels generally do not exceed levels found in the untreated menopausal population, although a dose- and duration-dependent increase in systemic levels may occur.²⁷

Dosing considerations

The vaginal ring and the vaginal tablet provide the lowest prefixed daily dose of estradiol (7.5 and 10 µg daily, respectively). Estrogen creams (estradiol, conjugated equine estrogens) are more readily absorbed, and dosing should be tapered to the lowest, most effective dose for symptom relief.

The FDA-approved doses for vaginal creams containing 17-beta estradiol are higher than the dose found to be effective in clinical practice (0.5 g twice a week). Most practitioners start with the lower dose, reserving the FDA-approved higher doses for patients who do not obtain adequate relief over 6 to 8 weeks of treatment. The conjugated-estrogen vaginal cream Premarin is the only locally applied estrogen approved by the FDA to treat dyspareunia. It is dosed at 0.5 g intravaginally for 21 days and is then either withdrawn for 7 days or, more commonly, administered at 0.5 g twice a week.

Initial treatment with vaginal cream may require more frequent vulvovaginal application, such as daily for 1 to 2 weeks. Women with vaginal fissures or tearing will benefit from externally applied creams in addition to internal applications. Response to therapy is usually seen within 4 to 6 weeks from onset of treatment. Once symptom relief is obtained, treatment should continue indefinitely. Although long-term safety studies are lacking, risks are believed to be minimal.

Endometrial impact. Women with contraindications to systemic estrogen should be counseled about possible small increases in serum levels of estradiol associated with locally applied estrogens and the potential risks and benefits those increases incur. Endometrial surveillance with either transvaginal ultrasonography or endometrial sampling is not required, even with long-term use, but it should be considered with higher doses or more frequent applications.

Similarly, progesterone replacement for endometrial protection is not recommended but can be considered in women with an intact uterus at high risk of endometrial cancer, such as obese patients. If a systemic progestational agent is considered, the risks and benefits should be weighed carefully. Even in women at high risk, endometrial surveillance may be the most appropriate option.²⁸ Uterine bleeding that occurs should be considered abnormal and should be investigated.

DHEA (prasterone)

In 2016, the FDA approved intravaginal prasterone, a DHEA-containing product for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy caused by menopause. DHEA is an endogenous steroid that is converted by aromatase activity into testosterone and estradiol.

Clinical trials have found that 12 weeks of vaginal DHEA supplementation (0.25%, 0.5%, and 1% DHEA ovules) was more effective than placebo in improving vaginal dryness and dyspareunia in women with GSM.^29–31 In these studies, locally applied DHEA decreased parabasal cells, decreased vaginal pH, increased vaginal secretions, and improved epithelial surface thickness and integrity without any significant impact on serum levels of DHEA, DHEA-sulfate, estradiol, testosterone, or their metabolites. Importantly, transvaginal DHEA had negligible endometrial effect.

The breast cancer risk associated with vaginal DHEA has not been fully evaluated. However, labeling lists breast cancer as a warning, not a contraindication.

 

 

Selective estrogen-receptor modulator

In 2013, the FDA approved ospemifene for the treatment of dyspareunia caused by GSM. Ospemifene, an estrogen agonist in the vagina, is taken daily as a 60-mg oral dose. Long-term safety studies suggested no adverse effects on the endometrium or breast for at least 52 weeks.³²

These studies also noted that ospemifene improved the vaginal maturation index (decreased parabasal cells and increased superficial cells) and decreased vaginal pH. It has further been shown to decrease severity of the self-identified most bothersome symptom—dyspareunia or vaginal dryness—compared with placebo.³³

Potential increases in hot flashes, which may occur in up to 7% of patients, and the risk of blood clots should be considered. Additionally, the safety of ospemifene in women with a history of breast cancer has not been established. Although early studies suggest it either has no effect or possibly a protective effect on breast tissue, the FDA does not recommend its use in women at risk for breast cancer. Long-term effects on bone are unknown.

The labeling for ospemifene includes a boxed warning about the risk of stroke, blood clots, and cancer of the lining of the uterus. Patients should be counseled about worrisome signs or symptoms that require medical attention.

ALTERNATIVE THERAPIES

Treatments for GSM not approved by the FDA include laser and radiofrequency therapies, testosterone, isoflavones, and bioidentical hormones.

Laser and radiofrequency therapies

Both of these therapies aim to promote tissue remodeling with increased collagen and elastin production and increased vascularity. This, in turn, increases muscle support and tone.

Laser therapies act by ablating and coagulating vaginal tissues; radiofrequency therapies directly heat the tissue. Both treatments are office-based, require up to 3 initial treatments, and are followed by retreatment at approximately 1-year intervals.

Studies have reported high patient satisfaction rates (91% to 100%), improved sexual functioning, and decreased GSM symptoms of vaginal dryness, burning, itching, and dyspareunia.^34–36 Data, however, are from observational studies, not placebo-controlled trials.

Although laser and radiofrequency therapies are FDA-approved for several indications, laser treatment for symptoms of vulvovaginal atrophy is not currently an approved indication. Patients should be advised of this.

Testosterone

Locally applied testosterone was shown in a small study to improve dyspareunia and vaginal dryness associated with aromatase inhibitor use in breast cancer patients.³⁷ However, due to the lack of safety and efficacy data from larger, controlled trials, testosterone therapy is not currently recommended.

Isoflavones

Isoflavones are phytoestrogens found in soy. In a 12-week, double-blind placebo-controlled study of vaginally applied 4% soy isoflavone gel, improvements in vaginal atrophy symptoms, maturation values, and vaginal pH were found in 60 postmenopausal women.³⁸ Additional data on efficacy and safety are needed before isoflavones should be considered as a treatment for GSM.

Bioidentical hormones

Bioidentical hormones are plant-derived hormones that are chemically similar or identical to those produced by the body. Although there are FDA-approved bioidentical hormones (eg, micronized progesterone, estradiol, DHEA), the term bioidentical usually refers to non-FDA-approved, commercially available hormones produced and compounded by specialty pharmacies.

Patients often view these substances as being better, safer, and more acceptable for use, and healthcare practitioners need to be prepared to address these beliefs. The FDA and the American College of Obstetricians and Gynecologists consider bioidentical hormones to be a marketing term and not an alternative treatment based on scientific evidence.³⁹ Patients should be informed that bioidentical hormones have the same risks as any similar hormone preparation along with additional risks related to potential lack of purity and potency. Further, they have not been adequately studied in controlled clinical trials.

FOLLOW-UP CARE

Healthcare providers caring for women should assume a proactive role in diagnosing and treating the symptoms of GSM. And once diagnosis of GSM is established and treatment is under way, practitioners can use symptom questionnaires and vaginal pH testing as easy and reliable means of measuring clinical response to therapy.