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Heart Failure with Preserved Ejection Fraction

The fifth episode features Geoffrey Mills, MD, PhD, covering heart failure with preserved ejection fraction, including the following topics

• Heart failure with preserved ejection fraction versus heart failure with reduced ejection fraction
• The difference between heart failure with preserved ejection fraction and diastolic dysfunction
• Treatment of heart failure with preserved ejection fraction

Featured Physician

Geoffrey Mills, MD, PhD
Assistant Residency Program Director, Assistant Professor
Department of Family and Community Medicine and Department of Physiology
Jefferson Medical College, Philadelphia, PA

Dr. Mills is a graduate of Temple University School of Medicine and did his Family Medicine training at Thomas Jefferson University Hospital in Philadelphia. He has a research background in cardiovascular physiology and has a dual appointment in the Departments of Family and Community Medicine and Department of Physiology at Jefferson Medical College. His teaching and clinical interests relate to cardiovascular disease and preventative medicine and he studies risk communication in primary care.

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Transcript:

Joining us today is Geoffrey Mills MD, PhD. Doctor, why did you choose heart failure with preserved ejection fraction as the topic for this month’s podcast?

Physicians are familiar with managing congestive heart failure – common symptoms and treatment approaches – but less familiar with the differences in treatment and management of patients exhibiting symptoms of heart failure, but with preserved left ventricular function.  Unfortunately, at this point, there are few large, high-quality trials available to guide treatment decisions in this patient population, so physicians often apply principles most appropriate for patients with reduced ejection fraction.  With our aging population, we will be seeing more HF with preserved ejection fraction so physicians should be comfortable identifying this condition.

What is the difference between heart failure with preserved ejection fraction and diastolic heart failure?

HF with preserved ejection fraction is the preferred terminology for diastolic heart failure.  There is an important distinction between HFPEF and diastolic dysfunction, which is often a finding on routine echocardiograms.  Diastolic dysfunction refers to an abnormality of diastolic compliance, filling or relaxation of the ventricle.  This can occur in the absence of symptoms classically associated with heart failure – shortness of breath, fatigue and volume overload.  If these signs and symptoms are present in a patient with a normal ejection fraction, they are said to have HFPEF.  Usually, you will find some evidence of diastolic dysfunction in these patients as well.

Who is most at risk to develop this condition?

When compared with HFREF, patients with preserved ejection fraction are older, more likely female and usually have a history of hypertension.  They are also more likely to have atrial fibrillation but less likely to have a history ischemic disease, although coronary artery disease is a common co-morbidity.  They have similar symptoms as those with reduced ejection fraction like reduced exercise capacity and reduced quality of life.  In patients presenting with these symptoms, consider HFPEF in your differential diagnoses, especially for older women with a history of long-standing hypertension.

Acute exacerbations of HFPEF cause the classic HF symptoms of fluid overload and chest pain in patients.  These flare-ups are most commonly triggered by hypertensive crises but can also be due to tachycardia, especially atrial fibrillation, renal impairment or other acute illnesses.

What is the course of HFPEF?

HFPEF is a chronic disease for most patients with a slow progression and occasional exacerbations.  Unfortunately, the presence of diastolic dysfunction by itself is associated with increased risk of cardiovascular events.  There is some controversy about whether there is a difference in the mortality rates between patients with HFPEF and HFREF but it is generally accepted that patients with HFPEF who are male, higher NHYA classification, ischemic disease or impaired renal function fare worse than other patients.

HFPEF is a chronic disease and physicians should aim to control hypertension, ventricular rate, fluid balance and, in some patients, consider revascularization.  Patients should be instructed in self-care behaviors like daily weights and medication adherence as well as dietary sodium restriction.

How should clinicians approach the treatment of HFPEF?

As I mentioned, the main treatment goals are treating hypertension, maintaining a normal heart rate and keeping the patient euvolemic.  The challenge in HFPEF is that there are few clinical trials demonstrating meaningful benefits in morbidity and mortality to guide the choice of pharmacologic agents.  For instance, ACE inhibitors and angiotensin receptor blockers can improve diastolic function and may improve functional class and exercise capacity but there is limited data showing improvements in morbidity and mortality.  Both are reasonable choices for blood pressure control, especially for patients with LV hypertrophy but they should not be used in combination.

Beta blockers can help in two ways: blood pressure control and heart rate control. Again, evidence for improved morbidity and mortality is lacking, but some trials have suggested benefits for this group of patients.  If we project treatment recommendations for patients with reduced ejection fraction, carvedilol, long-acting metoprolol and bisoprolol seem most promising for use in these patients until new data are available.

Calcium channel blockers will also help with hypertension and heart rate in these patients and may, in theory, improve diastolic function.  Verapamil has been shown in small studies to improve exercise capacity and HF symptoms in HFPEF.

New trials are looking at the role of aldosterone antagonist therapy in HFPEF with early studies suggesting that they may improve myocardial function.  Until more data are available, these drugs are not generally recommended for patients with preserved EF.

Diuretics such as furosemide are used in acute exacerbations to improve fluid overload but may be necessary in some patients to maintain fluid balance chronically.

I hope that we will have some more data to help guide these treatment decisions in this patient population, but until that time, most of our treatment options are drawn from studies in patients with reduced ejection fraction.

How is this different from heart failure with reduced ejection fraction?  Are there unique treatment considerations?

One unique difference is that patients with HFPEF seem to tolerate the initiation of beta blockers and calcium channel blockers during acute exacerbations.  Patients with systolic HF generally are not started on new beta blockers during acute exacerbations for fear of depressed contractility.  So, when heart rate control is needed, these agents can be used, even during acute exacerbations.  Another difference is that inotropic agents like digoxin and dobutamine are not indicated for use in acute or chronic HFPEF.  Finally, patients who are very sensitive to tachycardia from atrial fibrillation should be considered for rhythm control strategies to maintain sinus rhythm.  Guidelines also suggest that coronary revascularization should be considered in patients with CAD and diastolic dysfunction.

Are there particular lifestyle recommendations that patients should follow?

Weight loss, smoking cessation and dietary changes should be discussed with patients to reduce ischemic risk and improve blood pressure control.  Dietary sodium restriction to less than 2 grams per day will reduce mean arterial blood pressure and may prevent hypokalemia in patients on diuretics – I would recommend the sodium-restricted DASH diet, which has been shown to reduce blood pressure and improve exercise tolerance in patients with HFPEF.

Most patients should monitor daily weights and have some plan in place for what to do if they begin to gain weight or have symptoms of heart failure.  This type of action planning is a good way to engage patients in their medical care and can reduce the risk of hospitalization.  In addition, exercise training can improve functional capacity in patients with HFPEF – some areas will have access to cardiac rehabilitation services but most patients can safely participate in moderate intensity aerobic exercise 3-5 times per week.

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Abdominal Aortic Aneurysm

The fourth episode features Bon Ku, MD covering abdominal aortic aneurysm or AAA, including the following:

• Risk Factors for developing AAA
• Presentation of AAA and reliable screening
• Ultrasound and accurate diagnosis

FEATURED PHYSICIAN

Bon Ku, MD
Assistant Professor in the Department of Emergency Medicine
Thomas Jefferson University Hospital

Dr. Ku completed a fellowship in emergency ultrasound at the Hospital of the University of Pennsylvania and received a Master in Public Policy at the Woodrow Wilson School of Public and International Affairs at Princeton University. He graduated from the Penn State College of Medicine and completed an emergency medicine residency at Long Island Jewish Hospital. His research areas of focus are point-of-care ultrasound, utilization patterns of emergency departments and homeless populations.

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Transcript:

Thank you for being here today, Dr. Ku. Why did you choose abdominal aortic aneurysm (AAA) as the topic for this month’s podcast?

A ruptured AAA is a vascular catastrophe, responsible for 9,000 deaths yearly in the US. The prevalence of AAA ranges from 4-8% in males and 1% in females. It is a silent killer because patients often are asymptomatic until the aneurysm ruptures. Once ruptured, the mortality is greater than 80%. Because the mortality rate is so high, a rapid diagnosis of AAA may be lifesaving.

How reliable is the physical exam in diagnosing AAA?

Terrible. We physicians do a poor job at detecting its presence by physical examination. The odds of ruling out the presence of a AAA by palpation is like flipping a coin. Published reports have sensitivities ranging from 29-76%1 and the specificities are only slightly higher. There are a large number of false positives and false negatives, resulting in a poor predictive value2. Because abdominal palpitation has a low sensitivity for detecting aneurysms, especially ones <5 cm, I would argue that the physical exam should not play a role in ruling out AAA.

What imaging modality should be used as the first line of screening for detecting AAA?

Unequivocally ultrasound. Ultrasound for the detection of AAA has been shown to have a 95% sensitivity and a specificity approaching 100%. It is safe, non-invasive, cost-effective and can be performed quickly in emergent settings right at the patient’s bedside. A complete aorta scan can be completed in just over 2 minutes. In my current practice, I use ultrasound as a rapid point-of-care test for ruling out AAA in a similar fashion to how I use an EKG to rule out an acute myocardial infarction.

Who is at most risk for developing AAA?

The greatest risk factors are age greater than 65 years, male sex, and smoking. Other risk factors for AAA include a family history of AAA and atherosclerotic risk factors. In 2005, the U.S. Preventive Services Task Force made a Class B recommendation that men between the ages of 65-75 who have ever smoked should receive a one-time screening ultrasound. The UK has similar screening guidelines.

Does routine screening for AAA occur in Emergency Departments?

No. But one study suggested that EDs may provide an opportunity to screen asymptomatic, high-risk patients for AAA 3. The investigators found a 6.7% prevalence of AAA in a sample size of 179 patients who were >60 years, male and had at least 1 risk factor for AAA.

How does a patient with a ruptured AAA present?

We have been taught that patients present with the classic triad of abdominal pain, pulsatile abdominal mass, and hypotension. But patients rarely show all these telltale signs. Patients often have non-specific symptoms ranging from flank to back pain or syncope. A 30% misdiagnosis rate for ruptured AAA has been previously reported 4. The most common wrong diagnoses for ruptured AAA are renal colic, diverticulitis and gastrointestinal hemorrhage.

Where do most aneurysms rupture?

80% of abdominal aneurysms rupture into the retroperitoneal cavity while 20% rupture anteriorly into the peritoneal cavity. In rare cases, AAA can rupture into the IVC or the left renal vein causing spontaneous fistula formation 5. In rare instances, patients can have a delayed presentation of a ruptured aneurysm. This happens when a hematoma forms from a slow rupture. Contained ruptures, however, are at a high risk for spontaneous re-bleeding.

Who should receive an emergent point-of-care ultrasound?

There are 2 groups of patients who should receive an immediate ultrasound in the ED or in-patient hospital setting. The first group includes anyone with a major risk factor for AAA (male, age >65 years, or smoking use) with a suspicion for AAA. The other group of patients are those who have hypotension or shock of unknown etiology. “Rapid Ultrasound in Shock” aka “RUSH” is a protocol that involves the use of point-of-care ultrasound in evaluation of patients in shock. The RUSH protocol entails the following steps: evaluation of aorta size, a focused cardiac evaluation, IVC assessment, FAST, and lung exam for pneumothorax and pulmonary edema 6.

 How do you perform a point-of-care ultrasound evaluation for AAA?

A focused ultrasound exam for the evaluation of AAA involves real-time scanning of the entire aorta from the diaphragm to the iliac bifurcation in the transverse plane. The American College of Emergency Physicians recommends measuring the maximal aortic and iliac size — from outer wall to outer wall — in both the transverse and longitudinal planes. As stated before, ultrasound is extremely accurate in detection of AAA but it cannot be used to diagnose a ruptured aneurysm. Ultrasound is unable to reliably identify the presence of retroperitoneal fluid. Also it is important to keep in mind that the major technical limitations in examining the aorta are obesity, bowel gas and abdominal tenderness.

Referenced Sources

Lederle FA, Simel DL. The rational clinical examination. Does this patient have abdominal aortic aneurysm? JAMA. 1999 Jan 6;281(1):77-82.

Van der Vliet JA, Boll AP. Abdominal aortic aneurysm. Lancet. 1997 Mar
22;349(9055):863-6.

Moore CL, Holliday RS, Hwang JQ, Osborne MR. Screening for abdominal aortic aneurysm in asymptomatic at-risk patients using emergency ultrasound. Am J Emerg Med. 2008 Oct;26(8):883-7.

Marston WA, Ahlquist R, Johnson G Jr, Meyer AA. Misdiagnosis of ruptured abdominal aortic aneurysms. J Vasc Surg.1992 Jul;16(1):17-22.

Assar AN, Zarins CK. Ruptured abdominal aortic aneurysm: a surgical emergency with many clinical presentations. Postgrad Med J. 2009 May;85(1003):268-732

Seif D, Perera P, Mailhot T, Riley D, Mandavia D. Bedside Ultrasound in
Resuscitation and the Rapid Ultrasound in Shock Protocol. Critical Care Research and Practice. 2012.

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CARDIAC ARREST

The third episode features Marjorie Lazoff, MD covering cardiac arrest, including the following:

• Indicators of neurological survival
• Socioeconomic disparities in survival
• Cardiac arrest medicines used in resuscitation

FEATURED PHYSICIAN

Marjorie Lazoff, MD
Deputy Editor
ClinicalKey Point of Care

Dr. Lazoff is board certified in internal medicine and practiced academic emergency medicine for over 7 years at Temple University Hospital’s ER, where she also served as their director of quality assurance. Marjorie graduated from the University of Cincinnati College of Medicine and completed a residency in internal medicine at the Hospital of University of Pennsylvania in Philadelphia.

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Transcript:

Dr. Lazoff, the first study you’ll be discussing comes from a recent Archives of Internal Medicine. It is titled, “A validation prediction tool for initial survivors of in-hopsital cardiac arrest” Why did you select it for this month’s podcast?

Seasoned hospitalists and ER physicians are all too familiar with the ethical “dis-ease” we suffer every time a survivor of a cardiac arrest sustains significant, non-reversible neurological damage as a result of resuscitative efforts. When to continue and when to stop resuscitative efforts – the inevitability of death vs. the goal to keep a patient alive, whatever the quality of that life.

In my experience, most physicians fall somewhere in the middle of that spectrum. We tend to give maximum resuscitative efforts to younger, generally healthy patients who had good neurologic function and quality of life prior to the arrest – and, no surprise, these are among the eleven variables that Paul Chan and the Get With the Guidelines Resuscitation Registry Investigators found were associated with favorable neurological survival, using their Cardiac Arrest Survival Post resuscitation In-hospital (or CASPRI) score.

The authors evaluated nearly 43,000 patients from over 500 acute-care hospitals who sustained a cardiac arrest while a patient in the hospital. Two-thirds of the patients were used to develop the CASPRI score, and the rest were used to test the score’s validity and reliability. Validation was excellent; favorable neurological survival differed by only 0.1% between the two groups.

How do the authors define favorable neurological survival?

Very clinically — either defined as absence of severe neurological deficits, or based on the Cerebral Performance Category with a score of 1 or 2 out of 5. A “2” is defined as moderate cerebral disability, but with sufficient cerebral functioning for independent activities of daily life plus the ability to work in sheltered environment. (Full CPC available on the Web at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4100b1_03_CPC%20Scale.pdf).

Were there unexpected variables that correlated with favorable neurological survival?

Not really. After testing a total of 37 variables, the only other variables that correlated with favorable neurological outcome was an initial rhythm of VFib or pulseless VTach that was defibrillated within 2 minutes – the group of patients most likely to survive a cardiopulmonary perspective. Another variable was arrest location in a monitored setting (such as an ER or ICU), and finally the absence of hypotension prior to arrest, which assumes some form of pre-arrest monitoring as well.

The variables that contributed the greatest impact on the score were time to resuscitation, arrest rhythm, and pre-arrest neurologic status.

All CASPRI variables are pre-arrest in patients under medical care at the time of arrest, as opposed to the traditional post-arrest markers used to assess and predict neurological function in all patients — such as pupillary and motor response after 72 hours, EEG background; level of serum markers of brain injury such as neuron-specific enolase or NSE; and diffusion MRI.

How predictive were the pre-arrest variables?

Those patients who fell in the top 10% of their prediction tool had about a 70% probability of favorable neurological survival whereas those in the bottom 10% had less than a 3% probability of favorable neurological survival.

Were there any limitations with the study or in interpreting its results?

Well, some physicians might protest aspects of the study design and statistical methods, as did Doctors Huszti and Nichol out of University of Washington – Harborview Center for Prehospital Emergency Care in an accompanying commentary.  There was also no information regarding how therapeutic hypothermia might impact score results.

To some physicians, the ability to predict who is likely to survive with good neurological outcome during a code might encourage further resuscitation efforts beyond the ordinary, although other physicians might argue that such a prediction is fraught with potential error and misuse.

It will be interesting to see if, as Doctors Huszti and Nichol predict, improvement in cardiac arrest outcomes result more from increased use of new monitoring technologies pre-arrest rather than physicians adjusting resuscitative efforts during a code. In fact, with current trends in technology, the future of monitoring may soon include out-of-hospital high-risk patients using mobile devices and other interactive tools, thereby improving mortality among out-of-hospital cardiac arrests as well.

A second study on cardiac arrest was recently published in the New England Journal of Medicine, where Dr. Sasson and colleagues analyzed data from the Cardiac Arrest Registry to Enhance Survival (or CARES), to better understand the known socioeconomic disparities in survival among various racial and ethnic groups as related to bystander-initiated CPR.

What is that study about?

The authors analyzed over 14,000 patients with an out-of-hospital cardiac arrest using a three-level regression model that considered the neighborhood, and individual patient and bystander-resuscitator characteristics. The study found a direct relationship between the probability that a person would receive bystander-initiated CPR, and a neighborhood with a higher median income and white composition. Independent of the neighborhood’s socioeconomic status, blacks and Hispanics were about 30% less likely than whites to receive bystander-initiated CPR, and those who received CPR were more likely to be male than female.

All patients were less likely to receive bystander-initiated CPR if they had a cardiac arrest in a neighborhood that was low-income or predominantly black, so the authors suggest that public health efforts target low-income black neighborhoods for CPR training. But I wonder what public health initiative we target to remove the race and sex disparities in rates of CPR reported here that are independent of the neighborhood?

Tell us about the third article – a literature review on cardioactive drugs?

In their recent article published in the American Journal of Emergency Medicine, Doctors Boyd and Brady describe the rise and not-always-a-fall in popularity with the 5 most common cardiac arrest medicines used in resuscitation.  Indeed, after reviewing the evidence, the authors agree with the most recent AHA published guidelines on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care (2010), which now places greater emphasis on the immediate recognition and activation of emergency response team, effective chest compressions, rapid defibrillation, and integrated post resuscitation care than on ACLS medication.

Epinephrine is the core stable drug of CPR. What are its known benefits?

As most physicians know, the use of the “epi x3” during a code is based on tradition and animal models and not human research. Epinephrine causes a number of favorable short-term cardiac and cerebral changes, resulting mainly from its role as an alpha-receptor agonist, but increased survival is found only in animals, not humans.  During the 1990s, use of high dose epinephrine was all the rage, but then fell totally out of favor when studies could not document any improved long-term outcome measures. There is even a suggestion of some adverse effect, with high dose epinephrine.

What about Vasopressin?

Also in in the 1990s, discovery of increased levels of plasma vasopressin concentrations in successfully resuscitated patients resulted in the flurry of studies on vasopressin, either alone or with epinephrine, in coding patients. Hemodynamic changes after vasopressin administration were even more impressive than those found with epinephrine, but results in individual trials were mixed. Then, in 2005, a meta-analysis published in the Archives of Internal Medicine found no statistical difference between vasopressin and epinephrine – not in return of spontaneous circulation, death before admission, 24-hour survival, or hospital discharges. The authors here note that some physicians still favor replacing one dose of epinephrine with vasopressin, but that practice is not supported by evidence in the literature.

Lidocaine is also a common cardioactive drug.

Lidocaine is used to treat a number of cardiac arrhythmias. In the early 2000s, it was discovered that about 80% of patients who undergo successful defibrillation had a subsequent recurrence of ventricular fibrillation, and so lidocaine was tested both as a prophylaxis against recurrent VFib, and also to terminate stable Vtach, in arrest and pre-arrest patients — without success.

Amiodarone has also been used during cardiac arrests.

Yes, in the late 1980s and early 1990s, amiodarone replaced lidocaine as the “miracle drug” based on several retrospective studies and then randomized controlled trials that demonstrated increased immediate survival among patients given a Hail Mary dose of amiodarone after seemingly futile resuscitative efforts. However, there are no studies confirming long-term survival in patients who received amiodarone.

Is Atropine still used in cardiac arrests?

Not really. There are relatively few studies on atropine use in a cardiac arrest, and in fact the AHA has recalled their recommendation to routinely administer Atropine in pulseless electrical activity or in a systole.

What about combinations of medications?

The authors review 5 studies that examined ACLS drugs as a group and did not find any long-term benefit to their use.

If medications aren’t effective in resuscitating patients, is anything helpful?

Rather than drugs, the authors concur with the 2010 AHA guidelines, where current evidence supports that we “redirect our focus more to the quality of CPR provided and early defibrillation, each of which has been shown to be more important than ACLS medication.”

Referenced Sources

Chan PS, Spertus JA, Krumholz HM et al for the Get With the Guidelines–Resuscitation Registry Investigators, A Validated Prediction Tool for Initial Survivors of In-Hospital Cardiac Arrest.  Arch Intern Med 2012; 172(12):947-953 (http://archinte.jamanetwork.com/article.aspx?articleid=1162169)

Sasson C, Magid D, Chan P for the CARES Surveillance Group. Association of Neighborhood Characteristics with Bystander-Initiated CPR. N Engl J Med 2012; 367:1607-1615 (http://www.nejm.org/doi/full/10.1056/NEJMoa1110700)

Boyd T, Brady W. The “Code Drugs in Cardiac Arrest”—the use of cardioactive medications in cardiac arrest resuscitation. The American Journal of Emergency Medicine Volume 30, Issue 5, June 2012, Pages 811–818. (http://www.ajemjournal.com/article/S0735-6757%2811%2900166-5/abstract)

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Pertussis

The second episode features Dr. Margaret Hessen covering pertussis, including the following:

• Clinical presentation of patients
• Confirmation of diagnosis
• Benefits of antibiotics
• Vaccines and indications

FEATURED PHYSICIAN

Dr. Margaret Hessen
Editor-in-chief of Elsevier’s Point of Care content

Dr. Margaret Hessen is board certified in internal medicine and infectious disease, and was in clinical practice for 17 years. She has also worked with a number of professional organizations on a variety of public health initiatives relating to infectious diseases and disaster preparedness.

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Transcript:

1. Why are we hearing so much about pertussis in recent years, and why is it a concern?

After a long period of declining incidence following the introduction of whole cell pertussis vaccine in the 1940s, the first decade of the 21st century has seen an increase in cases. The reason for the increase is not entirely clear.

What is known is that neither vaccination nor naturally acquired disease provides lifelong immunity, so there is always a susceptible population that serves as a reservoir for the disease.

Pertussis is of concern because of its potentially fatal complications and the fact that manifestations are due to the production of bacterial toxins which, once produced, remain active and unaffected by antibiotic treatment. While antibiotics are given to eradicate the organism, they have little impact on the disease manifestations.

2. How does pertussis present, and when should a clinician suspect it?

Pertussis presents classically in three stages. The first is the catarrhal stage, indistinguishable from the common cold, with low-grade or no fever, coryza, sneezing and a mild cough which becomes progressively more severe 7-10 days into the course. The persistent, severe and prolonged cough characterizes the second, or paroxysmal stage. Long-lasting bursts of coughing result in the inspiratory “whoop” that gives the disease its vernacular name, whooping cough. The violence and duration of the paroxysm can result in rib fractures, pneumothorax, cerebral bleeding, seizures, and hernias. Inability to clear secretions despite vigorous coughing is a result of toxin mediated paralysis of the endobronchial ciliary, and contributes to pneumonia, the most common complication and the most frequent cause of death due to pertussis. Most patients present a week or 10 days into the paroxysmal phase, which may last 6 weeks or more before gradually waning in the convalescent period. Physicians should suspect the disease based on the characteristic features of prolonged paroxysms of coughing followed by an inspiratory whoop and even vomiting. Infants may lack the inspiratory force to produce a whoop, but may become cyanotic during the paroxysm. Patients often appear dramatically ill and distressed during and immediately following the paroxysm, but relatively well between spells.

3. How is the diagnosis of pertussis confirmed?
The gold standard is culture. That having been said, culture requires a nasopharyngeal specimen (not a throat swab) and special growth media. The organisms are very fastidious and viability is easily lost under suboptimal transport or storage prior to processing. Cultures may take over a week to grow, and recovery of organisms usually occurs only before the first week or two of the paroxysmal phase. Other laboratory studies may be of more immediate practical value. Direct fluorescent antibody testing, particularly with a monoclonal antibody, can be used on nasopharyngeal secretions. DFA tests are widely available and very specific, meaning that a positive result is likely a true positive. However, these tests lack sensitivity, and a negative does not rule out disease. Many labs are turning to polymerase chain reaction, which is highly sensitive but associated with high rates of false positives. Serology is usually not helpful unless the patient presents fairly late in the course of the illness, and even then, a single positive test does not distinguish between acute disease versus previous infection or immunization.  Non-microbiological laboratory support of the diagnosis may be seen in a high white blood cell count with a relative lymphocytosis. The bottom line is that practitioners should rely on their clinical judgment to identify the characteristic constellation of features, and may need to consider more than one modality to confirm the diagnosis. Laboratory directors and public health authorities may provide invaluable guidance.If the disease manifestations are due to a toxin that doesn’t respond to antibiotics, is there any value to prescribing them, and if so, what is the antibiotic of choice?

If the diagnosis is made early in the course of disease and antibiotics are administered promptly, they may be of some benefit to the patient by forestalling further production of toxin. The primary benefit, however, is in preventing transmission of this highly contagious infection to contacts. This is of paramount importance in contacts of infants who may not be fully immunized. Erythromycin, azithromycin or trimethoprim/sulfamethoxazole should be prescribed to the patient and also to household contacts. In addition to medication, household contacts who are less than 7 years old who have not completed the initial 4-dose course of vaccine should complete the series with the shortest recommended interval, and children between 4 and 6 years who have not received the 5th dose should have it.

Over the past few years, a number of new pertussis vaccines and indications have been approved. Could you review these developments? Whole cell pertussis vaccine was the standard formulation for many years. However, while effective, it was associated with moderate local reactions, fever, prolonged crying in infants, and possibly implicated in more severe reactions. Acellular pertussis vaccine was developed as an alternative, and became available in pediatric formulations in the 1990s. More recently, the FDA has approved formulations for adolescents and adults. Acellular pertussis vaccine is available only in combination with diphtheria and tetanus toxoids.

The proportions of the three components differ between pediatric and adolescent/adult preparations, and the differences are designated as DTaP for pediatrics and TDaP for adolescent and adult use. The age range for which the adolescent/adult vaccine is approved varies slightly from one manufacturer to another, so consult the package insert. Some combination vaccines also include other components such as hepatitis B and polio vaccines. Appropriate dosing schedules for these combinations are fairly complex, and again, it is best to check the package insert or ACIP guidelines carefully. These references also address issues of interchangeability. All children should receive acellular pertussis vaccine in some form at 2, 4, 6, and 15-18 months of age, for a total of 4 doses, followed by a booster at 4-6 years of age, preferably before starting school. During outbreaks or if a return visit is deemed unlikely, the 4th dose may be given at 12 months if it has been 6 months since the 3rd dose.The availability of TDaP for adolescents and adults introduced the possibility of boosting waning immunity in that population, thus potentially reducing the reservoir of pertussis. The majority of recent cases have been reported in adolescents and adults. The majority of fatal cases occurs in infants less than 3 months of age, and most of these cases are acquired from adolescents or adults. Reducing susceptibility in adults through immunization therefore may protect infants who are too young to be fully immunized. While a single dose of TDaP is recommended for all adolescents and adults, particular attention should be paid to those known to have close contact with an infant less than 12 months of age, a strategy known as “cocooning.” Pregnant women who have not had a dose of TDap should receive it during the last 20 weeks of pregnancy or as soon postpartum as possible.

The acellular vaccine was developed to address safety issues, but is it as effective as the older vaccine, or are we seeing more pertussis because the acellular vaccine is less effective?

There are probably a number of factors leading to the increase. The rise in pertussis cases actually began in the 1980s, before the acellular vaccine was in use. Improvements in diagnostic testing are thought to account for some of the increase. With regard to the vaccine, there are conflicting data. Early comparative studies actually showed acellular preparations to be more effective than whole cell vaccine in pediatric subjects, but some recent studies find the acellular vaccine less effective. Genetic changes in the pathogen have also been postulated to contribute to the rise in cases and to less effective vaccine protection. That having been said, it is important to remember that we see far less pertussis now than in the pre-vaccine era. The current prevalence is about 4% of that seen before immunization was available.

So what do you see happening with the incidence of pertussis, and what is the take home message? Predictions are difficult, because we don’t really know the reasons for the rising incidence of pertussis over the last few decades. But I’m hopeful that the availability of the adolescent/adult preparation will make significant inroads in the reservoir of infection. The take home message is that prevention is much more effective than treatment of this disease, and clinicians need to be aware that the adolescent/adult formulation is available and that a one-time adolescent or adult dose is recommended for everyone. It should be strenuously encouraged for anyone who has contact with an infant, whose life might depend on it.

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West Nile Virus

The premiere episode features Dr. Margaret Hessen covering West Nile virus, including the following:

• Clinical presentation of patients
• Diagnosing West Nile virus
• Virus complications and effective treatment
• Infection prevention options

Featured Physician

Dr. Margaret Hessen
Editor-in-chief of Elsevier’s Point of Care content

Dr. Margaret Hessen is board certified in internal medicine and infectious disease, and was in clinical practice for 17 years. She has also worked with a number of professional organizations on a variety of public health initiatives relating to infectious diseases and disaster preparedness.

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Transcript:

1. This year has seen the largest number of reported cases of West Nile Virus infection since its arrival in the United States. What are the reasons for this dramatic increase?

This year’s weather has presented the perfect conditions for an early and robust crop of the mosquito vectors that transmit the disease. Many areas in the country experienced a mild winter followed by an early spring of unusual warmth, allowing mosquitos an early and long breeding season. There has also been speculation that the economic recession has had an impact, as unattended standing water in the yards and swimming pools of foreclosed and abandoned properties adds uncontrolled breeding territory for mosquitoes.

2. What is the clinical presentation of patients with infection due to West Nile Virus?

The vast majority of patients (about 80%) with West Nile infection are actually asymptomatic. Among those who develop symptoms, most experience the West Nile fever syndrome, a mild flu-like illness, characterized by fever, malaise, anorexia, mild headache and arthralgias. Some patients complain of eye pain. Generalized lymphadenopathy and a mild maculopapular rash may be seen on exam. The illness generally subsides after several days to a week.

A small minority of infected patients (about 1%) have neuroinvasive disease, a much more serious form of infection that presents as meningo-encephalitis, with fever, altered mental status, headache, photophobia and stiff neck. Neurologic abnormalities often include tremors and gait disturbance; parkinsonian features such as bradykinesia may be seen. Myoclonus is common.   Weakness is characteristic, and may be generalized or focal (including cranial nerve dysfunction in about 20%). Flaccid paralysis has been reported. Neuroinvasive disease is more common in persons over the age of 60 and immunocompromised persons, including diabetics and patients with chronic renal disease. As might be expected, neuroinvasive disease is associated with significant sequelae in many cases. Mortality exceeds 10%.

3. How does one make the diagnosis?

The work-up depends upon the clinical presentation. The diagnosis requires a high degree of suspicion in patients who present with West Nile fever. The presence of generalized lymphadenopathy and rash may trigger suspicion, especially under appropriate epidemiologic circumstances such as season, history of outdoor activity or documented mosquito bites. Rare cases are also associated with transfusion (although donated blood is tested for West Nile infection) or organ transplantation. The disease should be considered in all patients who present with a picture of meningoencephalitis, particularly now, when the disease is known to be epidemic.

Routine labwork is nondiagnostic, but may demonstrate a mild leukocytosis. The diagnostic test most commonly used to confirm West Nile fever is a serum ELISA for IgM antibodies to West Nile Virus. All positives in the US are reported to public health for confirmation by state or CDC laboratories by PCR or plaque reduction assay.

Patients with meningoencephalitis should undergo neuroimaging studies. Half or more show abnormalities on brain MRI, characteristically in the thalamus, basal ganglia and brainstem. In patients with flaccid paralysis, spinal MRI may reveal anterior horn changes.

Cerebrospinal fluid  is characteristic of viral infection, including a pleocytosis of about 100 to 400 white cells, usually but not invariably with a lymphocytic predominance. CSF protein is usually elevated and glucose is normal. CSF tested by ELISA for IgM antibody to West Nile Virus is usually positive. PCR is less sensitive than the ELISA, but may be helpful very early in disease before significant antibody activity has developed, or in immunocompromised patients.

Further studies may be indicated in some patients. For example, EMG testing may be helpful in patients with flaccid paralysis to differentiate from Guillain-Barre and other similar syndromes.

4. Has any specific treatment been shown effective?

Unfortunately not yet. Various agents have been tested, including interferon alfa and IVIG with a high titer of West Nile Virus antibodies, but early results were not definitive and further trials are ongoing. A monoclonal antibody to the virus has also been developed and is being tested in clinical trials. Treatment thus is primarily supportive, including fluids and antipyretics. Severely affected patients, particularly those with flaccid paralysis, may require ventilator support.

5. You mentioned previously that some patients experience incomplete recovery or complications, particularly with neuroinvasive disease. Can you elaborate on that?

Neuroinvasive disease follows a longer time course than West Nile Fever, which usually resolves within a few days to a week, although it might take longer for patients to resume fully normal activity. Of patients who survive neuroinvasive disease, however, about half have prolonged cognitive dysfunction lasting several months or longer. A significant number also have residual motor deficits, tremors, parkinsonism and other symptoms that persist for a year or more. Worse, as already discussed, about 10-12% die during the acute phase of the illness.

6. What can be done to prevent infection?

A vaccine is being developed, but is not yet available. Therefore, prevention revolves around efforts to control mosquito populations and to avoid being bitten. The first is largely a public health endeavor. Mosquito populations are monitored and tested for prevalence of infection. In some areas, public health officials also monitor for die-off of birds, who serve as an amplifying host. Spraying of pesticides may be undertaken by public health authorities to reduce adult mosquito populations. Elimination or treatment of standing water is an important and effective means of removing breeding sites.. Standing water that can’t be removed or drained can be treated, with larvicidal agents. These include two Bacillus species (abbreviated and sold as Bti and Bsp) that are pathogenic for mosquitos but not for humans, animals, or aquatic plants.  Rain barrels, wading pools, old tires and so forth should be drained. Swimming pools and hot tubs should be chlorinated and maintained. Other household efforts should include use of window screens, which should be kept in good repair. Personal protection includes reduction of exposure to mosquitos, such as avoiding outdoor activity at dawn and dusk, when mosquitos are most active. Mosquito repellants can be applied to skin or clothing. The CDC advises use of repellants containing DEET or picardin. The percentage correlates with length of protection, up to about 50% of the active ingredient, which confers about 8h or protection. Other acceptable and effective agents include oil of lemon eucalyptus (or PMD, the synthetic version) or IR3535. Permethrin-containing repellants may be applied to clothing and camping gear. These products impregnate fabric and remain effective through several washings or rain exposures. Small children may be more susceptible to side effects from repellants, and parents should check the product label for instructions pertaining to children. Repellants should not be used on infants under the age of 6 months. Mosquito nets may be fitted around baby carriages. Lastly, although a minority of cases are transmitted by transfusion or organ transplantation, testing of blood and tissue donors for evidence of West Nile Virus infection is now undertaken routinely.