Prevention as Precipitant

Posted by • August 4th, 2016

8-4 article header picTwo days after undergoing uncomplicated bilateral total knee arthroplasties, a 72-year-old man had a temperature of 101°F and a pruritic, erythematous rash that originated on his trunk and spread peripherally to his arms and upper thighs over the course of 24 hours.

Although rare, cutaneous drug reactions such as acute generalized exanthematous pustulosis, the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, the Stevens–Johnson syndrome, and toxic epidermal necrolysis can cause dramatic presentations and critical illness. These syndromes have certain features in common, and there is some evidence that patients can have overlap syndromes. A new Clinical Problem-Solving article explains.

Clinical Pearl

How often is acute generalized exanthematous pustulosis caused by medications?

At least 90% of cases of acute generalized exanthematous pustulosis are attributed to medication exposure, with antibiotics, antiepileptic agents, and antihypertensive agents commonly cited as culprits. Other reported triggers include viral infection, mercury, and spider bites.

Clinical Pearl

What is known about the pathophysiology of acute generalized exanthematous pustulosis?

The pathophysiological basis of acute generalized exanthematous pustulosis remains unclear; however, researchers evaluating cells isolated from skin lesions have found that the initial cellular infiltrate consists primarily of CD4+ and CD8+ T cells. In cases of acute generalized exanthematous pustulosis that are precipitated by medications, these T cells are drug-specific. Data also suggest that the initial T-cell infiltrates release inflammatory mediators, such as interleukin-8.

Morning Report Questions

Q: Describe some of the clinical and histologic features of acute generalized exanthematous pustulosis.

A: Skin findings in this disorder typically consist of diffuse erythema and edema with pinpoint nonfollicular, sterile pustules that can develop hours or days after exposure to the offending agent. The pustules often develop initially in intertriginous areas but can spread diffusely and rapidly. After removal of the trigger, the intensity of the rash typically peaks within 2 weeks and is followed by superficial desquamation. A pathologically similar but more localized form, known as acute localized exanthematous pustulosis, can also occur. Other common clinical features in acute generalized exanthematous pustulosis include fever, leukocytosis, lymphadenopathy, transaminitis, hypocalcemia, and mild renal insufficiency. Patients may also report burning or itching. The diagnosis is confirmed on biopsy; common histologic features include subcorneal or intraepidermal spongiform pustules, edema, and neutrophilic or eosinophilic infiltrates.

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Q: How is acute generalized exanthematous pustulosis managed? 

A: The mainstay of treatment is removal of the offending agent, which typically leads to full resolution of the skin lesions. General skin care is important for the prevention of superinfection and to promote healing, and some centers have reported rapid improvement with topical glucocorticoid use. There are no clinical trial data to support systemic glucocorticoid administration, and many clinicians reserve glucocorticoid therapy for severely ill patients.

Fire-Related Inhalation Injury

Posted by • August 4th, 2016

8-4 article 2 header picDespite the fact that we have had many years’ experience with treating injuries related to fires, the complex physiological process of inhalation injury remains poorly understood, diagnostic criteria remain unclear, specific therapeutic interventions remain ineffective, the individual risk of death remains difficult to quantify, and the long-term implications for survivors remain ill defined.

Fire-related inhalation injury results from a combination of direct exposures, systemic effects of inhaled toxins, accrual of endobronchial debris, and secondary infection. This new Review Article discusses the pathogenesis of and approach to fire-related inhalation injury.

Clinical Pearl

What is the annual incidence of fire-related inhalation injury in the United States?

Data from the National Inpatient Sample and the National Burn Repository suggest that there are roughly 40,000 inpatient admissions for burns in the United States annually; at a conservative estimate, 2000 of these admissions (5%) involve concomitant inhalation injury. In virtually all epidemiologic studies of burns, inhalation injury is an independent predictor of death, particularly in patients with cutaneous burns over 20% or more of the body-surface area.

Clinical Pearl

Are the supraglottic and infraglottic regions similarly affected by a fire-related inhalation injury?

Direct thermal damage is generally confined to the supraglottic airway, except in rare cases of steam inhalation, such as those that involve the inhalation of pressurized steam in engineering spaces. Most injuries that occur below the glottis are caused by aerosolized chemicals and incomplete products of combustion. The type and severity of these injuries are highly unpredictable, depending on the agents released and the particle sizes inhaled; smaller particles travel to a more distal location in the airway before deposition.

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Morning Report Questions

Q: What is the role of imaging in the assessment of patients who sustain fire-related inhalation injury? 

A: Plain chest radiographs that are obtained immediately after admission are usually normal and are therefore not useful for diagnosis or severity stratification. Radionuclide ventilation scanning has been advocated; inhomogeneous clearing of tracer associated with small-airway obstruction signifies inhalation injury. However, because the radionuclide ventilation technique is cumbersome and has not been found to be universally reliable, clinical use of this technique is currently rare. Computed tomographic scanning has shown promise for stratification of severity and for predicting clinical course. However, the information from such scans is unlikely to change the management of inhalation injury in a patient and comes at a logistic and fiscal cost that is likely to preclude routine application.

Q: How are carbon monoxide and cyanide exposure managed in patients with fire-related inhalation injury?

 A: Carbon monoxide exposure is common with inhalation injuries and may be obscured by a rapid reduction in carboxyhemoglobin levels owing to the administration of oxygen before hospital admission. Controversy swirls around the role of hyperbaric oxygen treatment in patients with burns who had clinically significant carbon monoxide exposure. Our understanding of the neurophysiological processes involved is incomplete and does not unequivocally support purely oxygen-based therapies. From a practical perspective, wheezing and airway debris are relative contraindications to hyperbaric oxygen treatment because they increase the risk of gas embolism and pneumothorax at decompression. If a high carboxyhemoglobin level is documented, or if substantial carbon monoxide exposure is suspected, the standard treatment is 100% normobaric oxygen for 6 hours. Controversy also exists with respect to the usefulness of testing and treating cyanide exposure in patients with inhalation injury. Currently in North American burn centers, most patients with inhalation injury are neither tested nor treated for cyanide exposure.

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Asthma Risk, Farming, and Innate Immunity

Posted by • August 3rd, 2016

8-4 from pages to practice fig 1bMrs. Newton and Janice, her 2-year-old daughter, are seeing you for a child wellness check-up.  Mrs. Newton asks you about asthma risks and reports that she’s read somewhere in a parenting magazine that letting children play in the dirt and be exposed to animals reduces risks of asthma and allergies.  She asks what you know about this.

Both genetic risk factors and the environment play a critical role in the development of asthma and atopic diseases.  Asthma has increased in recent decades especially in urban and modernized regions of the world.  Epidemiologic studies show that children who grew up in rural areas have less asthma and atopy.  It is thought that frequent exposure to farm animals and the associated endotoxins and microbiomes protect against the development of asthma.

Who are the Amish and the Hutterites and why does it matter?

The Amish populations in Indiana and the Hutterite populations in South Dakota are communities that originated from Europe who share a common ancestry.  Both of these communities are farming communities that share similar faith and lead simple lives.  However, the Amish live in single farms and practice traditional farming techniques using animals for fieldwork and transportation while the Hutterite live on large, highly-industrialized communal farms.  The prevalence of childhood asthma is four-times higher in the Hutterite communities.

What explains the differences in rates of asthma?

What was this cross-sectional study about?

In a cross-sectional study, investigators studied sixty sex- and age-matched Amish and Hutterite children (thirty from each community) age 7 to 14 years in 2012 to determine the impact of environmental exposures on asthma immune responses. Investigators gathered questionnaire information on asthma symptoms, genetic and laboratory data, and sampled airborne house dust from the homes of the subjects.  Dust was analyzed for endotoxin composition and allergen levels, and blood was analyzed for signs of activation of innate or adaptive immunity.

What were the results?

The analysis of genomic DNA markers and allele frequency of single-nucleotide polymorphism show the children from the two communities have remarkable genetic similarities.  Yet, none of the Amish children and six (20%) of the Hutterite children had asthma.  Hutterite children had 3-times the level of total serum median IgE levels (64 versus 21 kU/L) and a higher percentage of Hutterite children had high levels of specific IgE >3.5 kUA/L against common allergens.  Although endotoxins were found in all homes, the median endotoxin level was nearly 7 times as high in Amish homes (4,3999 versus 648 EU/m2).  Common allergens such as cat, dogs, house dust mite, and cockroaches were also detected more frequently in Amish homes.

Analysis of peripheral blood collected from the children showed differences between the two groups with increased proportions of neutrophils and decreased proportions of eosinophils in the Amish children.  Dust extracts were tested in mouse models of experimental allergic asthma and showed significant inhibition of airway hyperresponsitivity and esosinophilia from the Amish dust extracts but not the Hutterites.  Analysis of blood samples and mice experiments showed greater activation of the innate immune response in the Amish than in the Hutterites.

What are innate and adaptive immune responses?

In general, innate immune response refers to a “non-specific” defense mechanism.   It involves cytokine production and the complement pathway, and clear foreign substances by activating macrophages.  In contrast, adaptive immune systems are “specific” and are activated through pathways that involve presentation of specific antigens activating specific immune responses.  These responses are longer-lasting.

So what is my take-away?

The authors postulated that frequent exposures to farming animals and its associated microbiomes and endotoxins as observed in the Amish community reduced the risk of asthma by engaging and shaping the innate immune responses.

Don’t miss the NEJM Quick Take video summary:

Twenty-Seven Overnight Shifts: Lessons Learned from Indian Health Service Providers

Posted by • August 2nd, 2016

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At GIMC with my colleague Dr. Adaira Chou

The morning after I arrived in New Mexico was beautiful and warm, a pleasant change from the Northeast winter. I was entering my second year of emergency ultrasound fellowship and about to teach a point-of-care ultrasound course to health care providers working for the Indian Health Service (IHS).

On that first day, as my colleagues and I were powering up the ultrasound machines and connecting the video projector before class, an IHS physician entered the room and asked if we could teach him how to perform an ultrasound-guided peripheral IV insertion. He said that many of his patients had difficult IV access and he was hoping that learning this skill would reduce the number of central lines he had to place. When we informed him that a skills station dedicated to ultrasound-guided peripheral IV insertion was scheduled for later that morning, he apologetically replied that he could not attend because he had just completed an overnight shift in the ED and had another shift that evening.

As fellow emergency medicine physicians, we sympathized with his situation and were impressed with his desire to learn a new skill after what he described as a busy overnight shift. As we prepared a gel-block, IV catheter, and ultrasound machine, we talked with the doctor and were immediately struck by his kind and passionate demeanor. We learned that he had been practicing for about 30 years and now mainly worked overnight shifts because he preferred the regular schedule. I assumed that as a nocturnist, he worked fewer hours than his colleagues, as is typically the practice in the urban academic hospitals where I have trained. But when we asked how many shifts he worked per month, he replied that he typically works 22 overnight shifts a month, but last month he worked 27 shifts. My colleagues and I stopped what we were doing and the room fell silent. Had we misheard him? He then explained, without a hint of resentment, that he worked the extra shifts because the ED had been short staffed.

This schedule made me think back to my intern year in the ED. In a typical month, I worked 21 shifts with a variety of day, evening, and night shifts. I remember being exhausted and having little free time but knew it was worth it given the prospect of a better schedule as an attending physician. When I asked our new colleague how he managed his schedule, he responded with such sincerity expressed in both his eyes and voice: “I love my job so it’s really not that bad. The patients are really appreciative and they need us here.”

We had similar encounters with many IHS providers throughout our time teaching at Gallup Indian Medical Center. Some IHS physicians from other sites travelled many hours to attend the course, yet they arrived with tremendous energy and enthusiasm for learning. Their dedication to improving their skills was motivated by a desire to provide the best possible care for their patients. This group of providers also had a special affinity with one another and felt supported by their communities, including friends and family who volunteered to be ultrasound models during the course.

During my final year of emergency medicine residency, I completed a clinical away elective at another site in New Mexico — the Zuni Comprehensive Care IHS site. I learned first-hand about the disparities that exist among practice environments and in the delivery of emergency care in this country. I learned to become a better physician by working at the bedside with the many remarkable physicians at Zuni who embodied the same dedication as the providers at Gallup. Furthermore, regardless of how long patients who sought care at Zuni had to wait, they were gracious, appreciative, and thankful. My time at Zuni reminded me of why I was pursuing a career in emergency medicine.

Although my experience with the IHS system during residency and fellowship was limited, I met many compassionate, dedicated, and talented emergency providers from IHS sites located in New Mexico (Zuni, Gallup, and Shiprock) and Arizona (Fort Defiance and Tuba City), including one of my residency classmates — Dr. Ken Bernard. A physician of Native American heritage, he currently works as an emergency medicine physician for the IHS and regularly publishes blog posts to raise awareness of the past and current state of the IHS. I encourage everyone to take a moment to learn from his unique perspective and life experiences by reading his posts on this site. He reminds us that as health care providers, we can make a difference by serving underserved populations in resource-limited settings both internationally and in our own country.

We all may not have the opportunity to donate time or contribute to the IHS, but we can and should acknowledge and learn from the dedication and tireless efforts of our colleagues who serve in the IHS. I went to New Mexico to teach a skill to these physicians but ultimately learned so much from them. We can all strive to embody their passion, commitment, and love for their jobs. I hope these worthwhile lessons will serve as touchstones to help me gain perspective on my own job, schedule, and work conditions. When I feel the urge to complain about working an extra overnight shift, I hope I will think back to the IHS colleague who, despite 27 overnight shifts, continued to participate in the early teaching sessions and was the first to arrive every morning, excited to learn a new skill to provide better care for his patients.

John Eiken, MD



John Eicken (@johneicken) is an emergency medicine ultrasound fellow at Brigham and Women’s Hospital in Boston, MA.  He completed his residency training in the Harvard Affiliated Emergency Medicine Residency program (BWH/MGH) and is currently pursuing a Master of Education degree in the Technology, Innovation, and Education (TIE) program at the Harvard Graduate School of Education.  John’s academic interests focus on contributing to and improving medical and ultrasound education for medical students, trainees, and providers.  

A Man with Somnolence after Surgery

Posted by • July 28th, 2016

7-28 article 2 figure 1Although several theories have been postulated to explain the pathogenesis of the fat embolism syndrome, the end result is the embolization and agglutination of lipids, a process that causes obstruction of local blood flow in end organs (such as the lungs, brain, and skin) and leads to symptoms.

A 46-year-old man had worsening somnolence 1 day after replacement surgery with a femoral endoprosthetic implant. Fever, tachycardia, hypertension, and tachypnea developed, and examination revealed somnolence, gaze deviation, rigidity, and hyperreflexia. A diagnosis was made in a new Case Record.

Clinical Pearl

• What clinical findings are associated with malignant hyperthermia?

Malignant hyperthermia occurs in susceptible persons who have been exposed to halogenated volatile anesthetic agents or depolarizing muscle relaxants. It usually occurs between 30 minutes and 24 hours after such an exposure. Malignant hyperthermia is manifested by marked (sometimes extreme) temperature elevation, tachycardia, profound rigidity, agitation, hypercarbia, and acidosis.

Clinical Pearl

• When would you expect the symptoms of the neuroleptic malignant syndrome to appear in an affected patient?

Neuroleptic agents are sometimes administered in patients who have postoperative delirium, and postoperative use of antiemetic agents is common. Medications from each of these therapeutic classes can be associated with the development of the neuroleptic malignant syndrome. The symptoms typically evolve over a period of 1 to 3 days and include mental-status changes, profound rigidity, bradykinesia, hyperthermia, and autonomic instability, which is manifested by hypertension, tachycardia, and tachypnea.

Morning Report Questions

Q: What are some of the features of the fat embolism syndrome? 

A: The classic triad of findings includes respiratory insufficiency (most commonly manifested by hypoxemia), neurologic abnormalities (usually somnolence), and a petechial rash, which typically appears on the head, neck, thorax, and axillae. The fat embolism syndrome has an incidence of 1 to 3% after a single long-bone fracture (most commonly the femur) and a higher incidence after multiple fractures. It is more common among younger patients and those with closed fractures. The syndrome most commonly occurs between 24 and 72 hours after the precipitating injury, but onset between 12 and 24 hours after the inciting event is not uncommon. Eighty-five to 95% of patients with cerebral fat embolism who receive the appropriate supportive care survive.

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Q: Is the presence of a petechial rash required for diagnosis of the fat embolism syndrome? 

A: Early clinical descriptions of the fat embolism syndrome included the major criteria of respiratory insufficiency, cerebral involvement, and petechial rash; fever and tachycardia, were two minor criteria. However, in a later study involving persons with the fat embolism syndrome, 34% had somnolence as the earliest clinical sign or symptom; 75% had respiratory manifestations, and in 20%, the respiratory manifestations were initially dyspnea or tachypnea rather than hypoxemia. A petechial rash was a sign at presentation in only 17% of patients. Thus, it appears that the absence of hypoxemia and rash at the time of medical consultation does not rule out this diagnosis.

Liraglutide in Type 2 Diabetes

Posted by • July 28th, 2016

Liraglutide in Type 2 Diabetes graphTo assess the long-term effects of liraglutide on cardiovascular outcomes and other clinically important events, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was initiated in 2010. Patients with type 2 diabetes who had a glycated hemoglobin level of 7.0% or more were eligible if they either had not received drugs for this condition previously or had been treated with one or more oral antihyperglycemic agents or insulin (human neutral protamine Hagedorn, long-acting analogue, or premixed) or a combination of these agents.

Patients with type 2 diabetes and high cardiovascular risk were assigned to receive either the glucagonlike peptide 1 analogue liraglutide or placebo. In this new Original Article, the rate of first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was lower with liraglutide.

Clinical Pearl

• What is the mechanism of action of liraglutide?

Liraglutide, an analogue of human glucagon-like peptide 1 (GLP-1), has been approved for the treatment of type 2 diabetes. Its efficacy in lowering glucose levels has been established, and it has been associated with slight reductions in weight and blood pressure.

Clinical Pearl

• Is liraglutide associated with cardiovascular benefit in patients with type 2 diabetes who are at high risk for cardiovascular disease?

In the LEADER trial, patients in the liraglutide group had a lower risk of the primary composite outcome — first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis — and lower risks of death from cardiovascular causes, death from any cause, and microvascular events than did those in the placebo group. The frequencies of nonfatal myocardial infarction and nonfatal stroke were lower in the liraglutide group than in the placebo group, although the differences were not significant.

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 Morning Report Questions

Q: What are some of the adverse events that were associated with liraglutide in the LEADER trial?

A: In the LEADER trial, adverse events leading to the permanent discontinuation of the trial regimen were more common with liraglutide than with placebo. This result appears to have been driven by gastrointestinal disorders in the liraglutide group. There were more episodes of gallstone disease with liraglutide, a finding that has been reported previously. Acute pancreatitis occurred in 18 patients in the liraglutide group and in 23 in the placebo group. There has been considerable interest in a potential association between the use of GLP-1–receptor agonists and pancreatitis and pancreatic cancer, although there is no consistent preclinical, pharmacovigilance, or epidemiologic evidence to date. Among rodents receiving liraglutide, higher rates of thyroid C-cell tumors and hyperplasia have been observed than were observed among control animals. In the LEADER trial, no episodes of C-cell hyperplasia or medullary thyroid carcinoma were observed in patients in the liraglutide group. Randomized trials of this type, despite their size, are not powered to determine the effect of drugs on cancer risk and can therefore neither confirm nor exclude such a possibility.

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Q: How do the results of the LEADER trial compare with those of other trials assessing the cardiovascular safety of newer anti-hyperglycemic therapies?

A: The pattern of cardiovascular benefits that were associated with liraglutide in the LEADER trial appears to differ from that with the sodium–glucose cotransporter 2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial. The time to benefit emerged earlier in that trial than in the LEADER trial, and the heterogeneity of the direction and magnitude of the effects on the components of the primary composite outcome in that trial contrasts with the consistency of the effect in the LEADER trial. It should be noted that in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, the GLP-1–receptor agonist lixisenatide, which is shorter-acting than and structurally dissimilar to liraglutide, did not show any cardiovascular benefit in patients with diabetes and a recent acute coronary syndrome. There are a number of other trials regarding cardiovascular outcomes in high-risk cohorts of patients with type 2 diabetes in which similar magnitude effects on glycemic control have been shown but without significant benefits with respect to rates of cardiovascular events or death. These include trials with insulin, thiazolidinediones, and DPP-4 inhibitors. The LEADER trial had greater statistical power and included patients with a higher baseline glycated hemoglobin level than did most previous studies. However, no obvious single explanation in terms of either the study designs or the included populations is apparent to explain the divergent findings across this body of medical literature.

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage

Posted by • July 27th, 2016

blood pressure figure 1 What is the ideal blood pressure goal for spontaneous cerebral hemorrhage? Results of the ATACH-2 trial are discussed.

As a surgery resident, one of the first concepts I learned was that high blood pressure was bad in a patient who was actively bleeding.  This meant that for a trauma patient with a large liver or splenic laceration, systolic blood pressure should be kept around 90 mm Hg.  Similarly, for a ruptured abdominal aortic aneurysm, one of our first steps in management is to place the patient on an esmolol drip to get the blood pressure down.  Intuitively, this makes sense — high pressure increases the rate of bleeding, likely leading to worse clinical outcomes and even death.  This concept might also apply to spontaneous cerebral hemorrhage, however, here there is also good reason to be concerned that lowering blood pressure could be harmful. In stroke, rapid blood pressure lowering is thought to adversely affect neurological outcomes.   The INTERACT-2 trial published in NEJM in 2013, did not show a significant difference in rate of death or severe disability with intensive systolic blood pressure lowering (to <140 mm Hg) within 6 hours of symptom onset as compared with standard blood pressure goals of <180 mm Hg.

While INTERACT-2 was a negative trial, there were findings that suggested that earlier intensive blood pressure lowering might have benefits. Recently published Online First in NEJM, Qureshi et al. investigate whether earlier intensive blood pressure lowering may improve outcomes in spontaneous cerebral hemorrhage in the ATACH-2 trial.

This multicenter, randomized, unblinded, open-label trial compared intensive systolic blood pressure lowering (goal systolic blood pressure 110-139 mm Hg) to standard anti-hypertensive treatment  (goal systolic blood pressure 140-179 mm Hg) initiated within 4.5 hours of symptom onset in patients with spontaneous supratentorial intracerebral hemorrhage and at least one systolic blood pressure reading of 180 mm Hg or more.  Patients were required to have a Glasgow Coma Scale (GSC) of 5 or more and a hematoma of less than 60cm3.  Assigned blood pressure control was continued for 24 hours.  Intravenous nicardipine was the first line anti-hypertensive followed by intravenous labetolol (or diltiazem or urapidil if labetolol unavailable).  The primary outcome was the proportion of patients who had moderately severe or severe disability (based on the Rankin score) or death at 3 months.  Secondary outcomes included quality of life (measured by the EQ-5D questionnaire or the proportion of patients with 33% expansion of the hematoma on repeat CT scan after 24 hours.

In this analysis with 500 patients in each arm, the mean systolic blood pressure in the intensive-treatment group was about 130 mm Hg versus about 140 mm Hg in the standard-treatment group.  Failure to achieve target blood pressure control within 2 hours occurred in about 12% in the intensive- treatment group compared to less than 1% in the standard-treatment group.

The rate of the primary outcome of death or disability was similar between the two groups, both close to 38%.    There was also no difference in quality of life, percentage of patients with hematoma expansion, rates of death at 3 months or in neurologic deterioration at 24 hours after randomization.  While there was no difference in immediate adverse events, there was a higher risk of adverse events in the intensive-treatment group in the 3 months after randomization compared to the standard group (~25% vs 20% p=0.05).  Specifically, there were more renal adverse events in the intensive-treatment group (9% vs 4%, p=0.002).

Overall, the results of the study are similar to those in the INTERACT-2 trial; there was no significant difference in death or disability with intensive blood pressure lowering compared with standard blood control.  These findings do not support intensive blood pressure lowering in spontaneous intracerebral hemorrhage.

Immunogenicity of a Meningococcal B Vaccine

Posted by • July 21st, 2016

7-21 article 2 In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitides B at a U.S. university. Data suggested that vaccination would control the university outbreak because it isolates expressed antigens that were closely related to the vaccine antigens.

The development of an effective meningococcal serotype B vaccine has been a challenge. In this new Original Article, estimates of potential seroprotection are determined during a vaccine campaign at a U.S. university in response to an outbreak of Neisseria meningitidis.

Clinical Pearl

• What has been an obstacle to the development of an effective vaccine against serotype B meningococcal disease?

Although the incidence of meningococcal disease has been declining, in part because of the routine administration of meningococcal A, C, W, and Y vaccines in adolescents, the prevention of serogroup B disease has presented particular challenges; it is not possible to use the meningococcal B polysaccharide as a vaccine antigen owing to its similarity to human glycoproteins, the presence of which could lead to an autoimmune response. Meningococcal B vaccines that are derived from the outer-membrane vesicles of specific outbreak strains have been developed, but these vaccines have not provided broad protection beyond the outbreak strain.

Clinical Pearl

• What does the Meningococcal Antigen Typing System predict regarding the protection afforded by 4CMenB against meningococcal B strains in the United States?

The Meningococcal Antigen Typing System predicts that 4CMenB will protect against 91% of U.S. meningococcal B strains. Although the system is designed to quantify the expression of antigen-using polyclonal antibodies against the fHbp, NHBA, and NadA components of 4CMenB and to determine whether bacterial expression is sufficient to elicit a vaccine response, the system cannot determine the degree to which heterogeneity in vaccine-induced immunity can be expected within populations. In addition, the results of the typing system cannot be generalized to patients of other ages or to different schedules of administration because the results are based on pooled serum specimens from infants who received four doses of 4CMenB. Serum bactericidal antibody (SBA) testing of individual serum specimens is the reference standard for quantifying immune responses and is thought to be more informative with regard to protection against disease. There is little indication of how broadly 4CMenB protects people against the diverse strains of meningococcal B. No large-scale assessment of the breadth of individual vaccine-induced immunity has been conducted.

Morning Report Questions

Q: In the study by Basta et al., what level of protective immunity against an outbreak strain was observed among university students who received the 4CMenB vaccine?

A: Data from the study by Basta et al. indicate that only 66.1% of U.S. university students who were fully vaccinated with 4CMenB had putatively protective immunity against a meningococcal B outbreak strain. This level of seropositivity was lower than expected, given the antigenic similarity between the outbreak strain and the components of the vaccine and given that the Meningococcal Antigen Typing System predicted that 4CMenB would induce responses against the outbreak strain. The authors also analyzed immune responses to two of the 4CMenB vaccine reference strains and found that for the 44/76-SL and 5/99 reference strains, 86.9 to 100% and 96.7 to 100% of students, respectively, who were vaccinated with two doses had putatively protective hSBA titers. The results indicate that knowledge of hSBA immunity against the vaccine reference strains is not sufficient to predict individual-level immunity against an outbreak strain, even when the strain expresses one or more antigens that are closely related to the vaccine antigens.

Q: How conclusive are the immunogenicity data in the study by Basta et al. regarding the efficacy of the 4CMenB vaccine?

A: Further evaluation of 4CMenB efficacy is needed because of the limitations in drawing inferences about protection from immunogenicity data alone. It is possible that vaccinees who had no detectable SBA titer against the outbreak strain but who had an immune response to the meningococcal antigens that were used to develop the vaccine may benefit from some degree of protection. The findings of Basta et al. also raise questions about whether a third dose of 4CMenB might increase the proportion of seropositive responses against strains that were not perfectly matched to the vaccine.

Extending Aromatase-Inhibitor Therapy

Posted by • July 21st, 2016

Goss OA 07.21.16The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. The MA.17R trial, conducted by Goss et al., examined the effects of treatment with an aromatase inhibitor for 10 years rather than 5 years after any duration of prior treatment with tamoxifen, in postmenopausal women with hormone-receptor–positive early breast cancer.

An additional 5 years of adjuvant aromatase-inhibitor therapy in women with early hormone-receptor–positive breast cancer resulted in longer disease-free survival and a lower incidence of contralateral breast cancer than placebo, but not in longer overall survival. An Original Article explains.

Clinical Pearl

• What are current strategies to reduce the risk of recurrence in postmenopausal women who receive treatment for hormone-receptor–positive early breast cancer?

Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety of adjuvant regimens, including tamoxifen for 10 years, tamoxifen for up to 5 years followed by an aromatase inhibitor for 5 years, or an initial aromatase inhibitor for 5 years. Extrapolating from these results, many patients have chosen to continue taking an aromatase inhibitor for more than 5 years (if they do not have unacceptable side effects), despite the lack of specific data on its value and pending the results of clinical trials.

Clinical Pearl

• Does extending aromatase-inhibitor therapy for an additional 5 years prolong disease-free survival in postmenopausal women with hormone-receptor–positive early breast cancer?

The MA.17R trial showed that treatment with an aromatase inhibitor for an additional 5 years after initial treatment for 4.5 to 6 years was beneficial in preventing disease recurrence, independently of nodal status, prior adjuvant chemotherapy, time since the last dose of aromatase inhibitor, and duration of prior therapy with tamoxifen or an aromatase inhibitor. The rate of 5-year disease-free survival was 95% (95% confidence interval [CI], 93 to 96) in the letrozole group and 91% (95% CI, 89 to 93) in the placebo group. The hazard ratio involving disease recurrence or the occurrence of contralateral breast cancer with letrozole versus placebo was 0.66 (95% CI, 0.48 to 0.91; P=0.01). The annual incidence rate of contralateral breast cancer was 0.21% (95% CI, 0.10 to 0.32) in the letrozole group and 0.49% (95% CI, 0.32 to 0.67) in the placebo group (P=0.007), with a hazard ratio of 0.42 (95% CI, 0.22 to 0.81).

Table 2: Recurrence of Breast Cancer or Occurrence of Contralateral Breast Cancer

Morning Report Questions

Q: What is the effect of extended aromatase-inhibitor therapy on overall survival in postmenopausal women with hormone-receptor–positive early breast cancer? 

A: In the MA.17R trial, a total of 200 participants had died by the time of data cutoff (100 in each study group). The major causes of death in the letrozole and placebo groups were breast cancer (31 and 34 deaths, respectively), other primary cancers (26 and 25), and cardiovascular events (14 and 11). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) in the letrozole group and 94% (95% CI, 92 to 95) in the placebo group, with a hazard ratio for death of 0.97 (95% CI, 0.73 to 1.28; P=0.83). No significant difference in overall survival between letrozole and placebo was found in any of the prespecified subgroups.

Figure 1: Kaplan–Meier Curves for Disease-free and Overall Survival

Q: What safety issues were associated with extended aromatase-inhibitor therapy in the MA.17R trial?

A: In the MA.17R trial, bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. Only a minority of the fractures in both groups were located in the hip, spine, pelvis, or femur, and no significant change in physical health was recorded in either group, perhaps because most of the women in both groups took bone-protecting supplements or medications during the study. Overall, the low incidence of reported toxic effects is probably due to self-selection on the part of study participants who had had few unacceptable side effects through the first 5 years of aromatase-inhibitor therapy and were thus willing to undergo another 5 years of treatment.

Table 3: Adverse Events


Initiation Strategies for Renal-Replacement Therapy

Posted by • July 14th, 2016

2016-07-08_11-02-36Renal-replacement therapy is the cornerstone of the management of severe acute kidney injury. Gaudry et al. compared a strategy of early initiation of renal-replacement therapy with a strategy of delayed initiation in patients in the intensive care unit who had acute kidney injury of Kidney Disease: Improving Global Outcomes (KDIGO) classification stage 3.

This multicenter randomized trial compared strategies of early and delayed renal-replacement therapy in patients with severe acute kidney injury. There was no significant difference in mortality, the primary outcome, between the study groups. A new Original Article summarizes.

Clinical Pearl

• What evidence is available from randomized trials regarding the optimal timing for the initiation of renal-replacement therapy in critically ill patients with severe acute kidney injury?

Many studies have focused on methods of renal-replacement therapy, but the issue of when to initiate the therapy in the absence of a potentially life-threatening complication directly related to renal failure remains a subject of debate. The available knowledge about the initiation of renal-replacement therapy during acute kidney injury derives predominantly from observational studies. Indirect evidence has suggested that early renal-replacement therapy could confer a survival benefit. However, two observational studies reported high survival rates among patients who did not receive renal-replacement therapy, and one study reported adverse outcomes in association with very early renal-replacement therapy in patients with sepsis.

Clinical Pearl

• What potential advantages do early initiation and delayed initiation of renal-replacement therapy each offer?

Early initiation of renal-replacement therapy may allow for better control of fluid and electrolyte status, removal of uremic toxins, and prevention of complications such as gastric hemorrhage and metabolic encephalopathy. Delaying renal-replacement therapy initiation is intuitively unlikely to have any immediate benefit per se. However, a delay may allow time for the stabilization of a patient’s condition before renal-replacement therapy is initiated and may avoid the need for such support, which is not devoid of risk.

Morning Report Questions

Q: Is there a survival or other benefit associated with a delayed strategy of renal-replacement therapy in critically ill patients with severe acute kidney injury? 

A: In the study by Gaudry et al., contrary to the authors’ hypothesis, no survival benefit was observed with the delayed strategy of renal-replacement therapy. Mortality did not differ significantly between the two study groups: 48.5% (95% CI, 42.6 to 53.8) in the early-strategy group and 49.7% (95% CI, 43.8 to 55.0) in the delayed-strategy group (P=0.79). In this trial, however, a strategy of delayed initiation of renal-replacement therapy in critically ill patients with severe acute kidney injury obviated the need for renal-replacement therapy in almost 50% of cases (resulting in a considerable difference in the total number of renal-replacement therapy sessions). The lengths of stay in the intensive care unit and in the hospital were similar in the two groups, which indicates that allowing time for renal function recovery did not lead to prolongation of the stay in the intensive care unit.

Q: Do the results of the study by Gaudry et al. suggest that a “wait and see” approach should be favored for all critically ill patients with severe acute kidney injury?

A: The authors of the Gaudry study state that their study should not be interpreted as suggesting that a “wait and see” approach is safe for all patients. Indeed, careful surveillance is mandatory when deciding to delay renal-replacement therapy in patients with severe acute kidney injury so that any complication will be detected and renal-replacement therapy initiated without delay.

Figure 1. Probability of Survival and Timing of Renal-Replacement Therapy.

Table 2.  Primary and Secondary Outcomes and Adverse Events.