A Woman with Decreased Vision and Diplopia

Posted by Carla Rothaus • June 12th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 41-year-old woman presented with decreased visual acuity in the left eye and diplopia. MRI of the head and orbits revealed abnormal soft tissue in the left sphenoid sinus and orbital apex, extending to the left cavernous sinus. A diagnostic procedure was performed.

Lymphoma of the orbit is typically painless and has an indolent course, and thus the presence of pain and subacute progression of symptoms may suggest a different diagnosis or a more aggressive type of lymphoma.

Clinical Pearls

What conditions may predispose to the development of orbital cellulitis?

Orbital cellulitis commonly results from bacterial infection, most often as an extension of ethmoid or frontal sinusitis, but it may also result from cutaneous trauma, dental abscess, or dacryocystitis.

The organisms most commonly associated with orbital cellulitis are streptococcal and staphylococcal species.

What diseases are included in the differential diagnosis of an inflammatory process involving the orbit?

Inflammatory disease of the orbit is common, and causes include idiopathic orbital inflammation, IgG4-related orbital inflammation, sarcoidosis, granulomatosis with polyangiitis, and proliferative disorders of histiocytes. Idiopathic orbital inflammation, which is by far the most common of these diseases, was previously known as orbital pseudotumor and refers to inflammation involving any structure of the orbit. Specific descriptive nomenclature includes dacryoadenitis, scleritis, and myositis, although many cases involve diffuse infiltration of the orbital fat. This usually painful condition often results in visible periorbital inflammation and may occasionally extend to involve the paranasal sinuses or dura. The presence of pain is often clinically useful in making the diagnosis, but the absence of pain can be misleading. IgG4-related disease is an orbital inflammatory disorder that is less common than idiopathic orbital inflammation. Patients with IgG4-related disease have clinical and radiographic presentations that are similar to those of patients with idiopathic orbital inflammation, but IgG4-related disease is more likely to be bilateral and associated with an inflammatory disorder of another organ system. Sarcoidosis is a granulomatous disease that may involve the lungs, liver, spleen, eyes, and orbit. Orbital sarcoidosis most often involves the lacrimal glands but may involve other orbital structures and extend through apical foramina to the surrounding structures.

Morning Report Questions

Q: What clinical and imaging features characterize lymphoid tumors involving the orbit?

A: Lymphoid tumors are common infiltrative orbital cancers and range from the most common variety, indolent mucosa-associated lymphoid-tissue lymphomas, to more rare, aggressive varieties.

Lymphoma may involve any orbital structure — commonly including the lacrimal gland, extraocular muscle, or fat — and may be part of a systemic process. B-cell lymphomas are the most common type to involve the orbit and tend to be unilateral, painless, and slow-growing. On radiography, lymphoma has an infiltrative pattern, with molding to the surrounding structures.

Q: Is CD30 expression a common feature of diffuse large B-cell lymphoma?

A: Diffuse large B-cell lymphoma represents a group of biologically heterogeneous cancers that may be divided into morphologic, genetic, and immunophenotypic subgroups and that include certain specific disease entities. Most cases do not fulfill diagnostic criteria for one of the specific disease entities and are classified as diffuse large B-cell lymphoma (not otherwise specified). CD30 expression is seen in only 14% of cases of diffuse large B-cell lymphoma, and CD30-positive cases have been reported to be associated with a superior 5-year overall and progression-free survival, as compared with CD30-negative cases, a difference that is maintained in both germinal-center and nongerminal-center subgroups. Gene-expression profiling studies have shown a distinct profile, suggesting that CD30-positive cases may represent a distinct subgroup of diffuse large B-cell lymphoma.

Early CPR in Out-of-Hospital Cardiac Arrests — Outcomes and Evaluation of a Mobile-Dispatch System

Posted by Andrea Merrill • June 10th, 2015

The first time I ever performed CPR was on my 19th birthday.  My official title was “summer employee,” a minimum wage job that encompassed a variety of menial but necessary tasks in the emergency department of a busy rural hospital.  One of the accompanying benefits of my job was the chance to learn CPR, and by the summer’s end, by my birthday, I had finally received my CPR certification.

Now, 12 years later, some details are a little hazy; but I remember that the patient was in her 80s and had gone into cardiac arrest at home.   The dispatched emergency medical services team had been providing chest compressions for 14 minutes by the time she arrived at the emergency department. I remember how quickly my arms tired, despite an adrenaline surge and my racing heart as I watched my compressions on the telemetry monitor, seeing that the force provided was adequate. But, most of all, I remember feeling sad and defeated when we could not save her.  Afterward, the emergency physician tried to comfort me, telling me that our efforts were likely futile from the start– that most patients who come into the hospital after an outside cardiac arrest do not survive.

Since that fateful afternoon, I have performed CPR many more times, usually with similar disappointing outcomes.  CPR guidelines have changed twice since my initial certification, and now focus on fast, hard compressions, often suggested, ironically, to be given to the beat of “Stayin’ Alive.”  However, despite our widespread CPR training, patients who develop cardiac arrest outside the hospital generally continue to have poor outcomes, spurring debate on the utility and value of CPR training for non-medical professionals.

This debate is the subject of two articles by a group from the Center for Resuscitation Science in Sweden that appear in this week’s NEJM that examine the potential benefits of early out-of-hospital bystander CPR in cardiac arrest.   In the first study by Hasselqvist-Ax et al., the authors used the Swedish Cardiac Arrest Registry in a retrospective analysis of outcomes from over 30,000 cases of witnessed cardiac arrest that occurred from 1990 to 2011.  About half of all cardiac arrest patients received out-of-hospital CPR by a bystander, while the other half did not.

Although survival overall was poor at 30 days, the survival for those who received out-of-hospital CPR was more than double that of those who did not (10.5% vs 4.0%, p<0.001).  These findings remained robust when the authors controlled for multiple potential confounding factors such as sex, age, cardiac etiology, initial heart rhythm, and location of cardiac arrest (in the home versus in a public place– Table 2 in the original article).  There was, however, in preplanned subgroup analysis, a positive interaction for male sex and arrest outside the home- these 2 subgroups had a more marked benefit from out-of-hospital CPR compared to other subgroups (in contrast to my first CPR patient).

There are a few characteristics of interest in the out-of-hospital CPR group.  First, men outnumbered women in the out-of-hospital group, and were more likely to have ventricular fibrillation as their initial ECG rhythm.  The out-of-hospital CPR group also had a shorter collapse-to-call time for EMS (by 1 minute), indicating that people trained in CPR appear to recognize a medical emergency faster and therefore call emergency services sooner.  Despite calling emergency services faster, however, there was a delay seen in time to EMS arrival after the call (difference of 2 minutes) as well as a delay in time from collapse to initiation of defibrillation (2 minutes).  Thus, early initiation of out-of-hospital CPR leads to improved survival benefits sufficiently robust to outweigh a delay in arrival of emergency medical services and a delay in initiation of defibrillation.

The second study, by Svensson and colleagues, evaluated the utility of a mobile phone positioning system to dispatch CPR-trained lay volunteers to out-of-hospital cardiac arrests in an effort to increase the rate of out-of-hospital CPR actually delivered.

Svensson et al. performed a community-based randomized controlled trial in the county of Stockholm, Sweden from April 2012 to December 2013.  5,989 CPR-trained lay volunteers were recruited at the beginning of the study.  When an out-of-hospital cardiac arrest was called into the dispatcher between 6am and 11pm, the mobile phone positioning system was launched to locate any trained lay volunteers within a 500-meters of the incident.  Randomization was performed in a 1:1 ratio by the mobile phone positioning system. In cases assigned to the intervention group, a voice call, text message and web link to a map showing the location was then sent out to any volunteers in a 500-meter radius.  The dispatcher and all investigators were blinded until the final analysis was completed.  Primary outcome was initiation of bystander CPR before arrival of EMS.  Secondary outcomes included return of spontaneous circulation and 30-day survival.

There were 667 out-of-hospital cardiac arrests randomized and evaluated (46% in the intervention group and 54% in the control group).  Baseline characteristics were similar for the two groups.  61.6% of patients randomized to the intervention group (utilization of mobile phone dispatch system) received bystander CPR compared to 47.8% of those in the control group, a difference of about 14% (p<0.001).  However, about 700 out-of-hospital cardiac arrests were not randomized by the dispatcher, which would reduce the effect of the intervention by about half, resulting in only a 7% difference when the whole population of persons having an out-of-hospital cardiac arrest is considered.

Despite the increase in bystander CPR in the intervention group, there was no significant difference in return of spontaneous circulation or 30-day survival between the two groups, which the authors postulate is because the trial was not adequately powered for those outcomes.  Additionally, only 65% of lay volunteers contacted by the mobile phone dispatch attempted to reach the scene. And even when lay volunteers reached the scene, only 13% of all cases for whom calls were dispatched had CPR initiated before trained personnel arrived (see Table 3 from study).

The technology to dispatch trained laypersons to a nearby cardiac arrest victim may have potential to increase bystander CPR rates, if implemented on a wider scale; but many obstacles may be encountered, including legal, social and economic factors.  One might speculate that greatest benefit may occur in rural communities, where there may be considerable delay until emergency medical services can reach the scene or in senior communities where many cardiac arrests events occur at home where CPR-trained and capable lay persons are not usually around.  Maybe my first patient 12 years ago would have benefited from such a system, or at least have had a slightly increased chance in survival once she got to the hospital under the care of the emergency room team, and my 19-year-old hands.

The authors of these studies are available through June 19th to answer your questions on the NEJM Group Open Forum


Vasopressin Antagonists

Posted by Carla Rothaus • June 5th, 2015

A new review in the Disorders of Fluids and Electrolytes series summarizes the salient discoveries that culminated in the development of vasopressin antagonists, focusing on their actions, side effects, emerging safety concerns, and important gaps in data. The review also considers how and when to use these agents.

Ample evidence is available to implicate vasopressin, a small polypeptide that is synthesized in the hypothalamus and secreted from the posterior pituitary, in the pathogenesis of many hyponatremic disorders. As the most common electrolyte disorder, hyponatremia is consistently associated with increased mortality and morbidity. The treatment of hyponatremia has been plagued by a paucity of controlled studies and by a lack of reliable and safe approaches. Therefore, the regulatory approval of vasopressin antagonists represents a milestone in the field.

Clinical Pearls

Describe the vasopressin receptors, and the mechanism of action of vasopressin antagonists.

The V1A receptor is found in liver, smooth muscle, myocardium, brain, and platelets; the V1B receptor is involved in the secretion of corticotropin in the anterior pituitary. The V2 receptor is located primarily in the basolateral membrane of collecting-duct cells. The binding of the hormone to the V2 receptor on the basolateral membrane of the principal cell of the collecting duct activates adenylyl cyclase and generates cyclic AMP (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates protein kinase A, which phosphorylates aquaporin water channels (AQP2) and induces them to relocate to the luminal membrane. This promotes the reabsorption of water from tubular fluid to blood, rendering the tubular fluid more concentrated (increased osmolality). In the presence of a vasopressin antagonist, the signaling pathway is not activated. As a consequence, the water permeability of the cell remains high and water is not reabsorbed, causing the excretion of dilute urine (decreased osmolality) and thereby increasing the level of sodium in the blood compartment.

Figure 1. Binding of Vasopressin to Its Receptor and Location of Antagonist.

Figure 2. Cellular Effects of Vasopressin and Consequences of Vasopressin Antagonism.

What vasopressin antagonists are approved for use in the United States?

Tolvaptan and conivaptan (with the latter blocking both the V1A and V2 receptors) have garnered approval for the treatment of euvolemic and hypervolemic hyponatremia in the United States. Conivaptan and tolvaptan have differing affinities for the vasopressin receptor. The relative inhibition of the two receptors (V2:V1 selectivity ratio) is much greater with tolvaptan (by a factor of 29) than with conivaptan (by a factor of 5.7). Thus, conivaptan is a nonselective vasopressin inhibitor, whereas tolvaptan is a more selective V2 inhibitor. Each of the drugs has a half-life that ranges from 6 to 10 hours and has activity that peaks several hours after administration. Both increase urine flow and the excretion of electrolyte-free water, without substantial changes in sodium or potassium excretion, leading to their designation as aquaretic agents.

Table 2. Inhibitory Constants and Pharmacokinetics of Two Vasopressin Antagonists.

Morning Report Questions

Q: When should vasopressin antagonists be avoided?

A: Dependence on the excretion of free water makes the response to vasopressin antagonists too slow to benefit patients with hyponatremia who have severe cerebral symptoms. Such patients require a prompt decrease in the volume of brain water, which is best achieved with hypertonic saline. Similarly, patients with hypovolemic hyponatremia require volume repletion to halt nonosmotic release of vasopressin. Furthermore, V1A-receptor antagonists can cause hypotension in such patients. Neither drug is effective in patients with advanced chronic kidney disease (stage 4 or 5).

Q: Is there consensus regarding the use of vasopressin antagonists?

A: Despite the paucity of data, panels have put forth recommendations for the treatment of hyponatremia. Of the available guidelines, two have garnered the most attention. The first set of guidelines was prepared by an expert panel that was supported by the manufacturer of tolvaptan; the second set, the European Clinical Practice Guideline, was developed by members of three medical societies with an interest in hyponatremia without support from the pharmaceutical industry. The two panels have divergent recommendations regarding the use of vasopressin antagonists. The European guidelines do not recommend the use of vasopressin antagonists in patients with euvolemia who have SIADH [syndrome of inappropriate secretion of antidiuretic hormone] and recommend against their use in patients with heart failure, in whom the need for water restriction and the wider use of urea are recommended. In contrast, the expert panel recommends that vasopressin antagonists be used in patients with SIADH when water restriction fails and states that vasopressin antagonists are “a viable option along with loop diuretics” in patients with heart failure. The European panelists express concern regarding the neurologic consequences of overcorrection, the risk of hepatotoxicity, and the lack of data supporting a survival benefit. The recommendations of the expert panel also have merit, particularly since none of the alternative approaches have been subjected to the rigors of a regulatory process requiring randomized, controlled trials nor have they received the approval of any regulatory agency.

Table 3. Recommendations for the Use of Vaptans in the Treatment of Hyponatremia.

In Sight and Out of Mind

Posted by Carla Rothaus • June 5th, 2015

In the latest Clinical Problem-Solving article, a 21-year-old man presented to the emergency department with fever and rash. His fever had started about 1 week before presentation and was associated with chills, myalgia, nausea, and vomiting. He also had a headache without photophobia.

In the United States, recent declines in the rate of vaccination against measles have led to several outbreaks. Given the resurgence  of measles and other vaccine-preventable diseases in the United

States, interventions are needed to reintroduce a discussion of these  rare conditions into medical education so that clinicians will consider them in differential diagnoses.

Clinical Pearls

What type of virus causes measles?

Measles (or rubeola — a term derived from “rubeo,” the Latin word for  “red”) is an acute viral illness that is caused by a single-stranded, enveloped RNA virus. It is classified as a member of the genus morbillivirus in the Paramyxoviridae family.

What aspects of a patient’s history or clinical presentation should raise suspicion for measles?

Measles should be suspected in any patient who presents with fever, rash, a history of travel to endemic areas or areas known to have recent transmission, or exposure to contacts with similar symptoms or a history of exposure to measles. The classic rash in patients with measles develops in a cephalocaudal and centrifugal distribution; if this pattern is described by the patient, it may provide an important clue. The prodromal symptoms, known as the “3Cs” of measles, are cough, coryza, and conjunctivitis. Koplik’s spots are transient and are noted in only 50 to 70% of patients with measles. Headache, mild gastrointestinal symptoms, and mild cerebrospinal fluid pleocytosis are common but nonspecific symptoms.

Morning Report Questions

Q: How contagious is measles?

A: Measles is extremely contagious, and contact tracing is imperative.

Clinical measles develops in approximately 9 of 10 susceptible persons who have had close contact with a person with measles. The virus is transmitted by direct contact with infectious droplets or by airborne spread when an infected person breathes, coughs, or sneezes.Transmission through aerosolized droplet nuclei has been detected in closed areas for up to 2 hours after a person with measles occupies the area. Patients are infectious for approximately 4 days before and 4 days after the onset of the rash.

Q: What are the guidelines for vaccination against measles?

A: The Advisory Committee on Immunization Practices recommends routine vaccination with two doses of measles-mumps-rubella vaccine for children, with the first dose administered at 12 to 15 months of age and the second dose administered at 4 to 6 years of age, before school entry. Two doses are recommended for unvaccinated adults who are at high risk for exposure and transmission, such as students attending colleges or other educational institutions after high school, health care personnel, and international travelers, and one dose is recommended for other adults who are 18 years of age or older. Use of the inactivated vaccine strain between 1963 and 1967 was considered to be ineffective, and persons who were vaccinated during that period should be revaccinated with live vaccine.

Vaccination against measles is not necessary if there is evidence of immunity or laboratory confirmation of prior illness.

Ezetimibe and Cardiovascular Outcomes

Posted by Chana Sacks • June 3rd, 2015

As you walk into Mr. R’s room to see if he has last-minute questions about his discharge medications, you can’t believe how different – how much better – he looks dressed in his usual clothes, instead of an errantly-snapped hospital gown.   You met him 4 days ago, when he was wheeled, pale and groggy, onto your unit directly from the cardiac catheterization lab.  There, a coronary stent was placed to open the blockage responsible for the crushing chest pain that had gripped him while he was at home working on his car.

Over the past few days, you have tried to teach him a bit about what caused his heart disease – and how to treat it.  You have discussed diet, exercise, anti-platelet drugs, and you have spent a lot of time talking about cholesterol.  He has told you that he has never before taken a medication regularly – “I just never thought of myself as a med person, doc” – and that he hasn’t seen a primary care physician in years.  But he tells you he is ready to make some changes.

You have told him what we know: that treatment with statins lowers LDL cholesterol and reduces the risk of another heart attack.   And while you were telling him that with such confidence, it was all that we still don’t know about cholesterol-lowering therapy that ran through your mind:  what is the optimal LDL for someone who has had a heart attack?  Should that be achieved with a statin alone, or is some combination of lipid-lowering medications ideal?

In an attempt to address some of the uncertainty about the potential benefit of adding non-statin treatment to a statin, the IMPROVE-IT investigators conducted a randomized trial, now published in NEJM, to compare two lipid-lowering regimens: a statin alone versus a statin plus ezetimibe, a medication that reduces the intestinal absorption of cholesterol.  The data seem to suggest that lower LDL is better, perhaps independent of how that is achieved.

18,000 patients hospitalized for an acute coronary syndrome were randomized to either simvastatin 40mg plus placebo or to simvastatin 40mg plus ezetimibe 10mg.  Like your patient, about 75% of participants were men, with an average age in their early 60s; two thirds had been on no lipid-lowering agents prior to this hospitalization.

The results: at the start of the trial, LDL in both groups was 94mg/dl. At one year, the mean LDL cholesterol was lower in the simvastatin/ezetimibe group (53 mg/dL) as compared with the simvastatin/placebo group (70 mg/dL).  At 7 years of follow-up, the primary endpoint of cardiovascular death, major coronary event, or non-fatal stroke occurred in 32.7% of the simvastatin/ezetimibe arm versus 34.7% of the statin/placebo arm, a statistically significant 2% difference.  This means that about 50 patients would need to be treated for 7 years to prevent one event.  No differences were observed in the pre-specified safety endpoints.  Importantly, after a median of 6 years, 42% of patients in each group had discontinued treatment.

So for Mr. R – should you add an ezetimibe prescription to his already impressive stack of new medications?  Not necessarily.  In an accompanying editorial entitled “Proof that Lower is Better,” NEJM editors Drs. John Jarcho and John Keaney describe the significance of this trial and caution against drawing that conclusion: “IMPROVE-IT should not be interpreted as demonstrating anything uniquely beneficial about the use of ezetimibe. Indeed, the real implication of IMPROVE-IT is to suggest that all LDL reductions, regardless of mechanism, are of equivalent benefit.”

So, as you and Mr. R spend your last few minutes together before discharge, maybe the focus shouldn’t be on the modest improvement achieved in this trial, but rather on emphasizing the importance of taking these medications and making lifestyle changes for the long haul.  Today, he feels motivated by his harrowing experience and empowered by the knowledge you have shared.  You encourage him to keep those feelings and his goals in mind, even as the memories of this hospitalization fade.  He nods and heads out – soon, he says, he wants to get back to working on that car.

View the Quick Take video summary of this article, and join the discussion with the authors on the NEJM Group Open Forum.

High-Flow Oxygen Therapy: a Lifesaver for Patients with Acute Hypoxemic Respiratory Failure

Posted by Rachel Wolfson • June 2nd, 2015

For hospitalists and residents across the country, this is an all too familiar scenario: a 60-year-old man is admitted to the hospital with pneumonia. Unfortunately, his course is complicated by acute hypoxemic respiratory failure secondary to the pneumonia, and he is transferred to the ICU. Physicians would like to avoid intubation if possible due to its invasiveness and attendant adverse consequences, but it is clear, something more must be done to support this patient.

What about noninvasive ventilation (NIV) delivered in the form of positive pressure via a facemask? It has been shown to be an effective therapy for patients with acute exacerbations of a chronic lung condition, like COPD, and cardiogenic pulmonary edema. By extension, it has been assumed that it would benefit others with acute respiratory failure, but it actually has not been tested in patients with de novo non-hypercapnic respiratory failure. On the other hand, high-flow oxygen therapy, in which oxygen is delivered through nasal cannula at high rates, has recently emerged as perhaps an alternative to NIV in the latter setting.

To address this issue, Frat et al. performed a prospective, multicenter randomized controlled trial to assess the effectiveness of NIV vs. high-flow oxygen in ICU patients with de novo non-hypercapnic respiratory failure. Just over 300 patients participated in the trial, and they were approximately evenly randomized to one of three therapies: standard oxygen, high-flow oxygen, or NIV. There was no significant difference between the three groups in terms of the primary outcome of intubation rate at day 28, although the rate in patients treated with high-flow oxygen was lower. However, high-flow oxygen did lead to a statistically significant increase in ventilator free days and decrease in 90-day mortality as compared to standard therapy or NIV. Furthermore, high-flow oxygen therapy improved patient comfort over the other two therapies.  However, all of these were secondary outcomes.

While this trial did not find a significant difference in terms of the primary outcome, the decreased 90-day mortality rate with high-flow oxygen therapy is an interesting and promising finding. Based on these data, Michael Matthay, MD, recommends in an accompanying editorial that high-flow oxygen treatment be considered for patients with non-hypercapnic, hypoxemic respiratory failure in settings where appropriate monitoring is available. However, he notes that more trials are needed. As for our elderly patients presenting with new respiratory failure from pneumonia like above, it may just be better to reach for a high-flow nasal cannula rather than the facemask.

Latent Tuberculosis Infection

Posted by Carla Rothaus • May 29th, 2015

About one third of the world population has latent M. tuberculosis infection. A new review explains the approach to patients with latent infection, including an update on the risks and benefits of treatment and assessment of the likelihood of progression to active disease.

Studies suggest that active tuberculosis will develop in 5 to 15% of persons with latent infection during their lifetimes.

Clinical Pearls

Describe the pathogenesis of latent Mycobacterium tuberculosis infection.

The natural history of tuberculosis begins with the inhalation of Mycobacterium tuberculosis organisms. A period of bacterial replication and dissemination ensues, followed by immunologic containment of viable bacilli. The result of this process is asymptomatic latent tuberculosis infection, which is defined as a state of persistent bacterial viability, immune control, and no evidence of clinically manifested active tuberculosis.

Who is most at risk for progression of latent infection to active clinical tuberculosis disease?

The likelihood of progression of latent infection to active clinical tuberculosis disease is determined by bacterial, host, and environmental factors. It has been postulated that there are differences in the ability of various strains of M. tuberculosis to cause disease, but little clinical or epidemiologic data support this theory. The initial bacterial load, inferred by the severity of disease in an index case and the closeness of the contact, is directly associated with the risk of development of the disease. Disease develops at a higher rate among infants and very young children who have latent infection than among older children with latent infection; after a child reaches approximately 5 years of age, age appears to have little correlation with the risk of disease. Suppression of cellular immunity by human immunodeficiency virus (HIV) infection, tumor necrosis factor alpha inhibitors, glucocorticoids, and organ or hematologic transplantation increases the risk of progression of latent infection substantially. End-stage renal disease confers an increased likelihood of progression to active tuberculosis. Silicosis and exposure to silica dust are also associated with increased rates of progression, and the combination of HIV and silicosis in South African miners has contributed to an explosive epidemic of tuberculosis in this population.

Table 1. Incidence of Active Tuberculosis and Prevalence of Latent Tuberculosis Infection in Selected High-Risk Groups, According to Published Studies.

Morning Report Questions

Q: What are limitations of the tuberculin skin test and the interferon-gamma release assay (IGRA) for the detection of latent tuberculosis?

A: The tuberculin skin test is widely used and inexpensive, but it has poor specificity in populations vaccinated with bacille Calmette-Guerin (BCG), is subject to cross-reactivity with environmental nontuberculosis mycobacteria, and has poor sensitivity in immunocompromised persons. There are also logistic drawbacks, including the need for a return visit in 2 to 5 days to read the amount of induration, since self-reading is associated with a high error rate. Furthermore, there is a worldwide shortage of tuberculin, attributed to market forces. IGRAs (the QuantiFERON-TB Gold In-Tube assay [Cellestis] and the T-SPOT.TB assay [Oxford Immunotec] measure in vitro responses of T cells or peripheral-blood mononuclear cells to M. tuberculosis antigens that are not found in BCG and most nontuberculous mycobacteria, and thus specificity for M. tuberculosis is higher than with the tuberculin skin test. However, recent studies involving serially tested health care workers in the United States have shown that false conversions (from a negative to a false positive result) and reversions (from a positive to a false negative result) are more common with IGRAs than with tuberculin skin tests. In addition, IGRAs are more costly and require more work in the laboratory.

Q: What options are available for the treatment of latent tuberculosis?

A: The aim of the treatment of latent tuberculosis infection is the prevention of progression to active clinical disease. In the absence of controlled clinical trials comparing isoniazid with placebo, the

9-month isoniazid regimen has been recommended as adequate treatment; however, a meta-analysis of 11 isoniazid trials involving 73,375 HIV-uninfected persons showed that, as compared with placebo, the risk of progression to active tuberculosis at 6 months is similar to that at 12 months. Other effective regimens are daily rifampin for 3 or 4 months, daily isoniazid and rifampin for 3 months, and isoniazid (900 mg) and rifapentine (900 mg) once weekly for 12 weeks. In a multicenter, randomized clinical trial, a regimen of daily rifampin for 4 months was associated with fewer serious adverse events and better adherence and was more cost-effective than a 9-month regimen of isoniazid. A fixed-dose combination of rifapentine (300 mg) and isoniazid (300 mg) is expected to be marketed soon in tablet form, which will facilitate treatment. The 3-month isoniazid-rifapentine regimen may be a cost-effective alternative to the 9-month isoniazid regimen, particularly if the cost of rifapentine decreases and the treatment is self-administered. Currently, the 3-month isoniazid-rifapentine regimen is not recommended for children younger than 2 years of age, persons with HIV infection who are receiving antiretroviral therapy, and women who are pregnant. A few small studies have explored treatment of latent tuberculosis infection in contacts (both children and adults) of persons with multidrug-resistant tuberculosis on the basis of the results of drug-susceptibility testing of the source patient. However, evidence is lacking on the best treatment approach. Rather, strict observation and monitoring for at least 2 years for the development of active tuberculosis disease are the preferred clinical measures.

Table 2. Regimens for Latent Tuberculosis Treatment, According to Pooled Efficacy, Risk of Hepatotoxicity, Adverse Events, and Drug Interactions.

Intractable Pain Due to Cancer

Posted by Carla Rothaus • May 29th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 44-year-old woman with metastatic non–small-cell lung carcinoma with an EGFR mutation presented with severe pain, which was worsened by opioids other than hydrocodone and was unresponsive to most other analgesics. Management decisions were made.

The discomfort of most dying patients can be controlled with state-of-the-art palliative care, but there are rare patients whose symptoms cannot be controlled. In these rare cases, palliative sedation is considered.

Clinical Pearls

What is the World Health Organization “ladder” for cancer-related pain?

The World Health Organization (WHO) “ladder” for cancer-related pain is a well-validated and generally effective approach to pain management that recommends nonopioid therapy for mild pain and opioid therapy for moderate or severe pain. However, 12 to 14% of patients have poorly controlled pain despite adherence to WHO guidelines. For cancer-related pain that is unresponsive to systemic analgesics, a fourth step on the WHO ladder — interventional therapies — has been proposed. Data suggest that interventions such as neurolytic blocks and neuraxial drug delivery may yield improved pain control with fewer side effects.

Does opioid-induced hyperalgesia occur only with chronic exposure to high doses of systemic opioids?

Opioid-induced hyperalgesia is a phenomenon whereby exposure to opioids sensitizes a patient to a pain stimulus, causing a paradoxical increase in pain. The risk factor is chronic exposure to high-dose systemic opioids, but there have been reports of opioid-induced hyperalgesia in patients who have not previously received opioids, patients receiving low-dose opioids, and patients receiving intrathecal analgesia. Central activation of the N-methyl-D-aspartate (NMDA) receptor has been suggested as one possible cause, and administration of NMDA antagonists has been recommended when opioid-induced hyperalgesia is suspected.

Morning Report Questions

Q: What is palliative sedation?

A: Palliative sedation is an intervention to relieve intractable pain in terminally ill patients by means of continuous infusion of a sedation medication. Palliative sedation is distinct from other sedation interventions performed at the end of life, such as respite sedation, physician-assisted suicide, and euthanasia. In respite sedation, the patient is sedated for a predetermined period, after which sedation is lifted to assess the response. Respite sedation and palliative sedation are both ethically distinct from physician-assisted suicide and voluntary active euthanasia. In palliative sedation and respite sedation, the intention is to alleviate pain and suffering but not to hasten death. The intention in physician-assisted suicide and voluntary active euthanasia is also to relieve unacceptable suffering, but the intervention intentionally ends the patient’s life.

Q: What is the legal and ethical foundation of palliative sedation?

A: There is a robust legal foundation for the initiation of palliative sedation. When the U.S. Supreme Court ruled that physician-assisted suicide is not a constitutional right, it affirmed that patients with terminal illness who are experiencing great pain should have “no legal barriers to obtaining medication, from qualified physicians, to alleviate that suffering, even to the point of causing unconsciousness and hastening death.” The relevant ethical principles include autonomy, beneficence, nonmaleficence, and proportionality. [Beneficence, nonmaleficence, and proportionality] are embodied in the principle of double effect, which states that as long as the only intention of an intervention is to achieve a morally good outcome (e.g., alleviating intractable pain and suffering) through a morally good or neutral action (e.g., administering sedation medications), then even if there are unintended bad effects (e.g., the patient does not wake up from sedation and the patient’s life is shortened by a small amount), the intervention may proceed. The bad effects can be foreseen but cannot be intended.

Table 2. Features of Sedation Interventions.

Table 3. Principle of Double Effect.

The Increasing Rate of Neonatal Withdrawal

Posted by Rena Xu • May 27th, 2015

When expecting mothers use opioids, their babies are exposed to the drugs in utero and, after birth, are at risk of withdrawal. The neonatal abstinence syndrome frequently necessitates admission to a Neonatal Intensive Care Unit (NICU) for treatment and monitoring. As the rate of opioid use among pregnant women has risen, the incidence of neonatal abstinence syndrome has increased, too, posing a growing medical and financial problem.

Just how big of a problem has it become? A recent study in NEJM looked at the rate of NICU admissions and average length of NICU stay for infants with neonatal abstinence syndrome. The study used data from 2004 to 2013 for nearly 300 neonatal intensive care units (NICUs), encompassing nearly 675,000 babies (two percent of whom had neonatal abstinence syndrome).

Over this period, there was a dramatic rise in the rate of NICU admissions for neonatal abstinence syndrome — from 7 cases to 27 cases per 1000 admissions. The median length of NICU stay also increased, from 13 days to 19 days. And the proportion of NICU days attributed to infants with neonatal abstinence syndrome increased nearly seven fold, from 0.6% to 4%.

Among mothers, there was an increase in the proportion of Caucasians (from 64% in 2004-05 to 73% in 2012-13) and corresponding decrease in the proportion of blacks and Hispanics. There were no significant changes in maternal age or the percentage of mothers receiving prenatal care.

Neonatal abstinence syndrome was first described in association with mothers who used illicit drugs, but more recently, the authors observe, these babies are being born to mothers taking opioid pain relievers. In 2012-2013, nearly a quarter of infants with neonatal abstinence syndrome had been exposed to opioid pain medications.

“Our data…are consistent with reports suggesting that the rising incidence of the neonatal abstinence syndrome is due in part to increasing opioid use among pregnant women, which is a component of the current epidemic of opioid use and abuse in the United States,” the authors write. “Our findings support the need for…approaches to reduce opioid use among pregnant women.”

And, although the study did not calculate the costs associated with the observed increase in frequency and duration of NICU admissions, the authors note: “These findings are especially worrisome in the context of the high costs of NICU care and of increasing inpatient costs for infants with the neonatal abstinence syndrome, in particular.”


In your practice, have you noticed changes in the incidence and/or management of neonatal abstinence syndrome?  What strategies have you found effective for managing opioid use among pregnant women and reducing the risk of neonatal abstinence syndrome?

Pelvic Inflammatory Disease

Posted by Carla Rothaus • May 22nd, 2015

Pelvic inflammatory disease can produce acute symptoms and result in infertility, ectopic pregnancy, and chronic pelvic pain. A new review summarizes current approaches to diagnosis and treatment and the future prospects for better prevention strategies.

Pelvic inflammatory disease is an infection-induced inflammation of the female upper reproductive tract (the endometrium, fallopian tubes, ovaries, or pelvic peritoneum). Many women have clinically silent spread of infection to the upper genital tract, which results in subclinical pelvic inflammatory disease. Pelvic inflammatory disease is a major concern because it can result in long-term reproductive disability, including infertility, ectopic pregnancy, and chronic pelvic pain.

Clinical Pearls

What organisms cause pelvic inflammatory disease and what are its clinical manifestations?

More than 85% of infections are due to sexually transmitted cervical pathogens or bacterial vaginosis-associated microbes, and approximately 15% are due to respiratory or enteric organisms that have colonized the lower genital tract. Ascending infection from the cervix is often due to sexually acquired infections with Neisseria gonorrhoeae or Chlamydia trachomatis. Acute pelvic inflammatory disease has classically been defined by the abrupt onset of severe lower abdominal pain during or shortly after menses, although it is now well recognized that both the onset and severity of symptoms can be more ill-defined and subtle. Atypical, milder clinical manifestations have become more common as rates of N. gonorrhoeae infection have fallen. The symptoms associated with acute pelvic inflammatory disease include pelvic or lower abdominal pain of varying severity, abnormal vaginal discharge, intermenstrual or postcoital bleeding, dyspareunia, and dysuria. Fever can occur, but systemic manifestations are not a prominent feature of pelvic inflammatory disease.

Table 1. Clinical Classification of Pelvic Inflammatory Disease and Likely Microbial Causes.

What clinical, laboratory, and imaging findings support a diagnosis of pelvic inflammatory disease?

The clinical diagnosis of pelvic inflammatory disease is based on the finding of pelvic organ tenderness, as indicated by cervical motion tenderness, adnexal tenderness, or uterine compression tenderness on bimanual examination, in conjunction with signs of lower genital tract inflammation. Signs of lower genital tract inflammation include cervical mucopus, which is visible as an exudate from the endocervix or as yellow or green mucous on a cotton-tipped swab placed gently into the cervical os (positive “swab test”); cervical friability (easily induced columnar epithelial bleeding); or increased numbers of white cells observed on saline microscopic examination of vaginal secretions (wet mount). All patients with suspected pelvic inflammatory disease should undergo cervical or vaginal nucleic acid amplification tests for N. gonorrhoeae and C. trachomatis infection; if the results are positive, the probability that pelvic inflammatory disease is present increases substantially. Transvaginal ultrasonography and magnetic resonance imaging (MRI) revealing thickened, fluid-filled tubes are timely and highly specific for

salpingitis. However, the sensitivity of ultrasonography is only fair, and although MRI has high sensitivity, it is expensive and not typically available in resource-poor settings. Power Doppler studies showing increased fallopian-tube blood flow are highly suggestive of infection.

Figure 2. Diagnosis of Pelvic Inflammatory Disease.

Morning Report Questions

Q: How is pelvic inflammatory disease treated?

A: Most patients are successfully treated as outpatients with single-dose intramuscular ceftriaxone, cefoxitin plus probenicid, or another third-generation cephalosporin (cefotaxime or ceftizoxime), followed by oral doxycycline with or without metronidazole for 2 weeks. For hospitalized patients, therapy with cefotetan or cefoxitin (administered parenterally until 24 to 48 hours after clinical improvement) together with doxycycline and followed by doxycycline with or without metronidazole to complete 2 weeks of treatment is recommended. An alternative regimen of clindamycin and an aminoglycoside may be particularly appropriate for patients with a tubo-ovarian abscess. Adjunctive nonsteroidal anti-inflammatory drugs do not improve the clinical outcome. Removal of an intrauterine device (IUD) does not hasten clinical resolution (and may delay it), and in most cases the IUD is left in place.

Table 2. First-Line Antimicrobial Treatment Recommended by the Centers for Disease Control and Prevention (CDC) for Pelvic Inflammatory Disease.

Q: Does treatment assure a satisfactory outcome and what are some of the  measures recommended to prevent pelvic inflammatory disease?

A: Although more than 90% of patients with pelvic inflammatory disease will have a clinical response to CDC-recommended treatment, the long-term outcome of treatment is still suboptimal. It remains unclear why the long-term outcome of treated pelvic inflammatory disease remains so dismal, given the high rates of clinical response. Perhaps infection-induced damage to the fallopian tubes has occurred by the time treatment is first given. This observation, together with the frequent occurrence of subclinical pelvic inflammatory disease, have highlighted the importance of recognizing prevention of pelvic inflammatory disease as a major public heath priority. The U.S. Preventive Services Task Force, CDC, and other professional organizations recommend annual C. trachomatis screening for all sexually active women younger than 25 years of age and older women at increased risk for infection (e.g., women with multiple or new sex partners). These groups also recommend testing for N. gonorrhoeae among women at increased risk for infection (e.g., women with multiple sex partners or previous gonorrhea infection and women living in communities with a high prevalence of disease).