Michael Murray

Lefamulin Approved For Community-Acquired Pneumonia

/ News /

In August 2019, the U.S. Food and Drug Administration (FDA) approved a new antibiotic for community-acquired bacterial pneumonia (CAP) and acute bacterial skin infections. Lefamulin (Xenleta, Nabriva Therapeutics) is in a class of antibiotics known as the pleuromutilins and represents the first antibiotic developed for systemic use in humans with a novel mechanism of action in over a decade (retapamulin was approved in 2007 for topical use).

Pleurotus fungus

Pleuromutilins were discovered in 1950 from the fungi Pleurotus mutilis and Pleurotus (now Clitopilus) passeckerianus (the pleuromutilins were not named for the membranes surrounding the lungs).

Like clindamycin, linezolid, and the macrolides, the pleuromutilins block bacterial protein synthesis via binding to the 50S ribosomal subunit. They bind at a different site on the subunit such that there is no cross-resistance with other antibiotics.

Lefamulin shows robust activity against gram-positive and fastidious gram-negative bacteria, and the organisms often referred to as “atypicals,” such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Lefamulin has equivalent oral and intravenous bioavailability and can be taken with or without food, making the oral formulation a convenient option. It also has a good safety profile, the most common side effects being diarrhea and nausea. More rarely, hepatic enzyme elevation has been observed, and concomitant administration with cytochrome P450 (CYP) 3A4 inhibitors should be avoided due to the risk of QT-prolongation.

Given the trend toward worsening bacterial resistance against current CAP antibiotics and the increasing number of FDA warnings concerning quinolones, lefamulin looks to be a promising addition to the antibiotic armamentarium. Antibiotic stewardship programs should be reinforced to maintain its excellent efficacy and resistance profiles.

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Saddled With Siderosis

/ Cases /

A 28-year-old man comes to primary care after perusing a health website, which recommended that he get a screening evaluation for hemochromatosis. It discussed the risk associated with being of European heritage (which he is), and after reading more about it, he became anxious and wants to know if he should be checked. He does not have any of the symptoms listed on the website and does not recall family members ever discussing it. He has no significant past medical history and takes no medications.

Exam – normal

Labs – normal CBC, Chem I

Discussion

To screen or not to screen…

Primary or hereditary hemochromatosis is a disorder of iron overload resulting from genetic mutations that lead to increased iron absorption from the small intestine. Most cases (about 86%) arise from a mutation in the HFE gene (H for hereditary hemochromatosis, FE for iron) on chromosome 6. The product of this gene is a regulator of hepcidin, which in turn, regulates iron metabolism.

The most common HFE mutation is a nucleotide substitution, guanine to adenine, which causes the amino acid cysteine to be substituted by tyrosine at position 282 (C282Y). Homozygosity for the mutation is required to develop iron overload because the normal allele present in heterozygotes makes sufficient protein to overcome the deficiency from the mutant allele (autosomal recessive pattern).

A less common HFE mutation causes an amino acid change from histidine to aspartic acid at position 63 (H63D). Homozygosity is not associated with clinical disease, but compound heterozygosity (one copy each of C282Y and H63D) is associated with iron overload.

A third HFE mutation, of less clinical relevance, involves a serine-to-cysteine amino acid substitution at position 65 (S65C). Also rare are many non-HFE mutations, including hemojuvelin (HJV), hepcidin antimicrobial peptide gene (HAMP), transferrin receptor 2 (TfR2), and ferroportin (SLC40A1 – solute carrier family 40 member 1).

Approximately 10% of those with northern European ancestry are heterozygotes (carriers) for hemochromatosis, and approximately 0.4 to 0.5% are homozygotes.

The HFE mutations decrease the function of hepcidin, causing increased duodenal iron uptake, up to a few milligrams per day above normal. Although a small amount, it is enough to overwhelm normal daily iron losses of 1-1.5 milligrams. No physiologic system exists to increase iron excretion in the case of excess. The increased absorption adds between ten to forty grams of iron over the course of a few decades (normal total body iron is three to four grams). After overwhelming the storage capacity of ferritin, free iron accumulates in the liver, pancreas, heart, and other organs, causing widespread damage.

Women are relatively protected from iron overload due to losses associated with menstruation and pregnancy. For example, in an average full-term pregnancy, the mother loses approximately 800 milligrams of iron. Thus, women typically manifest hemochromatosis later, most commonly after menopause.

The liver is usually the first organ affected, and hepatomegaly is the most common initial physical finding. Untreated, it can progress to cirrhosis, accompanied by portal hypertension and varices. Hepatocellular carcinoma occurs in approximately 30% of those who develop cirrhosis and is the most common cause of death in patients being treated for hemochromatosis.

Other common complications include cardiac dysrhythmias and congestive heart failure; diabetes mellitus from pancreatic involvement; hypogonadism and various hormonal deficiencies from testicular, pituitary and adrenal dysfunction; and arthritis – with the involvement of the second and third metacarpophalangeal joints (MCPs) a classic early finding. Excess iron also leads to increased susceptibility to infection from siderophilic bacteria, most commonly, Vibrio vulnificus, Listeria monocytogenes, and Yersinia enterocolitica.

Because many complications of hemochromatosis are not reversible, early diagnosis and treatment are critical for prevention. Features commonly reversed by treatment include fatigue, depression, abdominal discomfort, and bronze discoloration of the skin.

Screening assays for estimating total body iron stores are the serum iron level with percent transferrin saturation (serum iron divided by total iron-binding capacity), and the serum ferritin concentration. Every one microgram per liter increase in the serum ferritin concentration represents an increase of approximately five milligrams of iron stores.

Elevated ferritin alone is nonspecific, requiring a detailed history and physical with repeated lab studies to rule out other causes. With that in mind, if either the percent transferrin saturation or the serum ferritin concentration is elevated, genetic testing is recommended.

For those with results consistent with hemochromatosis, evaluation of the liver is critical to assess for the presence of cirrhosis. Over the past few years, improvements in lab studies, ultrasound, and magnetic resonance imaging (MRI) have significantly decreased the need for liver biopsy. For example, if the transaminase levels are normal, the serum ferritin is below approximately 1000 micrograms per liter, there is no hepatomegaly, and the patient does not drink excess alcohol, the risk of cirrhosis is extremely low. Also, MRI with T2* calculation is an accurate method for estimating hepatic iron content and has the advantage of being able to assess cardiac iron deposition. When there is a borderline case, or whenever there is doubt, liver biopsy remains the gold standard for diagnosing cirrhosis. 

Treatment of hemochromatosis involves removing the excess iron – via bleeding. Phlebotomy presents a very simple treatment in an age of increasing medical complexity, which is often a great relief to patients. This involves removing one pint (approximately 500 milliliters) of blood per session, which, depending on the patient’s hematocrit, contains between 200 to 250 grams of iron. Aside from treating the hemochromatosis patient, an advantage of phlebotomy is that the blood can be added to the donor pool (after standard blood screening).

Initially, phlebotomy is performed one to two times per week, as tolerated by the patient. It is then tapered to monthly, and then eventually to every few months, in order to maintain a ferritin level around 50 micrograms per liter or less. Since the average hemochromatosis patient has excess stores of about ten grams of iron, this represents approximately fifty phlebotomy sessions (not counting on-going iron absorption).꙳

For those with hemochromatosis, all adult first-degree relatives require genetic counseling and lab studies. In the case of children, testing the other parent usually suffices to determine their risk. If this is untenable, the child can wait until eighteen years of age to undergo genetic testing, given the time course of the disease.

For those who are asymptomatic and have no family history, the United States Preventative Health Task Force has come to no conclusions regarding screening. Arguments against screening involve the high costs of testing for a disease with variable penetrance (not everyone with the gene defect develops iron overload) and potential discrimination against patients by the insurance industry.

Given the high prevalence in those of northern European ancestry and the significant morbidity and mortality associated with untreated hemochromatosis, more experts are recommending at least targeted screening of late. They also recommend screening with genetic testing in order to detect those who have not yet developed iron overload, especially as these costs continue to decrease. Aside from these benefits, negative screening results are also helpful in relieving significant anxiety for patients and their families.

꙳ 1 ml RBCs = 1mg iron; a patient with a 40% hematocrit undergoing 500 ml phlebotomy loses 200 mg iron

References

Hemochromatosis, (2014), Retrieved from niddk.nih.gov/health-information/liver-disease/hemochromatosis (Accessed 03 October 2019).

Jameson, J.L., Fauci, A.S., et al, (Eds.)(2018). Harrison’s principles of internal medicine. 20th edition. New York: McGraw-Hill Education.

Kelley M, Joshi N, Xie Y, Borgaonker M. Iron overload is rare in patients homozygous for the H63D mutation. Can J Gastroenterol Hepatol. 2014;28(4):198-202.

Screening for hemochromatosis: recommendations from the U.S. preventive services task force. Ann Intern Med. 2006;145:I-18. doi: 10.7326/0003-4819-145-3-200608010-00002

Whitlock EP, Garlitz BA, Harris EL, et al. Screening for hereditary hemochromatosis: a systematic review for the U.S. preventive services task force. Ann Intern Med. 2006;145:209-23. doi: 10.7326/0003-4819-145-3-200608010-00009

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The Last Full Moon

/ Uncategorized /

The ward was quiet and still. The hallway lights seemed too bright for this late hour. I could hear hushed tones from the nurses huddled at the desk down the hall. I got to her room just after midnight, already behind schedule. I looked in, my eyes slowly adjusting to the light.

She lay so still I couldn’t see any movement with her breathing. A full moon hung centered in the window, silhouetting her and casting shapeless shadows around the room. A lone rose leaned out over an oversized vase on the bedside table. I couldn’t make out the color in the grayness.

“This is my last full moon,” she said, startling me.

“Oh, I didn’t want to wake you,” I said, after hesitating a while, then perfunctorily introducing myself as the medical student.

“I don’t sleep anymore.”

“It’s that bad?”

“I wanted a DNR – to stop all of this. How many times can I do this?” she said forcefully. “They said another treatment could knock this down again. I always feel so bad after. At least they let me have the DNR this time.”

“No one can force you not to have a DNR,” I said, trying to sound confident.

She described how her physicians didn’t like it if they were going to treat her cancer. But this time, she said, it was her only condition for going through chemo again.

I was a bit confused, like this was backward – she doesn’t want any treatment, yet here we are. I thought of the hospital stays, the chemo and other meds, the nurses, the labs, and so on; yet she wanted none of it.

She lost her husband a few years ago, he was sick for a while, and she hasn’t spoken with her two kids in years. She didn’t say why – I didn’t feel like I should ask.

She stared at the moon for a while. “You don’t have to check on me. I know they said someone would come by after the chemo today, but there’s no need. I’m not going to take any more of it anyway. I’ll tell them first thing tomorrow. Don’t worry about me.”

I didn’t know what to say. I asked if I could listen to her heart and lungs, and if she had any symptoms. She looked at me and chuckled. “Sure, go right ahead – you guys need to learn, right? You look so young, running around in your white coats.”

I asked her to sit up. I turned the light on over the head of her bed. She looked much older than sixty-five. Her skin was paper-thin, covered in bruises and excoriations. She said she scratched a lot because the medications made her feel so dry. I couldn’t get the stethoscope to sit flat on her back because her ribs protruded so much. She took a few breaths, then lay back.

In the light, I could see the color of the rose – bright yellow. I mentioned how pretty it looked. She told me yellow roses were her favorite and that a nurse she knew from a previous stay gave it to her.

“I’ll check in with you again before your team arrives in the morning.”

She said that it was very nice, but unnecessary, that she’s too tired for any more of this. I said I would at least stop by to say hi on my way to morning report. She just looked at me, and then turned back toward the moon, which by now was closer to the edge of the window.

We both looked out at it for a time, then I glanced back down at her. She was sleeping. I turned off the light and backed out, closing the door against the light of the hallway.

I worked most of the night, finally getting some rest around four o’clock. The pager buzzed me awake almost two hours later. After clarifying some orders on a new admission, I ran back to see Ms. M before heading to morning report.

Her room was empty. I looked for her name on the door – maybe I was on the wrong floor. Her nurse saw me and came over. Around four, Ms. M asked her for help getting up to take a walk in the hall. When she eventually got to her, she was not breathing. She couldn’t feel a pulse. Honoring her DNR, she called the intern to see her and take care of the usual paperwork. They decided not to call me since I had been up so late.

I stood at the doorway, staring into her empty room. “I was just talking to her,” I said to no one in particular.

Even the rose was gone. I walked to the window and looked out – the moon had already set. Alone.

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Omega-3 Fatty Acid Supplements Do Not Decrease Risk of Early Preterm Delivery

/ News /

Pregnant women who received omega-3 (n-3) long-chain polyunsaturated fatty acid supplements did not have a lower risk of early preterm delivery (prior to 34 weeks gestation), according to a new phase 3 trial.

Maria Makrides, PhD, with the South Australian Health and Medical Research Institute, Women’s and Children’s Hospital, North Adelaide, Australia, and colleagues reported their findings in the September 12, 2019 issue of The New England Journal of Medicine.

The World Health Organization (WHO) estimates 15 million babies are born preterm (prior to completing 37 weeks gestation), over 10% of births worldwide. Preterm birth is associated with increased rates of disability and is the leading cause of death in children under five.

Omega-6 (n-6) fatty acids are precursors of several mediators of inflammation, such as prostaglandins. Prostaglandin E2 and prostaglandin F2α have been shown to initiate labor by inducing cervical ripening and uterine contractions. The n-3 fatty acids, on the other hand, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of several anti-inflammatory mediators. They are inefficiently produced in mammals and often require dietary sources, such as fish, flaxseed, some vegetables, or supplements containing DHA or EPA, to maintain proper levels. The typical western diet, relatively low in n-3 fatty acids and high in n-6 fatty acids, shifts production to more pro-inflammatory mediators and, as a result, may influence preterm delivery.

Several epidemiological studies have shown an association between lower dietary fish intake and increased rates of preterm delivery, leading to the WHO recommendation that pregnant women take 300 mg of n-3 long-chain polyunsaturated fatty acids daily. A 2018 birth cohort study in Denmark corroborated this by showing a correlation between low plasma concentrations of EPA and DHA in pregnancy with an increased rate of early preterm birth.

A previous randomized controlled study, called DOMInO (DHA to Optimise Mother Infant Outcome), showed that while DHA had no effect on postpartum depression or infant brain development, a secondary analysis showed a decreased incidence in early preterm delivery compared with control. Thus, it is unclear whether supplementation with n-3 long-chain polyunsaturated fatty acids results in a lower rate of early preterm delivery.

This trial, called ORIP (Omega-3 to Reduce the Incidence of Preterm Birth), enrolled 5517 women, with a total of 5544 pregnancies, less than 20 weeks gestation, and taking no more than 150 mg of n-3 long-chain polyunsaturated fatty acid supplementation daily. 2770 pregnancies in 2766 women were randomly assigned to receive three 500-mg fish-oil capsules per day, containing approximately 800 mg of DHA and 100 mg of EPA daily until 34 weeks gestation or delivery, whichever occurred first. A control group included 2774 pregnancies in 2765 women randomly assigned to receive three 500-mg capsules of an isocaloric vegetable-oil blend, containing approximately 15 mg of DHA and 4 mg of EPA per day for the same duration. 5486 pregnancies (2734 in the n-3 group and 2752 in the control group) were included in the final analysis. The incidence of early preterm delivery was compared between groups.

Early preterm delivery occurred in 2.2% of the n-3 group and 2.0% of the control group (relative risk 1.13; 95% confidence interval [CI], 0.79 to 1.63; P=0.50).

There was no significant difference in the rate of serious adverse outcomes (5.0% in the n-3 group and 4.0% in the control group). There were more gastrointestinal side effects reported in the n-3 group, including burping, diarrhea, and constipation.

This study showed that DHA and EPA supplementation did not reduce the incidence of early preterm delivery, and does not confirm the result of the secondary outcome analysis in the DOMInO trial. The authors suggest that further studies are needed to evaluate subgroups that may show a benefit, for example, those with low levels of n-3 fatty acids.

The study was funded by the Australian National Health and Medical Research Council and the Thyne Reid Foundation.

Makrides, M, PhD, et al. A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery. N Engl J Med. 2019; 381:1035-45.

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SAGE-217 Shows Promise In Major Depression

/ News /

Patients with major depressive disorder who received SAGE-217 for fourteen days showed improvement in symptoms on day fifteen in a phase 2 safety and efficacy trial.

Handan Gunduz-Bruce, MD, with Sage Therapeutics, Cambridge, Massachusetts, and colleagues reported their findings in the September 5, 2019 issue of The New England Journal of Medicine.

Major depression is a complex mental disorder involving genetic and environmental factors, as well as multiple neurotransmitters. Gamma-aminobutyric acid (GABA) has been shown to play a major role in neural regulation as the primary inhibitory neurotransmitter of the central nervous system. Studies have shown decreased GABA levels in the plasma, cerebrospinal fluid, and brain tissue of patients with major depressive disorder.

Several medications show positive allosteric modulator activity on the GABA receptor, including benzodiazepines, barbiturates, muscle relaxants, alcohol, propofol, and etomidate, and thus are used as anxiolytics, sedatives, anticonvulsants, antispasmodics, and anesthetics. Neurosteroids are naturally occurring modulators of GABA receptors with pharmacologic activity that differs from that of glucocorticoids. Allopregnanolone, one such neurosteroid, acts as a positive allosteric modulator of the GABAA receptor. In studies of patients with post-partum depression (PPD), administration of intravenous brexanolone, the synthetic analog of allopregnanolone, resulted in significant reductions (improvement) in the Hamilton Rating Scale for Depression (HAM-D) score at sixty hours. This is consistent with the hypothesis that normalization of GABA function is clinically useful in the treatment of depression, and led to the approval of brexanolone by the U.S. Food and Drug Administration (FDA) on March 19, 2019.

This trial is a phase 2, randomized, double-blind, placebo-controlled study of the oral formulation of synthetic allopregnanolone, SAGE-217, in patients with major depressive disorder. Study investigators enrolled 89 adults with major depression with a HAM-D score of 22 or higher (moderate-to-severe depression), who were on stable doses of antidepressants for at least thirty days, or not taking any antidepressants. 45 patients were randomly assigned to receive SAGE-217 30 mg once daily for fourteen days, and 44 patients to placebo. The mean change in the baseline HAM-D scores on day fifteen was compared between groups.

The mean HAM-D score at baseline was 25.2 in the SAGE-217 group and 25.7 in the placebo group. On day 15, the mean change in the HAM-D score was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (between-group difference -7.1; 95% confidence interval [CI], -10.2 to -3.9; P<0.001).

Adverse events were reported by 53% in the SAGE-217 group and 45% in the placebo group. The most common adverse events reported in the SAGE-217 group were headache, nausea, and somnolence. No serious adverse events and no deaths were reported during the trial.

The study was funded by Sage Therapeutics.

Gunduz-Bruce, H, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019; 381:903-11.

Comments

  • this trial further supports the hypothesis that GABAA receptors play an important role in major depression
  • the effect of SAGE-217 was similar for patients taking conventional antidepressants during the trial and those not previously on antidepressant medication 
  • although the results of this trial show promise for patients suffering major depression, it is limited by being a short phase 2 trial with a small sample size (as designed); larger studies are needed with longer-term outcomes to better define efficacy and safety

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Oral Semaglutide Shows Cardiovascular Safety In Type 2 Diabetes

/ News /

Patients with Type 2 diabetes who received oral semaglutide had a non-inferior cardiovascular outcome compared with placebo, according to a new phase 3 trial.

Mansoor Husain, MD, with the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto, and colleagues reported their findings in the August 29, 2019 issue of The New England Journal of Medicine.

Patient compliance with injectable medications, such as insulin and the glucagon-like peptide-1 (GLP-1) receptor agonists is a significant challenge in the treatment of diabetes. Oral formulations are favored by patients when compared to injectable medications and are more likely to be initiated earlier. Oral semaglutide is a new oral formulation of the subcutaneous GLP-1 receptor agonist of the same name and has similar pharmacokinetic properties and effects.

In 2008, the U.S. Food and Drug Administration (FDA) began requiring cardiovascular risk assessments for new glucose-lowering drugs. All currently approved GLP-1 receptor agonists, including subcutaneous semaglutide, have shown cardiovascular safety or benefit. This study, Peptide Innovation for Early Diabetes Treatment (PIONEER) 6, is a phase 3a, randomized, placebo-controlled, preapproval cardiovascular outcomes trial with the oral formulation of semaglutide. Study participants were patients with Type 2 diabetes, fifty years of age or older with known cardiovascular disease or chronic kidney disease, or sixty years of age or older if they had cardiovascular risk factors only. The difference in time from randomization to the first occurrence of a major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was compared between groups. 1591 patients were randomized to receive oral semaglutide 14 mg daily and 1592 patients to placebo. 3172 patients (99.7%) completed the trial.

A major cardiovascular event occurred in 3.8% of patients receiving semaglutide and 4.8% of those taking placebo, a 21% relative risk reduction (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority; P=0.17 for superiority).

More patients permanently discontinued semaglutide than placebo (11.6% vs. 6.5%, respectively). This difference was driven mainly by gastrointestinal side effects, including nausea, vomiting, and diarrhea. There were fewer serious adverse events in the semaglutide group (18.9%) compared with the placebo group (22.5%), and the authors reported no unexpected adverse events in either group.

The study was funded by Novo Nordisk.

Husain M, et al. Oral semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2019; 381:841-51.

Comments

  • the trial was relatively short because it was an event-limited trial (trial period ends when a minimum number of events occurs – median time in the trial was 15.9 months)
  • the trial was powered for non-inferiority, not superiority
  • trial validity is increased by the high completion rate (99.7%)
  • the discontinuation rate in the semaglutide group was higher than in the placebo group but comparable to that observed with other (subcutaneous) GLP-1 receptor agonists
  • patients in the semaglutide group showed decreased glycated hemoglobin, weight, and systolic blood pressure compared to those in the placebo group
  • death from any cause was lower in the semaglutide group than in the placebo group (1.4% vs. 2.8%, respectively; hazard ratio, 0.51; 95% CI, 0.31 to 0.84).
  • these results may lead to better patient compliance with (oral) GLP-1 receptor agonists and thus, better diabetic outcomes

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Volatile Vaping

/ Cases /

A 23-year-old man arrives by ambulance to the Emergency Department with severe shortness of breath, cough, nausea, and vomiting for several hours. Between rapid breaths and frequent coughing, he is able to state he has been healthy, has not traveled recently, and has had no recent ill contacts. He smoked one-half to one pack of cigarettes daily for a few years “on and off,” and began using electronic cigarettes (e-cigarettes) a few months ago on advice from a friend as a way to quit tobacco.

Exam – P 115, regular; R 28; BP 140/86; T 37.5⁰C; Pulse ox 86% saturation on 2L NC O2; Chest – tachypneic, with decreased breath sounds and scattered rhonchi bilaterally; Cardiac – tachycardic, without murmurs; Abdomen, Skin, Neuro – normal

Labs – WBC 15,000, neutrophil predominant, o/w normal CBC and normal chem panel; CXR – diffuse, bilateral, poorly-defined opacities

O2 saturation continued to drop, he became less responsive and required intubation and ICU admission.

Discussion

Although available for decades, e-cigarettes have recently been gaining in popularity. There are now over 500 brands and 10,000 flavors of e-cigarettes and growing. They are becoming more popular at a time when the United States has effectively banished tobacco from most public areas. Global sales exceed 25 billion dollars annually and are predicted to double over the next few years.

E-cigarettes are marketed as a safe alternative to tobacco, and many advertising campaigns promote their utility in smoking cessation. There are, however, very few high-quality and no long-term studies of e-cigarettes in smoking cessation. Also, many studies classify smokers who switch from tobacco to e-cigarettes as having quit smoking.

Unlike tobacco, e-cigarettes allow the user individualized control over variables such as temperature, wattage, amount of nicotine, the glycerin-to-propylene glycol ratio, and inhalational style (mouth-to-lung vs. deep-lung), providing a highly customizable experience. E-cigarette users have also been known to add tetrahydrocannabinol (THC), the high-inducing chemical found in marijuana, and cannabidiol (CBD) oil, a phytocannabinoid, to the e-cigarette liquid.

Especially attractive to younger people is an e-cigarette that looks like a USB flash drive, and a myriad of “kid-friendly” flavors, including mint, cherry, candy crush, cotton candy, strawberry-watermelon, and gummy bear.

The potential for harm from the components of e-cigarettes and the ingredients in the liquids is a growing concern. E-cigarettes contain a battery-operated element which heats a coil inside a wick saturated with liquid. The liquid is heated to approximately 200⁰C (up to 300⁰ C in temperature-control e-cigarettes). The main components of the liquid are propylene glycol and vegetable glycerin, both of which have been approved for oral ingestion but have not been studied as inhalational agents. Several studies have shown that a wide variety of chemicals are suspended in what is commonly referred to as a “vapor” (i.e. steam) but is actually an aerosol. These aerosols have been found to contain free radicals, heavy metals, formaldehyde, and many other volatile organic compounds.

Most e-cigarette liquids also contain nicotine, at levels set by the user. This allows for tapering doses, a common practice in nicotine replacement programs. Nicotine is widely known to be very addictive, and many studies have shown that adolescents are more vulnerable to this effect than adults. Chronic nicotine use in adolescents is also associated with a decreased ability to concentrate and increased stress levels.

The Centers for Disease Control and Prevention (CDC) reports from the 2015 National Youth Tobacco Survey that 27.1% of U.S. adolescents (approximately 7.3 million people) have ever tried e-cigarettes. This includes 37.7% of high school students and 13.5% of those in middle school. In 2018, the surgeon general deemed youth e-cigarette use to be an epidemic, and surveys show it continues to be on the rise. Many young people now start smoking with e-cigarettes. As with tobacco, nicotine dependence occurs rapidly and often becomes chronic. Surveys have shown many go on to smoke tobacco as well, some remaining dual users.

Recently, increasing numbers of e-cigarette-related lung injury have been observed throughout the United States. A CDC alert was published on August 23, 2019, reporting 193 cases of lung injury associated with e-cigarette use in 22 states between June 28th and August 20th of this year, including the first known death related to e-cigarettes on August 23rd. It is likely that these numbers are even greater and have been occurring over a longer period, as many cases were not linked to e-cigarette use at the time.

The mechanism(s) of lung damage in these cases is unknown. They involve a wide age-range and geographic distribution, and the pattern of lung injury is varied – including lipoid pneumonia, acute eosinophilic pneumonia, cryptogenic organizing pneumonia, and alveolar hemorrhage syndrome.

Studies of the effects of condensed e-cigarette aerosols on in-vitro human alveolar macrophages have shown dose-dependent toxicity. Below cytotoxic doses, increasing levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed. These effects may be causing the inflammation and lung injury seen in these cases.

No link has been made to any specific product, ingredient, or infectious agent to date. One theory discussed on social media is that these cases are likely caused by CBD oil, given that the use of CBD is a more recent trend, and because it is an oil, unlike other e-cigarette liquids. Although there is no evidence to corroborate this theory, more research needs to be done. The CDC states it is continuing to work with state health departments in their investigations to find the source of this epidemic.

References

CDC, CDC, FDA, States Continue to Investigate Severe Pulmonary Disease Among People Who Use E-cigarettes, (2019), Retrieved from cdc.gov/media/releases/2019/s0821-cdc-fda-states-e-cigarettes.html (Accessed 26 August 2019).

CDC, Surgeon General’s Advisory on E-cigarette Use Among Youth, (2019), Retrieved from cdc.gov/tobacco/basic_information/e-cigarettes/surgeon-general-advisory/index.html (Accessed 26 August 2019).

Dinakar C, O’Connor GT. The health effects of electronic cigarettes. N Engl J Med 2016; 375: 1372-81. doi: 10.1056/NEJMra1502466

Scott A, Lugg ST, Aldredge K, et al. Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages. Thorax 2018; 73:1161-69.

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Serelaxin Does Not Reduce Cardiovascular Mortality In Acute Heart Failure

/ News /

Patients with acute heart failure who received the recombinant form of human relaxin-2, serelaxin, did not have a lower incidence of cardiovascular death at 180 days, or a lower incidence of worsening heart failure at 5 days, according to a new phase 3 trial.

Marco Metra, MD, with the Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy; John R. Teerlink, MD, with the Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco; and colleagues reported their findings in the August 22, 2019 issue of The New England Journal of Medicine.

The Centers for Disease Control and Prevention (CDC) reports that approximately 5.7 million adults in the United States have heart failure. Hospital admission for acute decompensated heart failure is associated with increased short and long-term cardiovascular mortality. About one-half of heart failure patients are rehospitalized within six months, and up to 15% of patients die within three months of their initial hospitalization. The CDC notes that one-half of those who develop heart failure die within five years of diagnosis.

The search for new and better therapies for acute heart failure has led to research into a hormone called relaxin. Discovered in 1926, relaxin is produced primarily by cells of the corpus luteum and is associated with several cardiovascular changes of pregnancy. It acts as a vasodilator, via the nitric oxide pathway, an antifibrotic, and an anti-inflammatory agent. Discovery of these properties led to the study of relaxin in heart failure, using a recombinant form of the hormone, called serelaxin. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin was associated with a lower incidence of worsening heart failure during hospitalization and lower cardiovascular mortality at 180 days when compared to placebo. The RELAX-AHF trial was not powered to show an effect on mortality; thus, whether serelaxin reduced cardiovascular mortality in acute heart failure remained unclear.

This study, RELAX-AHF-2, is a phase 3b, multi-center, randomized, placebo-controlled, event-driven trial. The trial enrolled 6600 adults hospitalized for acute heart failure, with dyspnea and vascular congestion on chest radiography, elevated natriuretic peptide levels, mild-moderate renal impairment, and systolic blood pressure of 125 mm Hg or greater. After excluding 55 patients randomized in error, 3274 patients were randomly assigned to receive serelaxin 30 µg per kilogram per day plus usual therapy, and 3271 patients to receive placebo plus usual therapy. The rates of cardiovascular death at 180 days and worsening heart failure at 5 days were compared between groups.

Measured at day 180, cardiovascular death occurred in 8.7% in the serelaxin group, and in 8.9% in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P=0.77). Measured at day 5, worsening heart failure occurred in 6.9% in the serelaxin group, and in 7.7% in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P=0.19). The length of hospital stay and the incidence of rehospitalization due to heart failure or renal failure were also unchanged between groups.

There was no significant difference in the rate of adverse events reported between the groups (53.1% in the serelaxin group and 52.1% in the placebo group reporting at least one adverse event).

The study was funded by Novartis Pharma.

Metra, M., et al. Effects of Serelaxin in Patients with Acute Heart Failure. N Engl J Med 2019; 381:716-26.

Comments

  • RELAX-AHF-2 shows the importance of a properly powered trial: the authors conclude that the lack of cardiovascular mortality benefit observed in this trial shows that the benefit seen in the RELAX-AHF trial was consistent with a chance outcome
  • Heart failure is a complex disease – further subgroup analyses of this and other heart failure trials may identify a particular patient population that benefits from relaxin therapy
  • Heart failure is a chronic disease – attention to pre-hospital care may see greater results in reducing cardiovascular mortality

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Liraglutide Improves Glycemic Control In Children And Adolescents With Type 2 Diabetes

/ News /

Children and adolescents with Type 2 diabetes, already taking metformin (with or without insulin) showed improvement in blood sugar control with the addition of liraglutide compared to similar patients who did not receive the treatment, according to a new phase 3 trial.

William V. Tamborlane, MD, with the Department of Pediatrics, Yale University, New Haven, CT, and colleagues reported their findings in the August 15, 2019 issue of The New England Journal of Medicine.

Metformin, a biguanide antihyperglycemic is first-line therapy for pediatric Type 2 diabetes. Several studies have shown that patients experience continued worsening in β-cell function and glycemic control, eventually requiring additional treatment. The only approved drug class for add-on therapy in the pediatric population is insulin, which is used in over half of patients within a few years of starting metformin. While many drug classes are available for adults, trials specifically proving safety and efficacy in the pediatric population are required for approval.

The glucagon-like peptide-1 (GLP-1) receptor agonists have been used in the treatment of adult Type 2 diabetes for over ten years. Liraglutide, one such GLP-1 receptor agonist, was studied in a pediatric phase 2 trial and demonstrated the safety and tolerability of the adult dose range. It is unclear, however, if liraglutide is safe and effective in a pediatric Type 2 diabetes population already taking metformin.

This study, called Ellipse (Evaluation of Liraglutide in Pediatrics with Diabetes), is a phase 3, randomized, placebo-controlled trial. Patients were between 10 and 17 years of age, had a body-mass index (BMI) greater than the 85th percentile, and had glycated hemoglobin levels between 7.0 and 11.0% if they were treated with diet and exercise alone, or between 6.5 and 11.0% if they were treated with metformin (with or without insulin). 135 patients were randomized (134 of whom received at least one dose of study drug or placebo) to receive subcutaneous liraglutide, at standard dose adjustments, or placebo for 26 weeks. The trial was continued for another 26-week open-label period in which the liraglutide group continued treatment, and the placebo group discontinued the placebo. 90.9% of patients in the liraglutide group and 84.1% in the placebo group completed 26 weeks of treatment, and 84.8% of patients in the liraglutide group and 76.8% in the placebo group completed 52 weeks. After the third week of the trial (dose escalation period), 55.6% of the liraglutide group and 72.7% of the placebo group reached the maximum dose of 1.8 mg. The mean changes in glycated hemoglobin were compared between groups.  

Measured at week 26, the mean glycated hemoglobin level decreased by 0.64 percentage points in the liraglutide group and increased by 0.42 percentage points in the placebo group (between-group difference -1.06 percentage points; 95% confidence interval [CI], -1.65 to -0.46; P<0.001). At week 52, the difference in mean glycated hemoglobin levels was increased (-1.30 percentage points; 95% [CI], -1.89 to -0.70). Secondary outcomes showed liraglutide is superior to placebo in reducing fasting plasma glucose levels, and in the number of patients reaching a glycated hemoglobin level of less than 7.0%. Unexpectedly, no difference was observed between groups in body weight or BMI score at week 26 (differences have been observed in adult trials of liraglutide).

The rate of adverse events was higher in the liraglutide group, mainly due to gastrointestinal complaints. Nausea and vomiting were the most frequently reported, however, all adverse events were reportedly mild. Hypoglycemia was also observed more frequently in the liraglutide group, but no episodes were reported as severe. One severe hypoglycemic episode did occur in the placebo group, in a patient taking insulin.

The study authors note that although the trial showed the safety and efficacy of liraglutide, a few aspects of the trial may be somewhat limiting. The relatively small number of patients in the trial may help explain the lack of difference in body weight and BMI between groups at week 26. The dosing schedule used may explain why only about one-half of the study patients received the highest dose of liraglutide. Also, the lack of diversity in the trial population may make the results difficult to generalize to other populations. Further studies will be required to help clarify these issues.

The study was funded by Novo Nordisk.

Tamborlane, WV, et al. Liraglutide in children and adolescents with type 2 diabetes. N Engl J Med. 2019; 381:637-46.

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Palmar Paresthesias

/ Cases /

A 58-year-old right-handed man comes to primary care complaining of hand pain for several weeks. One month ago, he noticed tingling and burning pain on the palmar side of his right thumb, index and middle fingers. He works in an office and does computer work every day. His symptoms occasionally feel worse when he is typing. They fluctuate during the day and gets worse again overnight. One week ago, he noticed similar symptoms beginning in his left hand, but not to the same degree. His hands feel puffy and swollen, although he hasn’t noticed any physical changes.

He has had no history of neck complaints and notices no arm or hand symptoms with changes in head position. He does not have similar symptoms elsewhere. He is married, does not smoke, has one to two drinks several nights per week, and takes no medications. He has no significant past medical history and has not traveled recently. He is sedentary and states that although he had been moderately overweight for many years, he is frustrated by further weight gain over the past several months. His wedding ring and shoes have felt tighter over the past year but he attributes this to his weight gain.

Exam – P – 86, BP – 160/86, T – afebrile, Pulse ox – 98%, BMI – 29; large, coarse facial features, with skin thickening; normal sensory and motor evaluation of the upper extremities, including normal thumb strength, and no thenar atrophy; Tinel’s test (percussion over volar wrist) – negative bilaterally; Phalen’s test (wrists flexed to 90⁰ for one minute) + tingling sensation over the front side of his right thumb, index, and middle fingers; negative on the left

Labs – normal CBC, chemistries, except blood glucose (random)  – 168 mg/dL

Discussion

Carpal tunnel syndrome is the most common entrapment neuropathy, experienced by approximately five percent of the U.S. population. Although working on a computer is frequently cited as a common cause of carpal tunnel syndrome, a direct link has never been proven. Poor desk ergonomics may cause muscle strain associated with hand and wrist pain, however, these symptoms are not necessarily due to carpal tunnel syndrome. Most cases of carpal tunnel syndrome do not have an identifiable cause.

The carpal tunnel contains nine flexor tendons (two for each finger, one for the thumb) and the median nerve. It is formed by the carpals and the flexor retinaculum, a fibrous band located on the palmar side of the wrist, bound to the pisiform and hook of the hamate on the ulnar side, and the scaphoid and trapezium on the radial side. Increased pressure in the tunnel compresses the median nerve, causing injury. Additionally, inflammation of the flexor tendons in the carpal tunnel, either primarily, as in a repetitive motion injury, or secondarily, from the increased pressure itself, may cause further nerve damage.

Early symptoms include tingling and burning pain over the distribution of the median nerve in the hand, with sparing of the proximal palm and thenar eminence, as pictured.

The spared areas are innervated by the palmar cutaneous branch of the median nerve. This sensory branch arises proximal to the wrist and travels to the hand outside of the carpal tunnel. Thus, the sensory examination can help differentiate carpal tunnel syndrome from other causes.

Without treatment, median nerve injury can progress from sensory to motor symptoms, which may involve loss of hand coordination and overt weakness. Eventually, thenar atrophy may develop (except in those who have ulnar nerve contribution to the thenar area).

When the history and physical exam suggest carpal tunnel syndrome, nerve conduction studies (NCS) and electromyography (EMG) are often used as confirmatory tests. Positive findings on NCS include slowed median nerve velocities over the carpal tunnel, and EMG can detect denervation of hand muscles early, even prior to the patient noticing any motor symptoms. It can also help discriminate between muscle and nerve abnormalities.

Although the majority of cases have no known cause, carpal tunnel syndrome has been associated with several conditions. It is important to rule out a secondary cause, as many of these are life-threatening, and carpal tunnel syndrome may be the first sign of underlying disease. Some of the more common conditions include obesity, hypothyroidism, diabetes, arthritis, and pregnancy. Less common are hyperparathyroidism, renal failure and dialysis, sarcoidosis, amyloidosis, and leukemia.

This case provides an example of a rare condition causing carpal tunnel syndrome. The weight gain, tight-fitting shoes and wedding ring, coarsening of skin and facial features, increased blood pressure, and possibly the increased blood sugar (sample was not drawn while the patient was fasting) point to acromegaly, a condition of excess growth hormone in an adult. Acromegaly is most commonly caused by a pituitary adenoma (about 95% of cases) and further evaluation with additional laboratory studies and brain imaging are the next step in its evaluation. The appropriate treatment of acromegaly has been shown to reverse carpal tunnel syndrome (and many other associated signs and symptoms). The first physical changes associated with acromegaly can be very subtle, and the diagnosis is often delayed. When diagnosed and treated early, the life expectancy of those with acromegaly has been observed to be the same as that of the normal population.

If a cause of carpal tunnel syndrome is not discovered, treatment is determined by the severity of signs and symptoms. Early or mild carpal tunnel syndrome is usually treated with conservative measures: avoidance of repetitive motion, neutral wrist splinting, and nonsteroidal anti-inflammatories. A local steroid injection may also be used to reduce inflammation and swelling. If symptoms are severe or do not improve with conservative measures, a surgical referral may be required. In surgery, the flexor retinaculum is divided, by either an open or endoscopic method, providing an immediate reduction in pressure on the median nerve. Most patients will get significant relief after surgery. However, if the nerve was significantly damaged prior to surgery, recovery may take several months or longer. Physical therapy is usually advised to assist the patient with regaining full function.

References

Anderson, J.E. (1983). Grant’s atlas of anatomy(8th edition). Baltimore: Williams & Wilkins.

Jameson, J.L., Fauci, A.S., et al., (Eds.)(2018). Harrison’s principles of internal medicine(20th edition). New York: McGraw-Hill Education.

LeBlanc, K.E. and Cestia, W. Carpal Tunnel Syndrome. Am Fam Physician 2011; 83(8): 952-58.

Middleton, S.D. and Anakwe, R.E. Carpal Tunnel Syndrome. BMJ 2014; 349g6437. doi: 10.1136/bmj.g6437

Sevy, J.O. and Varacallo, M. Carpal Tunnel Syndrome, (2019), Retrieved from ncbi.nlm.nih.gov/books/NBK448179/ (Accessed 11 August 2019).

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