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).

A Girl with Seizures

Posted by Carla Rothaus • May 22nd, 2015

In the latest Case Record of the Massachusetts General Hospital, a 9-year-old girl presented to the emergency department with loss of consciousness and a seizure. She had returned from a trip to Puerto Rico 3 weeks earlier. Unilateral inguinal lymphadenopathy was present, and rapidly progressive encephalopathy developed.

The diagnosis of cat scratch disease is based primarily on the presence of typical clinical findings and a history of exposure to cats or fleas. Testing for antibodies to Bartonella henselae is often helpful in confirming this diagnosis.

Clinical Pearls

- What is the most common neurologic presentation of cat scratch disease?

The most common neurologic presentation is acute seizures (status epilepticus), encephalopathy, and hemiparesis.

- What diagnostic tests may be useful to confirm clinically suspected B. henselae infection?

Cultures are usually negative because the gram-negative bacterium is fastidious, slow-growing, and difficult to isolate. Detection of B. henselae DNA by means of polymerase-chain-reaction (PCR) assay is diagnostic, although false negative results may occur. Testing for antibodies to B. henselae is often helpful in confirming this diagnosis. In cases in which serologic tests are equivocal or negative and a PCR assay of the blood is negative, a lymph-node biopsy for the detection of granulomatous inflammation and possibly a PCR assay or Warthin-Starry silver stain for the organism may be helpful.

Morning Report Questions

Q: What IgG antibody titer supports a diagnosis of B. henselae infection?

A: An IgG antibody titer greater than 1:256 strongly supports the diagnosis. A rising titer of IgG antibodies over time would also be convincing serologic evidence of recent infection, but for many patients with cat scratch disease, the IgG antibody titer is already maximally elevated by the time this diagnosis is considered. This is particularly true for patients with encephalopathy, because neurologic manifestations of B. henselae infection typically do not begin until 2 to 3 weeks after the onset of regional lymphadenopathy. IgG antibody titers fall in the months after infection, and only one quarter of patients continue to be seropositive after 1 year.

Q: Does a negative serologic test result for IgM antibodies to B. henselae rule out the possibility of recent infection?

A: IgM antibodies are infrequently found in the serum of patients with cat scratch disease. Titers of IgM antibodies to B. henselae tend to be lower than IgG antibody titers, and IgM antibody titers fall rapidly, generally becoming undetectable less than 3 months after their appearance. Therefore, a negative serologic test result for IgM antibodies does not rule out the possibility of recent infection.

 

Antimicrobial Therapy for Intraabdominal Infection

Posted by Chana Sacks • May 20th, 2015

When the paramedics wheeled Mr. L into the Emergency Department, you knew exactly what to do.  Low blood pressure: establish good IV access and start fluids. Fever of 102 and left lower quadrant abdominal pain: obtain blood cultures, order antibiotics, and get him to the CT scanner once his vitals stabilize.

In medical school, you think figuring out the diagnosis and deciding what treatment to initiate is the hard part.  But as your intern year winds down, you realize that often it’s what comes next that is the gray area of medicine.  Making the diagnosis for Mr. L was straightforward: intraabdominal sepsis. The first steps in management were equally clear – antibiotics, a drain for source control, admit.  But how long should treatment continue? What comes next?

Decisions about antibiotic duration are often based on expert opinion, rather than on definitive data.  In an effort to fill this void, Sawyer and colleagues designed the STOP-IT trial, now published in NEJM, to compare two treatment strategies to determine antibiotic duration: a longer course guided by the patient’s clinical course vs. a shorter, four-day regimen.  The data suggest that shorter may be just as effective.In this multi-center, open-label trial, investigators included just over 500 patients with complicated intra-abdominal infections who underwent an intervention to achieve adequate source control.  Participants were randomly assigned to one of two arms: to a traditional control group in which treatment was continued for 2 days after resolution of fever and leukocytosis, or to a fixed, four-day course of antibiotics.

The results: the data showed no significant difference in the composite primary endpoint of surgical-site infection, recurrent intra-abdominal infection, or death, which occurred in 22.3% of the control arm as compared with 21.8% of the experimental, short-course group (P=0.92).  The median duration of antibiotic therapy, however, was twice as long in the control group: 8 days versus 4 (P<0.001).  The trialists had planned to enroll 500 participants per group, but “owing largely to a concern for futility” at an interim analysis, only about half of the originally planned number of participants was included.

NEJM Deputy Editor Lindsey Baden describes the importance of this trial: “The appropriate duration of antimicrobial therapy for intra-abdominal infections has not been established. Now we have some data to suggest that a fixed, shorter course results in similar outcomes with less antibiotic exposure.”

In an accompanying editorial, Drs. Richard Wenzel and Michael Edmond point out that the trial lacks statistical power “to ensure equivalence” – this was a superiority trial, which did not show superiority rather than a non-inferiority trial. Still, they note the many potential benefits of shorter antibiotic courses for the estimated 300,000 people who have complicated intra-abdominal infections in the United States each year: “1.2 million days of antibiotic therapy could be saved….savings nationally could be more than $97 million per year. Reduced antibiotic exposure might also favorably influence the burden of related adverse events.”

To be sure, given the study’s limitations, you are still somewhat in the gray as you decide the duration of antibiotic treatment for Mr. L, but this trial offers new, important data that suggest it may be just as effective to STOP-IT early.

Watch the NEJM Quick Take video summary on antimicrobial therapy for acute intrabdominal infection.

Refractory Metastatic Colon Cancer

Posted by Carla Rothaus • May 15th, 2015

TAS-102, a combination of trifluridine and tipiracil in which tipiracil interferes with the deactivation of trifluridine, improved overall and progression-free survival in patients whose disease had progressed after treatment with fluorouracil-containing drug combinations. A new Original Article assesses the efficacy and safety of TAS-102 in a global population of such patients.

Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer.

Clinical Pearls

- What is the current treatment for colorectal cancer?

Fluoropyrimidines have long represented the cornerstone of treatment for colorectal cancer. Such compounds act primarily as inhibitors of thymidylate synthase, the rate-limiting enzyme in the synthesis of pyrimidine nucleotides. Fluorouracil has been combined with folinic acid (also known as leucovorin) to enhance the capacity of fluorouracil to bind to thymidylate synthase. The addition of irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) to fluorouracil and folinic acid, in combination with either a vascular endothelial growth factor inhibitor (bevacizumab) or an epidermal growth factor inhibitor (e.g., cetuximab or panitumumab) if the tumor contains a wild-type RAS gene, represents contemporary standard therapy and has extended the median survival among patients with metastatic colorectal cancer to almost 30 months.

- What is TAS-102?

TAS-102 is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine is the active cytotoxic component of TAS-102. Its triphosphate form is incorporated into DNA, and incorporation appears to result in its antitumor effects. Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase and, when combined with trifluridine to form TAS-102, prevents the rapid degradation of the trifluridine, allowing for the maintenance of adequate plasma levels of the active drug.

Morning Report Questions

Q: Does TAS-102 prolong overall survival and progression-free survival when compared to placebo in this population?

A: The results of this placebo-controlled, double-blind, phase 3 clinical trial conducted in Japan and in the United States, Europe, and Australia confirmed the results of previous assessments of oral TAS-102 in patients with metastatic colorectal cancer who had already undergone extensive treatment: TAS-102 was associated with a clinically relevant prolongation of overall survival in essentially all treatment subgroups. At the time that the target was reached (574 deaths), the median overall survival was 7.1 months (95% confidence interval [CI], 6.5 to 7.8) in the TAS-102 group and 5.3 months (95% CI, 4.6 to 6.0) in the placebo group. The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) in the TAS-102 group and 1.7 months (95% CI, 1.7 to 1.8) in the placebo group. The assessment of tumor status with regard to KRAS showed that 49% of the patients had wild-type tumors and 51% had mutant tumors. Benefit from treatment with TAS-102 was observed in both patient subgroups.

Figure 1. Kaplan-Meier Curves for Overall Survival and Forest Plot of Subgroup Analyses.

Figure 2. Kaplan-Meier Curves for Progression-free Survival and Forest Plot of Subgroup Analyses.

Q: What adverse events are associated with the use of TAS-102?

A: In the trial by Meyer et al., the most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. Grade 3 or 4 stomatitis, hand-foot syndrome, and coronary spasm, which are associated with the use of fluoropyrimidines, were encountered in less than 1% of the patients treated with TAS-102.

Table 2. Frequency of Adverse Events and Laboratory Abnormalities.

Appendectomy or “Antibiotics First”

Posted by Carla Rothaus • May 15th, 2015

Prompt appendectomy is generally recommended for uncomplicated appendicitis. Randomized trials comparing appendectomy with an antibiotics-first strategy have shown similar complication rates but substantial crossover to or later need for appendectomy with the latter strategy.  A new Clinical Practice review article covers this topic.

A major uncertainty in the management of appendicitis is whether an appendectomy is needed or whether antibiotics alone, with an appendectomy performed only if the appendicitis does not resolve (an “antibiotics first” strategy), is a reasonable alternative. Success with an antibiotics-alone approach in Navy personnel who developed appendicitis while at sea (without access to an operating room) supported this strategy. Subsequently, several [European] randomized trials compared appendectomy with an antibiotics-first strategy (with appendectomy as needed) for uncomplicated appendicitis.

Clinical Pearls

- What is the protocol for an antibiotics-first approach, and how do the clinical outcomes compare to those of appendectomy?

The European randomized trials involved a range of interventions and durations of treatment. A typical protocol included 48 hours of intravenous antibiotics while the patient was in the hospital, followed by 7 days of oral antibiotics that are sensitive to the typical organisms found in intraabdominal infection (e.g., ciprofloxacin and metronidazole), and did not include repeat imaging to confirm resolution of appendicitis. Clinical outcomes among patients randomly assigned to the antibiotics-first strategy were generally favorable, but the metrics of success were inconsistent (including reduction in white-cell count, avoidance of peritonitis, and general symptom reduction; several trials had very small samples). As compared with patients assigned to undergo prompt appendectomy, patients assigned to the antibiotics-first strategy had lower or similar pain scores, required fewer doses of narcotics, and had a quicker return to work, but these outcomes were not assessed in the studies. Perforation rates were not significantly higher among patients assigned to the antibiotics-first approach. The rate of crossover to surgery within 48 hours after the initiation of antibiotics ranged among trials from 0 to 53%. Because the studies used different criteria to trigger a crossover, this variability suggests substantial heterogeneity of treatment effect across patients or variation in clinicians’ willingness to adhere to the antibiotic approach.

Table 2. Common Features of Randomized Clinical Trials of “Antibiotics First” Regimens.

- What is the rate of recurrent appendicitis when initial antibiotic treatment has been successful?

In the European trials, eventual appendectomy after initial, successful treatment with antibiotics occurred in 10 to 37% of the patients randomly assigned to the antibiotics-first strategy (mean time to appendectomy, 4.2 to 7 months in the three studies in which this outcome was reported). Data from longer follow-up periods were unavailable, and therefore it is unclear whether the likelihood of appendectomy continued to increase or stabilized over time. In one report that included information on subsequent surgical pathological results, 13% of the patients who underwent later appendectomy (after initially successful treatment with an antibiotics-first strategy) did not actually have appendicitis; thus, the true rate of recurrent appendicitis is unknown.

Morning Report Questions

Q: What questions remain unanswered about the use of the antibiotics-first approach?

A: All these studies were performed in Europe, and the fact that surgical patients more often underwent “open” appendectomy (34 to 82%), with an associated longer duration of hospital stay after surgery (mean, approximately 3 days) than is typical in the United States, limits extrapolation of the results to the United States. Questions remain about whether complications related to delayed surgery, the number of days of antibiotic therapy, the amount of time spent in health care, anxiety about future episodes of abdominal pain, and total costs of care differ substantively between treatment options. Furthermore, factors associated with a higher risk of recurrence are unclear, and it is not currently possible to identify patients who should be directed to surgery or offered an antibiotics-first strategy.

Q: Do professional society guidelines support an antibiotics-first strategy for acute uncomplicated appendicitis?

A: The American College of Surgeons, the Society for Surgery of the Alimentary Tract, and the World Society of Emergency Surgery all describe appendectomy (either laparoscopic or open) as the treatment of choice for appendicitis. Regarding an antibiotics-first strategy, the American College of Surgeons patient information guide indicates that it “may be effective, but there is a higher chance of reoccurrence”; the Society for Surgery of the Alimentary Tract patient care guidelines suggest that it is “not a widely accepted treatment”; and the World Society of Emergency Surgery states that “this conservative approach features high rates of recurrence and is therefore inferior to the traditional appendectomy . . . Non-operative antibiotic treatment may be used as an alternative treatment for specific patients for whom surgery is contraindicated.”

Incentive Programs to Urge Smokers to Quit: Lessons from Behavioral Science

Posted by Rachel Wolfson • May 13th, 2015

Many of the major public health issues currently threatening our population, including smoking and obesity, require lifestyle and behavioral changes. Effecting these changes in patients has been challenging, but a deeper understanding of the forces that drive human behavior could inspire the design of better programs leading to behavioral change. For example, behavioral scientists have found that individuals seek more to minimize losses than to maximize gains, a phenomenon called “loss aversion.” Many of us have experienced the feeling of loss aversion personally; for some reason losing a $20 bill often feels more annoying than the satisfaction we get from finding a $20 bill. Further, individuals can be motivated by social dynamics and, in some cases, may be more likely to perform a certain task if they feel part of a group that is performing that task.

With these principles in mind, Halpern and colleagues designed a randomized clinical trial to assess the efficacy of different financial incentive programs for smoking cessation. Just over 2,500 active smokers were randomized to one of three interventions: a rewards program, a deposit program, or a usual care program (involving information and smoking cessation aids). In the rewards programs, participants could receive a total of $800 if they quit smoking, while in the deposit program an up-front deposit of $150 would be returned to the participants upon quitting smoking after 6 months, along with a total $650 reward. In addition, the authors tested the efficacy of the rewards and deposit programs in both an individual and group context.

Both the reward and deposit programs were significantly more effective than usual care (sustained abstinence rates for each program at 6 months were 6% for usual care, 15-16% for the rewards program, and 9-11% for the deposit program). Further, the deposit program had much lower enrollment rates than the reward program (13.7% vs. 90%) but much higher rates of smoking cessation amongst those who chose to do the programs (52.3% for the deposit program vs. 17.1% for the rewards program). Despite this difference, including all patients randomized to either program, the rewards program was more effective than the deposit program, given the low enrollment rate in the deposit program. Interestingly, the authors found no difference between the individual or group based programs with either incentive.

These results have exciting implications for how to help smokers quit. First, as behavioral scientists would have predicted, the risk of losing money is better for inspiring cessation behavior than the potential to make money. However, as Cass R. Sunstein, a lawyer at Harvard University and a leader in the field of behavioral economics points out in an accompanying editorial, the challenge with deposit programs will be finding a way to encourage smokers to enroll. More work is needed to decipher if a smaller deposit will stimulate larger enrollments in deposit programs.

View the NEJM Quick Take video summary of the results of the study, and join a discussion with authors and experts on the NEJM Group Open Forum.

Iron-Deficiency Anemia

Posted by Carla Rothaus • May 8th, 2015

Iron-deficiency anemia is the most common form of anemia in the world. A new review article covers the global nature of the disease, iron homeostasis in normal and iron-deficient states, clinical findings, treatment, and causes of iron-resistant iron deficiency.

Iron is crucial to biologic functions, including respiration, energy production, DNA synthesis, and cell proliferation. Although the prevalence of iron-deficiency anemia has declined somewhat recently, iron deficiency continues to be the top-ranking cause of anemia worldwide.

Clinical Pearls

- What mechanisms are central to iron homeostasis?

The human body has evolved to conserve iron in several ways, including the recycling of iron after the breakdown of red cells and the retention of iron in the absence of an excretion mechanism.

However, since excess levels of iron can be toxic, its absorption is limited to 1 to 2 mg daily, and most of the iron in the body (about 25 mg per day) is recycled by macrophages that phagocytose senescent erythrocytes. The latter two mechanisms are controlled by the hormone hepcidin, which maintains total-body iron within normal range, avoiding both iron deficiency and excess.

- How are hepcidin levels affected by iron deficiency anemia?

Hepcidin is a peptide hormone that is synthesized primarily in the liver. It functions as an acute-phase reactant that adjusts fluctuations in plasma iron levels by binding to and inducing the degradation of ferroportin, which exports iron from cells. In iron deficiency, the transcription of hepcidin is suppressed. This adaptive mechanism facilitates the absorption of iron and the release of iron from body stores.

Figure 1. The Iron Cycle — Mechanisms of Adaptation to Iron Deficiency.

Morning Report Questions

Q: What conditions should be considered when iron deficiency anemia is refractory to oral iron supplementation?

A: In most cases, iron resistance is due to disorders of the gastrointestinal tract. Partial or total gastrectomy or any surgical procedure that bypasses the duodenum can cause resistance to oral iron. Laparoscopic Roux-en-Y gastric bypass, which is performed in selected obese patients to reduce caloric intake and to correct diabetes, is an emerging cause of iron deficiency and anemia because the procedure effectively removes an active iron absorption site from the digestive process and increases gastric pH. Helicobacter pylori infection decreases iron absorption because the microorganism competes with its human host for available iron, reduces the bioavailability of vitamin C, and may lead to microerosions that cause bleeding. Since it is estimated that half the world’s population is infected with H. pylori, clinicians should be aware of the possibility of infection and provide treatment in order to eradicate this source of iron-resistant iron-deficiency anemia.

Q: What are some of the indications for parenteral iron?

A: Patients with malabsorption and genetic iron-refractory iron-deficiency anemia may require intravenous iron. Intravenous administration is also preferred when a rapid increase in hemoglobin level is required or when iron-deficiency anemia caused by chronic blood loss cannot be controlled with the use of oral iron, as is the case in patients with hereditary hemorrhagic telangiectasia. Active inflammatory bowel disease is an emerging indication for the use of intravenous iron; oral iron is not only ineffective but may also increase local inflammation. Intravenous iron is essential in the management of anemia in patients with chronic kidney disease who are receiving dialysis and treatment with erythropoiesis-stimulating agents.

Table 3. Indications for Parenteral Iron Therapy.

 

Sick as a Dog

Posted by Carla Rothaus • May 8th, 2015

In the latest Clinical Problem-Solving article, a 42-year-old man presented to an emergency department in rural Colorado with a 2-day history of fever, cough with scant hemoptysis, chest pain, and myalgias. He reported no sick contacts and no oropharyngeal or gastrointestinal symptoms, rashes, or lymphadenopathy.

Yersinia pestis is a gram-negative, facultatively anaerobic bacillus or coccobacillus and the causative organism for a spectrum of  diseases referred to as plague. Rodents, including prairie dogs, are the primary reservoir, although cases of plague transmission have been linked to domestic cats and dogs.

Clinical Pearls

- What are the mechanisms for disease transmission?

Y. pestis is found in temperate-to-tropical regions worldwide, with enzootic foci in the western United States. Disease in humans is most commonly transmitted by flea bite, which results in bubonic plague (80 to 90% of cases) or septicemic plague without bubo formation. Pneumonic plague is most often the result of hematogenous spread from  a systemic infection (secondary) but can, although rarely, occur by direct inhalation of aerosolized bacteria (primary).

- Does human-to-human transmission occur?

Although rates of human-to-human transmission are very low, droplet precautions should be instituted if Y. pestis infection is suspected and should be continued until appropriate antimicrobial therapy has been administered for at least 48 hours.

Morning Report Questions

Q: What are typical clinical and radiographic findings of primary pneumonic plague?

A: The incubation period for primary pneumonic plague has been variably reported from as short as several hours to as long as 6 days. Although bubonic plague presents with acute lymphadenitis near the bite of an infected flea, forming the characteristic bubo, primary pneumonic plague typically presents with sudden onset of cough with bloody sputum, dyspnea, and pleuritic chest pain. High fever, malaise, myalgias, and nausea may accompany both forms of disease and also tend to start abruptly. Radiography of primary pneumonic plague most commonly shows patchy, bilateral infiltrates, although a lobar appearance has been described.

Q: How is primary pneumonic plague treated?

A: Clinical trials are lacking to guide antimicrobial therapy for human plague. Streptomycin is considered the drug of choice, but owing to the limited availability of streptomycin and its ototoxicity, gentamicin is often effectively substituted, either alone or in combination with tetracyclines. Data on the use of fluoroquinolones in humans are limited, but the availability and safety of these drugs make them alternatives for treatment and preferred agents for postexposure prophylaxis of plague. The appropriate duration of therapy is unclear. Ten days has been suggested on the basis of animal models, but some experts recommend treating until 3 days after defervescence. The incidence of primary pneumonic plague is low, but mortality is as high as 100% without treatment and 50% with treatment.

Inflammatory Muscle Diseases

Posted by Carla Rothaus • May 1st, 2015

The four main types of inflammatory muscle disease — dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis — are summarized in a new review article. Pathogenesis, differential diagnosis, and treatment approaches are discussed.

The inflammatory myopathies constitute a heterogeneous group of disorders that are best classified, on the basis of distinct clinicopathologic features, as four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis.

Clinical Pearls

- What are the general clinical features of the inflammatory myopathies?

Patients with inflammatory myopathies have increasing difficulty with tasks requiring the use of proximal muscles, such as getting up from a chair, climbing steps, or lifting objects. In all disease subtypes, neck-extensor and pharyngeal muscles can be involved, which results in difficulty holding up the head (head drop) or in dysphagia. In advanced and rare acute cases, the respiratory muscles can be affected. Extramuscular manifestations may occur in all inflammatory myopathies, although they occur in inclusion-body myositis only in rare cases.

- Are there any clues to facilitate the early clinical diagnosis of inclusion-body myositis?

Inclusion-body myositis is the most common and disabling inflammatory myopathy among persons 50 years of age or older. Although inclusion-body myositis is commonly suspected when a patient with presumed polymyositis does not respond to therapy, features that can lead to an early clinical diagnosis include the observation of early involvement of distal muscles, especially foot extensors and finger flexors; evident atrophy of the forearms and quadriceps muscles; a history of frequent falls due to quadriceps muscle weakness causing buckling of the knees; and the presence of mild facial-muscle weakness.

Morning Report Questions

Q: What are some of the features of polymyositis and necrotizing autoimmune myositis?

A: Polymyositis is rare and often misdiagnosed. It remains a diagnosis of exclusion and is best defined as a subacute proximal myopathy in adults who do not have rash, a family history of neuromuscular disease, exposure to myotoxic drugs (e.g., statins, penicillamine, and zidovudine), involvement of facial and extraocular muscles, endocrinopathy, or the clinical phenotype of inclusion-body myositis. Necrotizing autoimmune myositis is a distinct clinicopathologic entity that occurs more frequently than polymyositis, accounting for up to 19% of all inflammatory myopathies. It can occur at any age but is seen primarily in adults; it starts either acutely, reaching its peak over a period of days or weeks, or subacutely, progressing steadily and causing severe weakness and very high creatine kinase levels. Necrotizing autoimmune myositis occurs alone or after viral infections, in association with cancer, or in patients taking statins, in whom the myopathy continues to worsen after statin withdrawal. Most patients with necrotizing autoimmune myositis have antibodies against signal recognition particle (SRP) or against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR).

Q: How are the inflammatory myopathies diagnosed and treated?

A: The diagnosis of the exact subtype of inflammatory myopathy is based on the combination of clinical history, tempo of disease progression, pattern of muscle involvement, muscle enzyme levels, electromyographic findings, muscle-biopsy analysis, and for some conditions, the presence of certain autoantibodies. Oral prednisone administered once daily after breakfast at a dose of 1 mg per kilogram of body weight, up to 100 mg per day, is the first-line drug for the treatment of dermatomyositis, polymyositis, and necrotizing autoimmune myositis; this choice of drug is based on experience but not on controlled trials. In patients whose condition responds to glucocorticoids, azathioprine, mycophenolate mofetil, methotrexate, or cyclosporine is empirically used for glucocorticoid sparing. When glucocorticoids fail to induce remission or in rapidly progressive cases, intravenous immune globulin therapy is appropriate. With respect to inclusion-body myositis, glucocorticoids, methotrexate, cyclosporine, azathioprine, and mycophenolate are ineffective, and although some patients initially have mild improvements when treated with one of these agents, no long-term benefit is achieved.

Intravenous immune globulin has been found to be ineffective in controlled trials but may transiently help some patients, especially those with dysphagia.

Table 1. Criteria Supporting the Diagnosis of Inflammatory Myopathies.

Table 2. Treatment of Inflammatory Myopathies: A Step-by-Step Approach.