Prophylactic Platelet Transfusions: Are They Really Necessary?

Posted by Rena Xu • May 8th, 2013

Many patients with hematologic malignancies develop dangerously low platelet counts due to their disease, their treatment, or both. To mitigate the risk of bleeding, such patients have historically received prophylactic platelet transfusions. Recently, however, the value of this practice has been called into question. Does it really help to give platelets on a preventative basis? Or is it sufficient to provide therapeutic transfusions when bleeding occurs?

Stanworth et al.sought to answer this question by conducting a randomized controlled trial of 600 patients with hematologic malignancies who were thrombocytopenic (platelet count <50×109/L) or expected to become thrombocytopenic.  Half were randomized to receive prophylactic platelet transfusions if the platelet count fell below a threshold of 10×109/L, while the other half received no prophylaxis.  The primary outcome was the percentage of patients who developed World Health Organization (WHO) grade 2-4 bleeding within 30 days, where grade 2 is defined as moderate bleeding (transfusion not acutely needed), grade 3 is severe (transfusion required within 24 hours), and grade 4 is life-threatening.

Fewer transfusions per patient were performed in the no-prophylaxis arm as compared to the prophylaxis arm (1.7 versus3.0 transfusions [SD 3.2]). However, the study failed to show that a “no prophylaxis” strategy was non-inferior to the accepted practice of prophylactic transfusions. WHO grade 2-4 bleeding occurred in 50% of patients in the no-prophylaxis group, as compared to 43% of patients in the prophylaxis group. In other words, prophylactic transfusions reduced the proportion of patients with bleeding by 7%.

More patients in the no-prophylaxis group developed grade 3-4 bleeding, although this difference was not statistically significant. Patients in the no-prophylaxis group experienced longer bleeding durations and shorter times to the first bleed.

The investigators also performed a sub-group analysis for patients who had undergone autologous stem cell transplants (auto SCT) as treatment for their malignancy. In previous studies, auto SCT patients who were assigned to the no-prophylaxis group experienced higher rates of bleeding as compared to those who received prophylaxis. In this study, however, no significant difference was found in bleeding rate between the groups.

In an accompanying editorial, Sherrill J. Slichter, M.D., of the University of Washington School of Medicine writes: “[T]he reduction in the use of platelet transfusions does not justify subjecting patients to the increased bleeding risks associated with a therapeutic-only platelet-transfusion strategy in any category of patients with hypoproliferative thrombocytopenia.”

NEJM Deputy Editor Dan Longo, M.D., states: “Prophylactic platelet transfusions do not fulfill Benjamin Franklin’s famous aphorism that an ounce of prevention is worth a pound of cure, but they are sufficiently beneficial that their standard use seems warranted in patients with platelet counts of 10,000/microliter or less.”

This study offered the benefit of a clinically relevant primary outcome. Bleeding rates, more than units transfused, capture the impact of prophylaxis or lack of prophylaxis on health. Does prophylaxis actually benefit patients who face the risk of thrombocytopenia? At least based on these results, the answer is yes, and prophylactic transfusions should continue to be used.

How do you manage the risk of bleeding in patients with hematologic malignancy and thrombocytopenia? Does your approach differ for patients who pursue auto SCT versus other treatments for their malignancy?

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In the Thick of It

Posted by Sara Fazio • May 3rd, 2013

In our latest Clinical Problem-Solving article, a 52-year-old man presented to the emergency department with an acute onset of palpitations and chest pressure. He had felt well until 2 days earlier, when epigastric burning, fatigue, weakness, and emesis had developed.

The presence of a delta wave together with a short PR interval suggests the presence of an alternative pathway of conduction from the atrium to the ventricles. In the most common form, this pathway is atrioventricular, bypassing the atrioventricular node and His-Purkinje system; the delta wave indicates that the pathway involves the ventricular myocardium rather than the specialized conduction system.

Clinical Pearls

• What are the characteristics of cardiac storage disorders that cause cardiomyopathy?

Cardiac storage disorders that may cause severe biventricular hypertrophy include deficiency in the (gamma)2 subunit of AMP-activated protein kinase (PRKAG2 deficiency), deficiency in (alpha)-galactosidase (Fabry’s disease), and deficiency in lysosome-associated membrane protein 2 (Danon’s disease). Danon’s disease typically causes refractory heart failure, sudden death, or both before 25 years of age and is often associated with proximal weakness and cognitive impairment. Patients with either Fabry’s disease or PRKAG2 deficiency can present in adulthood with cardiac hypertrophy and preexcitation. PRKAG2 deficiency is typically manifested as an isolated cardiac phenotype, whereas Fabry’s disease is often characterized by multisystem involvement. Renal failure is a frequent complication of Fabry’s disease but is not characteristic of hypertrophic cardiomyopathy or the other storage disorders.

• What is the genetic basis and pathophysiology of Fabry’s disease?

Fabry’s disease is caused by a loss of function of the lysosomal hydrolase (alpha)-galactosidase, which leads to the accumulation of glycosphingolipids, primarily globotriaosylceramide, within lysosomes. In cardiomyocytes, this deposition causes intramyocyte vacuolization with accumulation of lamellar bodies, which, when seen on electron-microscopical examination of an endomyocardial-biopsy specimen, can be diagnostic of the disease. GLA, the gene mutated in Fabry’s disease, is carried on the X chromosome. Affected men are therefore hemizygous for the mutation, and the incidence of overt Fabry’s disease is higher among men than among women; however, Fabry’s disease develops in 70% of women who are heterozygous for a GLA mutation, often with a later and milder presentation. For both men and women, long delays between symptom onset and the diagnosis of Fabry’s disease are common.

Morning Report Questions

Q: What are the clinical manifestations of Fabry’s disease?

A: Fabry’s disease is increasingly recognized as a cause of cardiac hypertrophy and has been estimated to cause 0.5 to 5% of previously unexplained cases of left ventricular hypertrophy. The majority of patients with Fabry’s disease have at least one cardiovascular manifestation, such as ventricular hypertrophy, conduction disease, arrhythmia, stroke, or, less commonly, a reduced left ventricular ejection fraction or valvular dysfunction. In the classic presentation of Fabry’s disease in men, glycosphingolipid accumulates in multiple sites, including the skin (angiokeratomas and hypohidrosis), eyes, kidneys, heart, and nervous system (neuropathic pain, cerebrovascular disease, and hearing loss). Cerebrovascular disease is a particular concern in patients with Fabry’s disease and may occur before 30 years of age. Renal insufficiency develops in the majority of patients, and Fabry’s disease is estimated to account for approximately 0.3% of cases of end-stage renal disease in men. Renal injury in Fabry’s disease often is accompanied by proteinuria.

Q: What are the principles of evaluation and treatment of Fabry’s disease?

A: Given the X-linked nature of Fabry’s disease, prompt evaluation of relatives who may share an X chromosome with the affected patient is essential to identify persons with early or subclinical disease. Timely diagnosis is of particular importance because this disease may be treated by enzyme-replacement therapy, usually in the form of infusions of recombinant (alpha)-galactosidase every 2 weeks. A randomized, controlled trial involving patients with Fabry’s disease suggested that enzyme-replacement therapy delays the time to a composite end point of a renal, cardiac, or cerebrovascular event or death. Enzyme-replacement therapy has been shown to reduce neuropathic pain and reverse abnormalities in cerebral blood flow and has been associated with a reduction in left ventricular mass and an improvement in health-related quality of life.

 

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Injuries

Posted by Sara Fazio • May 3rd, 2013

Injuries, whether intentional or unintentional, account for a substantial burden on the health care system. The latest article in our new Global Health series describes the magnitude of the problem worldwide, enumerates ongoing efforts to prevent injuries, and summarizes systems that need to be in place to care for the injured.

In 2010, there were 5.1 million deaths from injuries — almost 1 out of every 10 deaths in the world — and the total number of deaths from injuries was greater than the number of deaths from infection with the human immunodeficiency virus (HIV)-acquired immune deficiency syndrome (AIDS), tuberculosis, and malaria combined (3.8 million).

Clinical Pearls

• What demographic groups are more likely to sustain injuries?

Male children, adolescents, and men, who accounted for about 68% of all injury-related deaths in 2010, sustain a disproportionate number of injuries. Although injuries are sustained across the life cycle, they affect young people (persons between 10 and 24 years of age) in particular, accounting for 40% of deaths in this age group. More than half of all deaths (52%) occurring in male adolescents and young men 10 to 24 years of age are caused by injuries.

• What was the leading cause of injury-related death in 2010?

In 2010, unintentional injuries were the cause of the majority of injury-related deaths (69%), as well as the majority of DALYs [disability-adjusted life-years] (72%). Transportation-related injuries (including injuries from both road-traffic incidents and non-road-traffic causes, such as incidents on the water or in the air) were the leading cause of injury-related deaths in 2010 and were responsible for 1.4 million deaths. Injuries from road-traffic incidents were the eighth leading cause of death overall and the leading cause of death among persons 10 to 24 years of age and were responsible for 17% of all deaths among males in this age group.

Table 1. Deaths from Cause-Specific Injuries in 2010.

Table 2. Estimates of the Rate of Death per 100,000 Persons Associated with Cause-Specific Injuries, According to Income Level and Region, in 2008.

Morning Report Questions

Q: What is the best means of preventing self-directed violence?

A: The best available evidence regarding the prevention of self-directed violence suggests that the medical sector has a significant role to play. Specifically, there is increasingly strong evidence of the effectiveness of educating clinicians in the appropriate identification and treatment of persons with mood disorders. In addition, there is good evidence to suggest that restricting access to the means of committing suicide, including access to pesticides, guns, and unprotected heights, is an effective preventive strategy, although it is one that is outside the realm of the health sector.

Q: How has in-hospital management for injured patients changed over the past decade?

A: In the past decade, large-scale, randomized, controlled trials conducted in emergency departments and intensive care units, including research focused specifically on the care of injured patients, have set new benchmarks for the provision of evidence-based, in-hospital trauma care. Not only are these trials providing evidence regarding effective treatments, such as the use of tranexamic acid to reduce the risk of death in patients with trauma-related bleeding (as shown in the Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage 2 [CRASH 2] study), but they are also providing evidence of useless and potentially harmful practices, such as the administration of glucocorticoids and the use of albumin for fluid resuscitation in the treatment of patients with major head injury. In low-resource settings, where surgeons are not readily available, evidence indicates that outcomes can be improved if general practitioners (or even nondoctors) can be trained in certain skills that would normally be carried out by emergency physicians or trauma surgeons in centers with better resources.

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Meniscal tear: Operate or PT?

Posted by Rachel Wolfson • May 1st, 2013

Mr. Richardson is a 55-year-old man who comes into your clinic complaining of knee pain. He used to enjoy going on long jogs, but as the years have gone by the pain in his joint has increased and he’s lost a lot of mobility. He’s frustrated by the weight that he’s put on due to lack of mobility, and ibuprofen is no longer working to lessen his ever increasing pain. You order an MRI, which shows radiographic evidence of a meniscal tear and osteoarthritis (OA). Now, you have to decide how to treat Mr. Richardson. Should you immediately send Mr. Richardson to surgery, or will he benefit from PT? If you send him to PT first, will the delay to surgery impair his outcome? For the most part, in the world of mechanical joint diseases, surgery reigns supreme. But until now, it has not been clear if surgery provides a benefit to patients with a meniscal tear and osteoarthritis (OA) in comparison to standard physical therapy.

In this week’s NEJM, Katz and colleagues report the results of a randomized controlled trial addressing this uncertainty. Across seven U.S. centers, 351 symptomatic patients over the age of 45 who have radiographic evidence of OA and a meniscal tear were assigned to either surgery or physical therapy. At both 6 months and 12 months after randomization, there were no statistically significant differences in pain or improvement in function between the two groups. Notably, 30% of patients assigned to the physical therapy group had chosen to have surgery by 6 months. However, by 12 months, these patients’ functional improvement was not significantly different from those of the other two groups, implying that the delay to surgery did not affect their final outcome.

The findings of this article are important reminders that surgery may not always be the best first treatment option. In an accompanying editorial, Rachelle Buchbinder, PhD, stresses that these results should change practice. She suggests that a change in the approach to caring for these patients can occur, and that it is reasonable, in light of these results, to use PT as a first therapy. She also points out that, although the article reported no difference in adverse effects, further follow up will need to be performed to assess any long-term risks associated with these therapies.

This article suggests that there should be a change in the treatment strategy for patients like Mr. Richardson: we can safely try PT first and, if he doesn’t respond, he can get surgery later.

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A 6-Year-Old Girl with Bone and Joint Pain

Posted by Sara Fazio • April 26th, 2013

In the latest Case Record of the Massachusetts General Hospital, a 6-year-old girl was admitted to this hospital because of bone and joint pain for 1 year and recent onset of fever and abdominal distention. Imaging revealed a mass in the abdominal and pelvic region and lesions in the liver, kidneys, and multiple bones.

A diagnosis of Langerhans’-cell histiocytosis should be considered in a child with bone pain and lytic skeletal lesions. Patients with Langerhans’-cell histiocytosis may present with disease of a single site, most commonly bone, or with multisystem disease. Patients with multisystem disease can present with rash, bone pain, hepatosplenomegaly, and signs of bone marrow infiltration.

Clinical Pearls

• What infectious diseases should be considered in a young child presenting with myalgias and arthralgias?

Lyme disease should be considered when a young child from an area where Lyme disease is endemic presents with myalgias and arthralgias. It would be important to inquire about the presence of an erythema migrans rash. Objective arthritis is often evident on physical exam, and tests for antibodies to Borrelia burgdorferi would be confirmatory. Patients who have been infected with Bartonella henselae through a cat scratch or bite or a flea bite may present with fever and regional lymphadenopathy; therefore, a diagnosis of cat scratch disease should be considered. Similarly, tularemia should be considered in patients who have been exposed to rabbits or rodents and have an acute presentation with fever and lymphadenopathy. Parvovirus infections can be followed by arthralgias and arthritis. Myalgias, arthralgias, and bone pain are clinical findings associated with subacute bacterial endocarditis. Tuberculosis should be considered in a child with lymphadenopathy and bony disease.

• What is the classic presentation of systemic onset juvenile idiopathic arthritis?

Patients with systemic onset juvenile idiopathic arthritis typically have daily spiking fevers, objective arthritis, rash (commonly salmon colored), and a markedly elevated white-cell count. A significantly elevated platelet count and anemia are also commonly present. Arthritis may not be present early in the course of disease, but is necessary to make the diagnosis.

Morning Report Questions

Q: What is the epidemiology and typical presentation of Burkitt’s lymphoma?  

A: Burkitt’s lymphoma is the most common lymphoma in children, accounting for approximately 35 to 40% of the cases. The peak incidence of Burkitt’s lymphoma is in children 5 to 10 years of age. The abdomen is the most common site of disease. Patients may present with massive abdominal disease involving the mesentery, retroperitoneum, kidneys, and ovaries. Bone involvement, however, is uncommon. Because of the rapid proliferation of Burkitt’s lymphoma, patients classically present with high uric acid and lactate dehydrogenase levels.

Q: What are the characteristics of B-cell acute lymphoblastic leukemia-lymphoblastic lymphoma (B-cell ALL/LBL)?    

A: In the past, ALL and lymphoblastic lymphoma were considered distinct diseases, but they are now regarded as different clinical stages of the same disease — B-cell acute lymphoblastic leukemia-lymphoblastic lymphoma (B-ALL/LBL). Because genetic findings can have specific clinicopathological associations and prognostic implications, final classification of B-ALL/LBL requires cytogenetic analysis. Common translocations seen in B-ALL/LBL include t(9;22)(q34;q11) (BCR-ABL), t(12;21)(p13;q22) (TEL-AML1), and t(11q23) (MLL). Cases in which there is no specific cytogenetic abnormality are considered to have an intermediate prognosis. A slow rate of early response to treatment and the presence of minimal residual disease at the end of induction therapy have been shown to be strong predictors for relapse.

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Chronic Pruritus

Posted by Sara Fazio • April 26th, 2013

Chronic pruritus requires careful evaluation for primary dermatologic or systemic causes. In addition to treatment of the underlying cause, when identified, various topical and systemic therapies may be used, although supporting data from randomized trials are scarce. The latest article in our Clinical Practice series comes from Dr. Gil Yosipovitch of Wake Forest University Baptist Medical Center.

Chronic pruritus is associated with markedly reduced quality of life; a recent study demonstrated that chronic itch is as debilitating as chronic pain. Deranged sleep patterns and mood disturbances including anxiety and depression are common, and may further exacerbate itch.

Clinical Pearls

• What is the definition and epidemiology of chronic pruritus?

Chronic pruritus, defined as itch persisting for more than 6 weeks, is common. It may involve the entire skin (generalized pruritus) or only particular areas such as the scalp, upper back, arms, or groin (localized pruritus). Chronic pruritus increases with age, is more common in women than in men, and in Asians more than in Caucasians.

• What are the causes of chronic pruritus?

Chronic pruritus is characteristic of several dermatologic diseases (e.g., atopic eczema, psoriasis, lichen planus, and scabies) but also occurs in a variety of nondermatologic disorders. The causes of chronic pruritus can be broadly categorized into four major groups: dermatologic; systemic (e.g., cholestasis, chronic kidney disease, myeloproliferative disorders, and hyperthyroidism); neurologic (e.g., notalgia paresthetica [a distinctive itch of the upper back] and brachioradial pruritus [a characteristic itch of the arms], probably caused by spinal nerve impingement); and psychogenic. Itching of any type may elicit secondary skin changes thanks to scratching, rubbing, and picking, and thus the presence of skin findings does not rule out a systemic cause. Excoriation and nonspecific dermatitis can camouflage both cutaneous and noncutaneous causes of itch.

Morning Report Questions

Q: What is the appropriate evaluation of a patient with chronic pruritus?

A: The first step in the evaluation of chronic pruritus is to determine if the itch can be attributed to a dermatologic disease, or whether an underlying noncutaneous cause is present. A detailed review of systems and a thorough drug history should be performed. Pruritus is sometimes the first manifestation of systemic diseases such as Hodgkin’s disease or primary biliary cirrhosis, antedating other symptoms by months or longer. The skin should be examined carefully to assess for primary skin lesions. It should be recognized that excoriations, nonspecific dermatitis, prurigo nodularis, and LSC (lichen simplex chronicus) are secondary lesions, for which an underlying cause should be sought. Excessively dry skin (xerosis) usually presents with minimally detectable changes, but erythematous and scaly inflammatory patches may develop. In addition to the history and physical examination, screening studies are suggested should include a CBC (complete blood count) with differential, tests of hepatic, renal, and thyroid function, and a chest radiograph. An HIV test and sedimentation rate should also be considered.

Figure 3. Diagnostic Workup for Chronic Pruritus.

Q: What is the role for neuroactive medications in the treatment of chronic pruritus?

A: Gabapentin and pregabalin, structural analogues of the neurotransmitter gamma-aminobutyric acid, are effective for several types of pruritus. In controlled trials in patients with CKD (chronic kidney disease) pruritus, low doses of gabapentin (100 to 300 mg three times a week) were significantly more effective in reducing itch than placebo. Case reports have described their use in practice to reduce neuropathic itch such as post herpetic itch, brachioradial pruritus, and prurigo nodularis, although there are no controlled studies of these conditions. The mechanisms of action are unclear. The most frequent adverse effects are constipation, weight gain, drowsiness, ataxia and blurred vision.

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Global Health Author Q&A: ANU’s Anthony McMichael on globalization and climate change

Posted by Jennifer Zeis • April 25th, 2013

In a new feature for Now@NEJM, we ask the authors of the new Global Health review article series — all with different backgrounds, experiences, and perspectives — the same set of questions. 

Answers from Anthony J. McMichael, M.B., B.S., Ph.D., of the National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT, Australia.

Dr. McMichael is author of the April 4 article, “Globalization, Climate Change, and Human Health“

What do you regard as the most significant success in global health within the past decade?

On a mission-accomplished basis, polio eradication almost wins the accolade. However, on the basis of long-term health-related investments, there has been an important increase in the recognition and development of much better and wider-spread population health infrastructure and integrative public health thinking. The limits of enhanced clinical biotechnology and specialised medical/hospital treatments and salvage, provided in settings of poverty, under-education, and fundamental deficiencies in nutrition, water quality and general hygiene, have become increasingly acknowledged (often despite commercial interests).

The difficulties in achieving the UN Millennium Development Goals in many regions have underscored the need to integrate environmental quality and sustainability…and to not treat “the environment” as an add-on task.

The difficulties in achieving the UN Millennium Development Goals in many regions have underscored the need to integrate environmental quality and sustainability into the programs to reduce poverty, hunger, maternal and child mortality, and major infections — and to not treat “the environment” as an add-on task. Meanwhile, the work of WHO’s Commission on the Social Determinants of Health has underscored the need to think and act in relation to the pervasive underlying social, cultural, and economic forces and influences that impede good health and its equal sharing.

The determinants of social and environmental conditions lie predominantly outside the health sector. This is now being recognised in policies of the World Bank and the Asian Development Bank; both are looking beyond the constricting walls of neoclassical economics and seeing that population wellbeing, health, and survival are at risk from unbalanced GDP-enhancing development strategies. These broadened and ecologically-framed concepts have enriched primary health care and the general upgrading of health services in many lower-income countries. At last we are starting to think and act holistically. That should yield a triumph of enlightenment.

In the coming decade, which arena of global health do you feel warrants increased attention and awareness?

As my recent article in the NEJM (April 4) argues, we now face a new and unfamiliar generation of large-scale environmental risks, of our own making. These are fundamentally different in nature from the conventional environmental concerns over local chemical, physical, and radiation hazards, including urban air pollution. The new risks arise from systemic disruptions to the planet’s biophysical operating system — its climate, elemental cycles, soil replenishment, ocean chemistry, stock of biodiversity, and others. These are a consequence of excessive and energy-intensive economic activity in combination with a growing world population. Both components make governments uneasy (and the clearly unsustainable continuing growth of human numbers has, as a topic, been shamefully off-limits for political, religious and moral reasons for the past two decades).

These new human-induced global environmental changes are disrupting the foundations of population health and survival – food supplies, water flows, soil quality, the resilience that biodiversity affords us, and a liveable climate. The consequences for population health are much more serious and widespread than any other foreseeable global threat to health (except perhaps for an unprecedentedly catastrophic pandemic).

If we could bring this topic onto the international political radar screen, and raise awareness of the risks to population health and survival, this could achieve considerable and much-needed acceleration and strengthening of national and international policies to act — to slow and arrest climate change and its syndromic bed-fellows and commit seriously to transforming our ways of living that are healthy, equitable, rich in opportunities, and sustainable.

We now face a new and unfamiliar generation of large-scale environmental risks, of our own making.

This is a key, urgent, health-securing task for the coming decade.

How can we best harness the revolution in IT to improve health outcomes in the developing world?

In public health and preventive medicine, information and public understanding is vital. (This applies too to networking between medical practitioner networks and information sources.) In semi-literate (e.g. poor rural) populations in lower-income countries, village radios and TVs are a precious source of otherwise unavailable information. The dissemination of mobile phone facilities and internet connectivity will greatly enhance this resource.

The IT revolution also enables quick access to open access publishing. Hopefully this facility will also increase and become more user-friendly (and without the infernal need to store/remember too many passwords!).

When American physicians think of global health, many are dissuaded from a global health career because they cannot spend a majority of their time abroad.  What are other ways for physicians to contribute to this discipline?

Many useful contributions can be made without relocating abroad. Traditional “international health,” often conducted on a bilateral basis, has typically required travelling to the partner country and spending time specialising in that particular research topic or implementation program.

“Global health” is broader in scope and more systemic, and needs diverse inputs from interested and capable persons able to participate in developing new understanding, drafting strategy documents for international agencies and NGOs, and reviewing draft reports. (For example, working from my home base in Canberra, Australia, I have recently reviewed drafts of two new World Bank reports on the risks posed by a possible Plus 4C World by 2100. I have also just completed chairing a 4-year project for the Tropical Diseases Research Program (WHO) resulting in the recently-published report [WHO Technical Report Series, No. 976, 2013] on the need for and methods of integrating understanding and activity in the environmental, agricultural, and social sectors in relation to the emergence and spread of infectious diseases. That latter task has involved four one-week overseas meetings with the drafting team in four years.)

Otherwise, American physicians, as for all other physicians, can engage in good progressive citizenry that supports pre-existing international campaigns — for example, campaigns to constrain the marginalisation of health considerations by the World Trade Organization, to rein in population growth and to support family planning facilities, to curb the emissions of greenhouse gases, and to ensure that important medications are affordably available to low-income populations.

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Diabetes Care Goals: Are We Making Progress?

Posted by Jamie Colbert • April 24th, 2013

As a medical resident in primary care over the past three years, I cared for a large number of diabetic patients, and each one seemed to present a unique challenge. For instance, Walter, who was legally blind, lived alone, and required daily treatment with insulin. After numerous discussions with our clinic pharmacist and social worker, we devised a plan so that Walter could use an insulin pen that was pre-filled with medication. Walter could dial the pen and listen to the number of clicks to determine the insulin dosage. Then there was Roberta, a strong-willed woman who was resistant to the idea of taking any medication for her diabetes. However, once we enlisted the support of her family members, she agreed to take her pills (most of the time). Finally, Larry’s hemoglobin A1c never dropped below 12 despite the efforts of our entire clinic staff. Eventually, after many unanswered phone calls and fruitless outreach efforts, we learned that Larry was homeless and could not focus on addressing his diabetes until he had secured permanent housing.

These experiences taught me that successful diabetes treatment is much more challenging than simply prescribing medications based on treatment algorithms. In general, I found that working with a multidisciplinary team of care providers helped patients to achieve the best results. Yet, with my singular perspective it was difficult to say for certain how much better off my diabetic patients were doing as a whole. While some patients achieved great control over their diabetes, others just never seemed to make any progress at all.

This week’s NEJM features a special article by Ali et al. which asks an important question: How are we doing at managing diabetes at the population level here in the United States? The authors of this study analyzed data from large national surveys and medical exams to paint a picture of how we as a nation are doing with regards to meeting target care goals for patients with diabetes.

Some of the results are encouraging. More adults with diabetes are achieving recommended targets for hemoglobin A1c, blood pressure, and LDL cholesterol. Cardiovascular risk overall decreased amongst diabetics. More patients are receiving influenza and pneumococcal vaccinations, getting their lipids checked, undergoing annual foot exams, and are self-monitoring their blood glucose.

Yet, there are also discouraging findings in this report. Large numbers of diabetics have not reached clinical targets: 13% had a hemoglobin A1c greater than nine, 49% had a blood pressure greater than 130/80, and 43% had an LDL cholesterol greater than 100. Smoking in the presence of diabetes leads to even greater risk for vascular events, yet still 22% of diabetics were smoking in 2010. Finally, only 14% of diabetics met all four targets for hemoglobin A1c, blood pressure, LDL cholesterol and not smoking.

How should we interpret the results of this report? In an accompanying editorial, Graham McMahon and Robert Dluhy help put these data into perspective. They write, “While there is reason to celebrate the modest improvement in performance suggested by these data, there’s a long way to go to deliver the quality diabetes care that truly meets our patients’ needs.” In particular, McMahon and Dluhy provide suggestions for how we as a society can better meet the care needs of our growing population of diabetics. First, we will need to embrace the Chronic Care Model, in which care for our diabetics is reorganized into care teams involving both physicians and other care professionals working together and sharing responsibility for achieving desired outcomes. Next, curricular changes will need to be implemented to give physicians and allied health providers the skills necessary to work collaboratively in care teams. We must create an incentive structure for providers that rewards improvement in outcomes rather than just achievement of thresholds. And finally, we need to ensure that the measures we track are not just those that are of interest to clinicians, but are actually patient-centric and include such variables as reported well-being and access to care.

There are approximately 19 million diabetics in the United States today. This report by Ali et al. gives us a benchmark for how we are doing as a healthcare system in managing these patients and also serves as a reminder that we must improve our systems of care delivery to better meet the needs of these patients. The challenge is daunting, but the opportunities for innovation are also exciting to those of us who care for diabetic patients. After reading this report, I look forward to spending some time with my own practice colleagues to think about how we can better work collaboratively to improve care for patients with diabetes.

Connect with Dr. Colbert on Twitter: @jcolbertMD

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18-Year-Old with Respiratory Failure

Posted by Sara Fazio • April 19th, 2013

In the latest Case Record of the Massachusetts General Hospital, an 18-year-old woman was admitted to this hospital because of pulmonary infiltrates and respiratory failure. Three weeks before admission, fever, cough, and painful pharyngitis developed. Diagnostic tests were performed.

In a young patient without comorbid illnesses, there are many potential infectious causes of pneumonia. The medical history may provide clues that help in reducing the list of possible pathogens.

Clinical Pearls

• What tickborne illnesses are associated with pulmonary complications?  

Tickborne illnesses associated with pulmonary complications include B. burgdorferi, Rickettsia rickettsii, Ehrlichia chaffeensis, Babesia microti, and Francisella tularensis.

• What is the typical presentation of tularemia pneumonia?  

Tularemia pneumonia is unusual, with only 100 to 200 cases noted per year. It occurs almost exclusively in the northern hemisphere. The incubation period for tularemia averages 3 to 5 days, with a range of 1 to 21 days. The illness begins abruptly with fever, chills, headache, malaise, anorexia, and fatigue, but the presentation may also include cough, myalgias, chest discomfort, vomiting, sore throat, abdominal pain, and diarrhea. Multilobar or diffuse infiltrates occur in 30 to 74% of reported cases, whereas effusions are present in 21 to 30%, and hilar lymphadenopathy in up to 45% of cases. A review of a 30-year experience of tularemia pneumonia indicates that sputum examination is not helpful, white-cell counts on admission range from 5000 to 22,000, elevation of lactate dehydrogenase is common, pharyngitis may be mistaken for infectious mononucleosis, and pericarditis may occur. Tularemia has been described as “an enigmatic community-acquired pneumonia that does not respond to routine therapies.”

Morning Report Questions

Q: What are the classic cytopathic changes seen with herpes simplex virus?   

A: Cytological examination demonstrates multinucleated cells, in which the nuclei are molded together, and the chromatin pattern is washed out and clumped around the peripheral nuclear membrane. This ground-glass kind of nuclear change is called a Cowdry type B viral inclusion, which is a classic Tzanck cell.

Q: What is Guillain-Barre syndrome, and what are the classic cerebrospinal fluid (CSF) findings?          

A: Guillain-Barre syndrome is most often an acute inflammatory demyelinating polyneuropathy. Cardinal manifestations are ascending motor weakness accompanied by absent or decreased deep tendon reflexes. The typical CSF findings are known as “albuminocytologic dissociation” (i.e., high levels of protein in the cerebrospinal fluid and normal cell counts).

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Belimumab for SLE

Posted by Sara Fazio • April 19th, 2013

In the latest review article in our Clinical Therapeutics series, a 20-year-old woman with SLE presents with disease flares and receives belimumab, a monoclonal antibody that binds to B-cell activating factor, inhibiting B-cell stimulation. Belimumab is considered for patients who do not have a response or have adverse effects with first-line therapies.

Clinical Pearls

• What is the epidemiology of SLE?     

Seventy to 90% of affected persons are women, with onset usually in the child-bearing years. The prevalence is 20 to 70 per 100,000 women, and varies by race; the higher prevalence rates are in Latinos, African Americans and Afro-Caribbeans; the lower prevalence rates are in Caucasians and Asians. Overall survival rates also vary by race, with a five-year survival of approximately 95% in whites, 90% in African Americans, and 87% in Hispanics. Men, persons in lower socioeconomic groups, and patients with nephritis have lower survival rates.

• What is the pathophysiology of SLE? 

SLE is caused by pathogenic autoantibodies (which generally appear a few years before the first clinical symptoms) and immune complexes that bind to tissue, fix complement, activate inflammatory responses, and mediate tissue damage. In people genetically predisposed to develop autoimmune processes, including SLE, normal immune responses become dysregulated; autoantibody production increases and persists; both innate and adaptive immune systems remain in activated state. Environmental triggers include Epstein-Barr virus infection and exposure to ultraviolet light, estrogen-containing medications, silica dust, and smoking. B cells are central in the pathogenesis of SLE, since they are precursors for plasma cells that secrete  antibodies; they also present antigens and secrete proinflammatory cytokines.

Morning Report Questions

Q: What is the mechanism of action of belimumab and what is its clinical indication?

A: The indication for use of belimumab is to induce clinical improvement in seropositive patients with SLE who have active disease despite standard treatment. Determining what constitutes “standard treatment” is a matter of physician judgment. Belimumab is generally given to patients with profiles similar to those in the phase III clinical trials, i.e., persons with enough clinical disease activity to interfere with quality of life, or with unacceptable side effects of the dose of glucocorticoids required for comfort and function, despite current treatment with antimalarial agents (chloroquine and hydroxychloroquine) plus glucocorticoids and one additional immunosuppressant (mycophenolate mofetil, azathioprine, or methotrexate).

Q: What factors make a patient more likely to respond to belimumab, and when is its use contraindicated?

A: Seropositivity to antinuclear antibodies and the presence of anti-double-stranded DNA antibodies identifies likely responders to belimumab. Levels of serum complement are also useful since low levels also identify patients likely to respond, and rising levels are one indication that response is occurring. Contraindications to belimumab therapy include presence of active or chronic infections.

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