Treatment of Tuberculosis

Posted by Carla Rothaus • November 27th, 2015

Treatment of Tuberculosis 2Tuberculosis is often a difficult infection to treat. A new review article summarizes the many manifestations of the disease and the major treatment options in the various contexts in which the disease occurs.

Tuberculosis, a scourge since prehistoric times, affects more than 9 million people and causes death in 1.5 million people each year. Effective treatment has been available for 60 years, but generally takes 6 months, and resistance to the drugs, which is increasing throughout the world, threatens the effectiveness of treatment.

Clinical Pearls

• What is the standard regimen for drug-susceptible tuberculosis?

The standard treatment regimen for presumably drug-susceptible tuberculosis includes an induction phase consisting of rifampin, isoniazid, and pyrazinamide, to which ethambutol is added as protection against unrecognized resistance to one of the three core drugs. Once susceptibility to isoniazid, rifampin, and pyrazinamide has been confirmed, ethambutol can be discontinued. The induction phase is followed by a consolidation phase consisting of rifampin and isoniazid for an additional 4 months of treatment.

• What challenges are associated with the relatively lengthy course of treatment for tuberculosis?

The standard 6-month treatment regimen for drug-susceptible tuberculosis is an exceptionally long course of treatment as compared with the duration of treatment of other bacterial infectious diseases. The prolonged regimen poses two major challenges to success: managing drug toxicity and ensuring that patients adhere to the full course of treatment. Drug toxicity is substantial; a review of retrospective studies using similar definitions estimates that 3 to 13% of patients have hepatotoxic effects. A recent prospective cohort study of patients with drug-susceptible disease who received standard tuberculosis therapy documented a 15% incidence of adverse drug reactions resulting in interruption or discontinuation of one or more of the drugs. Of these adverse reactions, 7.7% resulted in hospitalization, disability, or death. A wide variety of reactions were reported; the most common were hepatotoxic effects, gastrointestinal disorders, allergic reactions, and arthralgias. Overall, 16 to 49% of patients do not complete the regimen. Reasons for failure to complete treatment are varied and include adverse drug reactions, cost of treatment, stigma, and the patient’s belief that cure has been achieved when symptoms have resolved and bacteria can no longer be recovered from the sputum. Treatment support and direct-observation programs are useful in improving adherence but have not entirely overcome these factors.

Morning Report Questions

Q: What factors might explain the poor response of some patients to antimycobacterial therapy?

A: Recent studies suggest that in many patients, Mycobacterium tuberculosis bacteria are sequestered in compartments that are inaccessible to antibiotic action; this could explain the poor long-term treatment response in some patients despite clearance of bacteria from the sputum. The leading candidates for these sequestered compartments are the interior of granulomas, abscesses, and cavities. Another potential explanation for the poor clinical responses in some patients is inadequate serum antimycobacterial drug levels, since low serum levels further impede the ability of drugs to penetrate infectious foci. One cause of low serum levels can be inadequate absorption. Isoniazid, rifampin, and pyrazinamide levels are decreased when the drug is taken with food, whereas rifapentine absorption is increased with a high-fat meal; fluoroquinolone absorption is decreased by antacids. Genetically determined metabolic pathways can also influence serum drug levels. N-acetyltransferase is an enzyme that is involved in isoniazid clearance; human genetic variation in the gene encoding N-acetyltransferase (NAT2) can lead to underexposure (in “fast acetylators”) or to an elevated risk of hepatotoxicity (in “slow acetylators”); this slow-acetylator genotype is present in more than 50% of white populations.

Figure 1. Biphasic Decline in Viable Bacteria during Treatment for Tuberculosis.

Q: What new antimycobacterial drugs are on the horizon?

A: Several new classes of antimycobacterial drugs have been developed in the past 15 years. Two of these agents, the diarylquinoline bedaquiline and the nitroimidazooxazole delamanid, have received accelerated regulatory approval and are currently being confirmed in phase 3 clinical trials. It is hoped that such agents will lead to shorter and more effective regimens for the treatment of multidrug-resistant tuberculosis and will allow clinicians to avoid the use of injectable agents, which have unacceptably high rates of ototoxicity and renal toxicity. At the present time, the role of the new agents in the treatment of drug-susceptible tuberculosis appears to be limited. Other new drug classes (benzothiazinones and imidazopyridines) show promise in preclinical studies but have not yet progressed to clinical trials.

Table 1. Tuberculosis Drugs, Recommended Dosages, and Common Adverse Events.

Figure 3. Sites and Mechanisms of Action of Antimycobacterial Agents.

A Man with Pulmonary Infiltrates

Posted by Carla Rothaus • November 27th, 2015

A 76-Year-Old Man with Fevers, Leukopenia, and Pulmonary InfiltratesIn a new Case Record of the Massachusetts General Hospital, a 76-year-old man with a history of transitional-cell carcinoma of the bladder presented with persistent fever, leukopenia, and pulmonary infiltrates. Examination of a lung-biopsy specimen revealed noncaseating granulomatous inflammation. A diagnostic test was performed.

Bacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis and a mainstay of therapy for superficial bladder cancer.

Clinical Pearls

• What are some of the features of lymphoid interstitial pneumonia?

Of the idiopathic interstitial pneumonias, lymphoid interstitial pneumonia is the only disorder that is associated with granulomas. Lymphoid interstitial pneumonia is often diagnosed in patients with immunologic disorders, such as Sjogren’s syndrome, hypogammaglobulinemia, and HIV infection. Lymphoid interstitial pneumonia typically has an insidious onset, and the clinical presentation tends to be dominated by dyspnea, often with a dry cough. Hemoptysis is rare, but constitutional symptom occur in about one third of patients.

• What causes “hot-tub” lung?

So-called “hot-tub lung,” which is a response to Mycobacterium avium complex that is similar to hypersensitivity pneumonitis, can cause large, well-formed granulomas. Hot tubs provide an ideal temperature for the growth of M. avium complex and a means for aerosolization and inhalation. In both hypersensitivity pneumonitis and hot-tub lung, granulomas are found around airways and in airspaces.

Morning Report Questions

Q: Describe aspects of disseminated tuberculosis.

A: Tuberculosis is caused by any one of the three mycobacterial pathogens that form the Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, and M. africanum. More than 50% of patients with disseminated disease have pulmonary symptoms. Gastrointestinal symptoms are common and include abdominal tenderness and diarrhea. Tuberculous meningitis has been reported in 10 to 30% of patients with disseminated disease. Laboratory evaluation frequently reveals hematologic abnormalities, including normocytic normochromic anemia. Pancytopenia should prompt evaluation for tuberculosis with bone    marrow involvement. The majority of patients have an elevated level of alkaline phosphatase, and almost half have mildly elevated aminotransferase levels. Anergy to tuberculin is common in disseminated disease and can be seen in more than half of patients. Thus, a negative tuberculin skin test does not rule out this disease. Similarly, a negative interferon-gamma release assay does not rule out the possibility of active tuberculosis.

Q: Is intravesicular BCG therapy for bladder cancer associated with a significant risk of systemic complications?

A: Systemic complications of intravesicular BCG therapy are rare, occurring in less than 1% of patients. Pulmonary complications of intravesicular BCG therapy include bilateral interstitial pneumonitis and non-necrotizing granulomas. The pathogenesis is incompletely understood, but it is thought that the organisms gain access to the lymphatics and blood through disruption of the uroepithelium and then disseminate to multiple sites. Granulomatous reactions in the absence of organisms (which are thought to represent hypersensitivity reactions) and active infection have been reported. There are case reports of infections occurring months and even years after BCG therapy. Tuberculosis due to M. bovis is clinically and radiographically indistinguishable from tuberculosis due to M. tuberculosis.

Cardiovascular Safety of Empagliflozin in Patients with Type 2 Diabetes

Posted by James Yeh, M.D. M.P.H. • November 25th, 2015

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 DiabetesYou are a primary care provider and you’ve heard about a new class of anti-diabetic drugs called the “flozins,” including empagliflozin. You wonder what this drug class is and what we know about its safety and its effect on cardiovascular events.

What is empagliflozin?

Empagliflozin is a sodium-glucose transporter-2 (SGLT-2) inhibitor. Since glucose is freely filtered in the glomeruli and SGLT-2 reabsorbs 90% of the filtered glucose in the renal tubule, the inhibition of SGLT-2 can reduce blood glucose levels and, ultimately, lower HbA1c. There are a number of SGLT-2 inhibitors currently on the market.

What is this study about?

In the late 2000s, the FDA began to require drug companies to conduct studies to assess the cardiovascular (CV) risks of new anti-diabetic drugs.

In this week’s issue of NEJM, Zinman and colleagues present their findings from a double-blind randomized controlled trial evaluating the long-term cardiovascular safety of empagliflozin versus placebo.

The trial was conducted at nearly 600 sites in over 40 countries. Over 7000 patients with diabetes who were at high-risk for CV events and were either drug-naïve or on background glucose-lowering therapy were randomized to receive either empagliflozin (10 mg or 25 mg) or placebo on top of standard of care. The primary outcome was the first occurrence of a 3-point major cardiovascular event– CV death, non-fatal MI, or non-fatal stroke. The patients were followed for a median time of 3.1 years.

Who is in the study?

At baseline, about 30% of the participants were on monotherapy with either metformin or insulin and 45%, on dual therapy with either metformin with sulfonylurea or metformin and insulin. 85% of the patients were on aspirin and over 75%, on a statin therapy. Study participants had baseline HbA1c of slightly over 8%.

What were the results?

At the end of 12 weeks, patients taking empagliflozin had a reduction in their HbA1c of about 0.5% and at the end of 207 weeks a reduction of about 0.25%. Patients taking empagliflozin had lower rates of the primary outcome (composite events of CV death, non-fatal MI, or non-fatal stroke) than those on placebo (10.5% versus 12.1%, HR 0.86, P=0.04). The primary outcome was driven by CV deaths (12.4% versus 20.2%, HR 0.68).

Treatment with empagliflozin reduced hospitalization for heart failure (HR 0.65, P=0.002) and all-cause mortality (5.7 versus 8.3%, HR=0.68, P<0.001). Outcomes for fatal and non-fatal strokes and MIs were not statistically different. Overall, adverse events were similar between the empagliflozin and placebo groups. However, genital infections were more common in those taking empagliflozin (6.4% versus 1.8%).

What is known about CV events in previous trials?

The evidence for macrovascular benefit is mixed. The DCCT/EDIC study showed that intensive glucose control reduced CV risks in individuals with type 1 diabetes while the VADT and the UKPDS studies demonstrated reduced CV risks in type 2 diabetes. On the other hand, the ACCORD and ADVANCE studies showed no clear macrovascular benefit in type 2 diabetes.

Does this study result apply to my patients and are there any other drug safety concerns?

A NEJM editorial by Ingelfinger and Rosen cautions that the results of this study may not be generalizable to everyone, since the study population had very high cardiovascular risks at baseline: “nearly half had prior myocardial infarctions, and about three quarters had evidence of coronary artery disease, 25% had previous strokes, and 20%, peripheral vascular disease.”

Additionally, the FDA had recently issued a number of safety warnings on the SGLT-2 class of drugs including the risk of increased ketoacidosis and increased bone fractures.

What is my take-away?

The addition of empagliflozin to background therapy in patients with type 2 diabetes resulted in fewer CV events. However, the long-term effects on CV events as well as drug safety concerns about this drug and this drug class will have to be assessed.

A Lesion of the Ear Canal

Posted by Carla Rothaus • November 20th, 2015

Lesion of the Ear CanalIn a new Case Record of the Massachusetts General Hospital, a 27-year-old woman presented with a pruritic lesion of the left ear canal, with recurrent bleeding. The lesion had a cobblestone appearance and several prominent vessels. A diagnostic procedure was performed.

Epithelioid hemangioma is also known as angiolymphoid hyperplasia with eosinophilia.

Clinical Pearls

• What are some of the entities included in the differential diagnosis for a lesion in the external auditory canal?

The most common infectious cause of a lesion in the ear canal is otitis externa, which is typically due to Pseudomonas aeruginosa. A common inflammatory cause of a lesion in the ear canal is atopic dermatitis (i.e., eczema). This diagnosis is supported by the presence of an intensely pruritic, erythematous lesion with scaly crusting and small, sometimes confluent vesicles. Another relatively common inflammatory process that occurs in the ear canal is an insect bite. Another entity to consider is cutaneous lymphoid hyperplasia; the cutaneous lymphoid hyperplasia lesion is typically less than 1 cm in diameter, and in 70% of cases, it occurs on the face or other sites on the head and neck, including the external ear. Malignant tumors of the external auditory canal are rare. The most common primary malignant tumor to occur in this location is squamous-cell carcinoma, which is much more common than basal-cell or ceruminous-gland carcinoma.

Table 1. Differential Diagnosis of Lesions of the External Auditory Canal.

• What are characteristic features of epithelioid hemangioma?

Epithelioid hemangioma is an uncommon, benign neoplasm that is characterized by isolated or grouped papules, plaques, or nodules and occurs in the skin of the head and neck, most commonly in the periauricular skin, forehead, and scalp. An isolated lesion, which is typically 0.5 to 2.0 cm in diameter, occurs in 80% of cases. The lesion is characteristically pruritic, painful, and prone to bleeding. Several studies indicate a higher incidence in women than in men, and the median age of onset is 30 years (range, 20 to 50). Epithelioid hemangiomas are generally located in the dermis or subcutaneous tissue and less commonly located in deep soft tissues. Because the depth of the tumor from the surface can vary and the tumor can have indistinct borders, complete excision is difficult and recurrence is common.

Morning Report Questions

Q: What treatment options are available for recurrent epithelioid hemangiomas?

A: Options for drug therapy include intralesional injections of glucocorticoids or interferon alfa-2b, topical treatment with imiquimod or tacrolimus, and systemic administration of glucocorticoids, isotretinoin, or mepolizumab (anti-interleukin-5 antibody). The main advantage of drug therapies is a good cosmetic outcome. However, such therapies are not curative, rely on patient adherence, and may be associated with systemic side effects. Surgical options include laser therapy, cryosurgery, electrosurgery, and reexcision with either a traditional method or Mohs micrographic surgery. The advantage of surgical treatment is that it addresses the vascular segment at the base of the lesion to minimize the likelihood of disease recurrence. A disadvantage is postoperative scarring. Laser therapy typically requires multiple treatments, and effectiveness is inversely correlated with the depth of invasion or vessel size.

Q: What are some of the histologic features of epithelioid hemangioma?

A: In the periphery of the lesion, the blood vessels are well formed, but in the center, the blood vessels are less well formed and often surround a single, centrally located, larger vessel. The characteristic endothelial cells are plump, with ample eosinophilic cytoplasm and nuclei that may contain a prominent nucleolus. Epithelioid hemangiomas have cuboidal-to-hobnail (tombstone-like) projections into the vascular lumina; they have a multilobular growth pattern and tend to be more often circumscribed in subcutaneous tissue than in the dermis, where they may be poorly circumscribed. They may occasionally have an infiltrative pattern in deep soft tissue and may have spindled, cellular areas and a fibromyxoid stroma. The neoplastic blood vessels are accompanied by a variable inflammatory infiltrate that is composed largely of lymphocytes and eosinophils but also of mast and plasma cells.

Figure 1. Excision Specimens from the External Auditory Canal.

Generalized Anxiety Disorder

Posted by Carla Rothaus • November 20th, 2015

Generalized Anxiety DisorderPersistent anxiety and uncontrollable worry for at least 6 months characterize generalized anxiety disorder. First-line treatments are cognitive behavioral therapy or pharmacotherapy with a selective serotonin-reuptake or serotonin–norepinephrine reuptake inhibitor. A new Clinical Practice article summarizes.

A psychological construct known as intolerance of uncertainty — the tendency to react negatively to situations that are uncertain — has been shown to be a relatively specific characteristic of persons with generalized anxiety disorder. Although it is unclear whether the origin of this construct is experiential or genetic, the observation that a reduction in intolerance of uncertainty is an important mediator of outcomes of cognitive behavioral therapy provides support for its central role in this disorder.

Table 1. Criteria for the Diagnosis of Generalized Anxiety Disorder.

Clinical Pearls

• Are patients with generalized anxiety disorder at risk for other mental and physical health problems?

Patients with generalized anxiety disorder have increased risks of other mental and physical health conditions (e.g., chronic pain syndromes, asthma or chronic obstructive pulmonary disease, and inflammatory bowel disease). Approximately 35% of people with generalized anxiety disorder self-medicate with alcohol and drugs to reduce the symptoms of anxiety, and this pattern of use is thought to contribute to the increased risk of alcohol and drug-use problems among these persons.

• What is the relation between generalized anxiety disorder and major depression?

Major depression is a common coexisting condition, although major depression may be difficult to distinguish from generalized anxiety disorder because many symptoms of generalized anxiety disorder (e.g., fatigue and insomnia) overlap with those of major depression.” Persistent anhedonia (the inability to experience pleasure), which is characteristic of major depression, is not a symptom of generalized anxiety disorder. Nevertheless, persons with generalized anxiety disorder are at increased risk for deliberate self-harm, including suicide attempts. In many patients, generalized anxiety disorder is an underlying waxing-and-waning condition, with episodic bouts of major depression emerging during particularly stressful life circumstances. This dual occurrence of generalized anxiety disorder and major depression constitutes what is sometimes referred to as “anxious depression,” a particularly common clinical presentation in primary care settings.

Morning Report Questions

Q: What are some of the initial components of the recommended stepped approach to the treatment of generalized anxiety disorder?

A: Randomized, controlled trials provide strong evidence of the benefits of certain types of pharmacotherapy, psychotherapy, or both for generalized anxiety disorder. A stepped-care approach is recommended. The initial choice of treatment should depend largely on patient preference (with the majority of patients choosing psychotherapy). Before patients embark on a course of pharmacotherapy or psychotherapy, they should be directed to unbiased sources of information about anxiety disorders (e.g., the Anxiety and Depression Society of America; Clinical experience and randomized, controlled trials provide support for the prescription of exercise for anxiety, though effect sizes are modest. Since insomnia is a prominent symptom of generalized anxiety disorder, the patient should be encouraged to practice positive sleep-hygiene behaviors. However, randomized trials are lacking to support specific benefits of sleep hygiene for patients with generalized anxiety disorder.

Table 2. Stepped-Care Approach for Management of Generalized Anxiety Disorder.

Q: What drug classes are considered first-line pharmacotherapy for generalized anxiety disorder?

A: Selective serotonin-reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are generally considered to be first-line pharmacotherapies for generalized anxiety disorder, with response rates in the range of 30 to 50%. No SSRI or SNRI has been shown to be superior to any other in the treatment of generalized anxiety disorder, so the choice of drug should be based on the patient’s prior response to or the physician’s familiarity with a particular agent. When SSRIs and SNRIs are used for generalized anxiety disorder, they are administered at the same doses as those used for the treatment of major depression, with the same expectation of time to response (4 to 6 weeks) and with the same precautions and anticipated adverse effects.

Table 3. Medications Commonly Prescribed for the Treatment of Generalized Anxiety Disorder.

Prospective Validation of a 21-Gene Expression Assay (OncotypeDX) in Breast Cancer

Posted by Andrea Merrill • November 18th, 2015

Prospective Validation of a 21-Gene Expression Assay in Breast CancerImagine it is 1970. You are a 50-something year old woman and your doctor has just palpated a 1 cm mass in your left breast.  What are your options for treatment?  Unfortunately, radical mastectomy, introduced by Dr. William Halsted in 1894, remained the standard of care at that time.  Breast cancer treatment as it was in 1970, just 45 years ago, would be unrecognizable today.

Over the ensuing decade, a growing body of literature began to question this radical approach, with promising results for more limited operations such as simple mastectomy and lumpectomy. Further advances in chemotherapy and radiation therapy allowed for more limited surgery, creating the systemic, multidisciplinary approaches used today. Additionally, with new discoveries of genetic mutations specific to breast cancer, therapies are becoming more targeted and individualized. What might be suitable for one woman with a 1 cm breast cancer may not be adequate in another whose tumor has a different genetic profile.

While we have come very far in breast cancer treatment, we continue to ask ourselves, what more can we do to treat and prevent breast cancer recurrences? How much treatment is too much? How can we identify those who will benefit from less treatment?  Although previous studies have recommended chemotherapy for the majority of women with localized breast cancer regardless of node or hormonal status, about 85% of these women would be recurrence-free with endocrine therapy alone.

Enter the OncotypeDx Recurrence Score®, a 21-gene multiparameter assay designed to stratify risk of recurrence in women who otherwise would be recommended by current guidelines to undergo adjuvant chemotherapy. The TAILORx trial in this week’s NEJM now reports the results of the first prospective clinical trial utilizing the OncotypeDx Recurrence Score® to assess the benefit of chemotherapy by recurrence score. The results of the initial study were published in NEJM in 2004

The clinical trial enrolled women ages 18-75 with estrogen receptor (ER) positive, HER2/neu negative, node negative invasive breast cancers either greater than 1cm or 0.6 to 1 cm with intermediate to high histologic grade. All women with low risk recurrence scores 0-10 (on the 0-100 OncotypeDX scale) were assigned to receive 5 years of adjuvant endocrine therapy alone after surgery.

Of the 10,253 eligible patients, 1629 (~16%) had OncotypeDX risk scores of 0-10.  Overall, event rate was low after 5 years of follow-up. Rate of invasive disease-free survival was 93.8%, freedom from recurrence of breast cancer at a distant site was 99.3%, rate of freedom from recurrence was 98.7% and rate of overall survival was 98%.  Multivariate analysis did not reveal an effect of age, tumor size, or type of surgery on rate of recurrence or survival. Histologic grade did show an association with risk of recurrence, but recurrence rates remained low.

This study provides prospective validation for using the OncotypeDX Recurrence Score® to spare patients from chemotherapy who would otherwise be recommended to receive it. However, this low-risk group of ER positive, HER2/neu negative, node negative patients with the lowest scores (0-10) represents only 16% of all those in the original study cohort. Additionally, the OncotypeDX score was designed to assess 5-year risk, and it is known that late recurrence after 5 years accounts for about half of all distant recurrences in this group.

Regardless of its limitations, “it is one more step toward precision” says Dr. Clifford A. Hudis in the accompanying editorial. He adds, “This multigene assay is unlikely to be the only test that can provide a prediction of chemotherapy benefit. A less expensive and broadly distributed test would be valuable globally. For now, however, this assay is the most rigorously tested option and provides proof of the principle that we can develop reproducible predictive tests to select patients who should not receive chemotherapy.”

NEJM Deputy Editor Dr. Dan Longo concurs: “The benefits from adjuvant chemotherapy have always been accrued by a minority of the breast cancer patients receiving it. We have accepted giving toxicities to many patients to benefit a few. With advances in assessing risks based on tumor genotype, it is now possible to reduce the fraction of patients treated with adjuvant chemotherapy who are unlikely to benefit from it. ”

Results from the other arms of the OncotypeDX clinical trial should hopefully provide more guidance for those at intermediate and high risk of recurrence, with potential to restrict the use of chemotherapy to those most likely to benefit from it. Clearly we have come a long way from Halsted’s day of the radical mastectomy but still have far to go.

A Woman with Proteinuria

Posted by Carla Rothaus • November 13th, 2015

72-Year-Old Woman with ProteinuriaIn a new Case Record of the Massachusetts General Hospital, a 72-year-old woman presented with flank pain, proteinuria, and a new kidney mass. Magnetic resonance imaging of the kidney revealed a complex, solid mass (3 cm x 2.9 cm x 2.9 cm) in the lower pole of the right kidney. Diagnostic tests were performed.

Membranous nephropathy, an immune-complex glomerular disease, is the most common cause of the nephrotic syndrome in white adults.

Clinical Pearls

• Describe some of the features of adult minimal change disease.

Adult minimal change disease is rare and seen in only 10 to 15% of biopsy specimens from patients with nephrotic-range proteinuria, although the prevalence is increased among white patients who are 80 years of age or older. Patients with adult minimal change disease may present with a rapid onset of features of the classic nephrotic syndrome, with abrupt development of hypoalbuminemia (within days to weeks) and edema and possibly even acute kidney injury due to intravascular volume depletion. Overt hematuria is uncommon.

• What is the association between membranous nephropathy and cancer?

It is not entirely clear whether there is an association between the development of membranous nephropathy and cancer, but evidence suggests that the incidence of malignant tumors among patients with histologically proven membranous nephropathy is in the range of 5 to 10%. This rate may be increased in elderly patients. The pathogenesis of membranous nephropathy in patients with cancer remains uncertain.

Morning Report Questions

Q: What cancers have most commonly been associated with membranous nephropathy?

A: Membranous nephropathy is the most common glomerular disease that is associated with solid cancers. Lung, gastrointestinal, prostate, and breast cancers are the cancers that have most commonly been associated with membranous nephropathy. There are only a few reported cases of membranous nephropathy with concurrent renal-cell carcinoma.

Q: What evidence suggests that idiopathic membranous nephropathy may be an autoimmune disease?

A: Approximately 75 to 80% of cases of membranous nephropathy are idiopathic, without a known, specific, identifiable inciting event, such as a medication, infection, or cancer. Membranous nephropathy is characterized by deposits that develop on the subepithelial surfaces of the glomerular capillary wall, mainly on the podocytes. An autoantibody targeting the M-type phospholipase A2 receptor (PLA2R), an antigen normally expressed on the surface of podocyte-cell membranes, has been discovered; it has been suggested that cases of idiopathic membranous nephropathy may actually be cases of an autoimmune disease targeting podocytes with autoantibodies to PLA2R. Approximately 75 to 80% of cases of primary membranous nephropathy are associated with a positive test for antibodies to PLA2R at the time of diagnosis.

Figure 3. Biopsy Specimens of the Uninvolved Kidney.

Elder Abuse

Posted by Carla Rothaus • November 13th, 2015

elderly abuseBecause older victims of abuse tend to be isolated, their interactions with physicians are important opportunities to recognize abuse and intervene. A new review article explores the manifestations of elder abuse and the role of multidisciplinary teams in its assessment and management.

Elder abuse has a range of negative sequelae that extend well beyond the obvious traumatic injury and pain to which the victims may be subjected. Studies have shown that victims of elder abuse are at increased risk for death, after adjustment for any chronic illness they may have. Elder abuse greatly increases the likelihood of placement in a nursing home and of hospitalization. Recent studies suggest that financial exploitation is emerging as the most prevalent form of abuse; by the time cases are detected, the older adult’s financial resources have often been drastically reduced — a fact that makes swift detection and intervention critical.

Clinical Pearls

• How common is elder abuse?

When the available evidence is taken into consideration, an estimated overall prevalence of elder abuse of approximately 10% appears reasonable. Thus, a busy physician caring for older adults will encounter a victim of such abuse on a frequent basis, regardless of whether the physician recognizes the abuse.

• What is known about elder abuse in long-term care facilities?

Although no scientific studies of the prevalence of abuse have been conducted in these settings, the available observational and clinical evidence suggests that mistreatment of residents by staff members occurs with sufficient frequency to be of concern to physicians. Studies have pointed to the very high prevalence of mistreatment of nursing home residents by other residents, in the form of physical, verbal, and sexual aggression. Physicians should be alert to this possibility when examining and treating nursing home residents, because clinically significant injuries have been found to result from resident-to-resident aggression.

Morning Report Questions

Q: What are some of the signs of elder abuse that physicians should consider?

A: With respect to physical abuse, researchers have been unable to identify injuries that are clearly diagnostic of abuse in older persons, as has been possible for child abuse. Although forensic research has demonstrated some emerging patterns of physical abuse (e.g., that older victims are more likely to have bruising on the face, lateral aspects of the right arm, and posterior torso, including back, chest, lumbar, and gluteal regions, than older adults who have bruising unrelated to abuse), these findings are useful primarily to alert the clinician to the possibility of abuse and should not be viewed as diagnostic for either medical or legal purposes without other corroborating clinical findings or historical information. Verbal and psychological abuse may be markers for other forms of abuse and may be the only form that can be observed by clinicians and office staff. The clinical manifestations of verbal and psychological abuse — depression, anxiety, and other forms of psychological distress — which may normally be amenable to pharmacologic and psychotherapeutic intervention, are not likely to remit unless the underlying abuse is detected and mitigated. Abrupt changes in either direction in the financial circumstances of the caregiver (e.g., sudden unemployment or extravagant purchases) may also herald an increased risk of financial exploitation or suggest that exploitation is already under way.

Table 1. Forms of Elder Abuse and Clinical Procedures for Assessment by the Physician.

Q: What is the role of the physician in cases of suspected or known elder abuse?

A: There have been no large, high-quality randomized, controlled studies of specific and discrete interventions in cases of elder abuse — a situation that has been identified as leading to a critical knowledge gap in the field. However, decades of clinical experience and documented best practices in the field provide guidance for practitioners in helping victims. Successful treatment rarely involves the swift and definitive extrication of the victim of abuse from his or her predicament with a single intervention. Instead, successful interventions in cases of elder abuse are typically interprofessional, ongoing, community-based, and resource-intensive. Although physicians have an important role to play in the medical components of those interventions, it will usually not be feasible for them to initiate or sustain successful interventions in cases of elder abuse on their own. Therefore, the most important tasks for the physician are to recognize and identify elder abuse, to become familiar with resources for intervention that are available in the local community, and to refer the patient to and coordinate care with those resources.

Figure 1. Recommended Strategies for Intervention by Physicians in Suspected Cases of Elder Abuse.

Table 2. Groups Involved in Interprofessional Assessment and Intervention in Cases of Suspected Elder Abuse.

Acetaminophen for Fevers in the Critically Ill: Good for Patients, or Are We Treating Ourselves?

Posted by Joshua Allen-Dicker • November 11th, 2015

Acetaminophen for Fever in Critically Ill PatientsIt is 3AM and you are called about Mr. Smith, a 74-year-old man who presented to the hospital tonight with a cough and was found to have pneumonia and sepsis. You have started him on antibiotics, but he now has a temperature of 38.3°C (100.9°F). His nurse asks, “Should we give him something for that fever?”  

Some of us, concerned that fevers may put excess stress on the critically ill, might order acetaminophen as an antipyretic. Others, acknowledging studies that suggest elevated temperatures may enhance immune cell function and inhibition of pathogen growth, might recommend against lowering Mr. Smith’s fever. The HEAT trial (Permissive Hyperthermia through Avoidance of Acetaminophen in Known or Suspected Infection in the Intensive Care Unit), published OLF last month in NEJM, aims to provide some clarity for those who have struggled with this same question: does treatment with acetaminophen improve or worsen outcomes in the critically ill and febrile?

The HEAT authors, Young et al., conducted a blinded, randomized controlled trial at 23 medical- and surgical-intensive care units in New Zealand and Australia, comparing scheduled 1 gram IV acetaminophen to placebo (5% dextrose in water) every 6 hours. HEAT enrolled patients ≥16 years of age with a temperature of at least 38°C (100.4°F) who were on antibiotics for a known or suspected infection. Study treatment was to be continued for 28 days, or until one of the following occurred: the patient was discharged from the ICU, the patient’s fever resolved, antibiotics were stopped, the patient developed a contraindication to ongoing therapy, or the patient died. Study outcomes included ICU-free days, mortality, length of stay, fever characteristics and specific laboratory values.

Following analysis of the 346 patients in the acetaminophen group and the 344 patients in the placebo group, the authors found that the acetaminophen group had significantly lower mean daily peak temperature (38.4° vs 38.6°) and mean daily average temperature (37.0° vs 37.3°). Despite this, the authors did not detect a significant difference between the acetaminophen and placebo groups when it came to ICU-free days to day 28 (23 days vs 22 days, p=0.07) and 90-day mortality (15.9% vs 16.6%, p=0.84), as well as ICU length of stay, hospital length of stay, and key laboratory results. Additionally, no significant differences in outcomes were noted between four pre-specified subgroups: those with septic shock vs those without, those taking aspirin vs those not taking aspirin, those with “high fever” (≥39°C/102.2°F) versus those without, and those identified as having community- versus hospital- versus ICU-acquired infections.

However, study authors warn about two key limitations. First, duration of treatment was short (median number of doses given was 8 in the acetaminophen group, and 9 in the placebo group). Second, there was frequent use of open-label acetaminophen in both groups after completion of the study drug course (30.0% of the patients in the acetaminophen group, 29.4% of patients in the placebo group). As such, this study may only apply to the consideration of acetaminophen early in an ICU course.

Keeping these limitations in mind, HEAT still provides us with a reasonably powered randomized controlled trial that finds neither a significant benefit or harm from scheduled IV acetaminophen use in patients who are critically ill and febrile from a suspected infection.

You assess Mr. Smith who remains febrile and appears uncomfortable. His wife and nurse are at the bedside and agree. You discuss that while acetaminophen may reduce his fever, it is unlikely to result in longer-term clinical benefit or harm. Given his discomfort, you all agree on a trial of acetaminophen with reassessment of his fever and discomfort in the morning.

Blood Pressure Control: SPRINTing Towards a Lower Blood Pressure Target

Posted by James Yeh, M.D. M.P.H. • November 9th, 2015

SPRINT TrialMrs. Weymouth has hypertension and she is at your office for a check-up. Her blood pressure is 136/72 mm Hg. What do you tell her about her blood pressure control?

Hypertension affects nearly 1 out of 2 individuals world-wide between the ages of 35 and 70. The goal of blood pressure control is to reduce cardiovascular and renal morbidity and mortality. The most recent blood pressure guideline (JNC-8) published in 2014 recommended a blood pressure goal of < 140/90 mm Hg for those under age 60 and < 150/90 mm Hg for those over age 60. For individuals with diabetes or chronic kidney disease the goal is < 140/90 mm Hg.

Should the blood pressure goal be lower than these values? After all, some observational data have suggested better cardiovascular outcomes when blood pressure is as low as 115 mm Hg systolic.

Wright and colleagues conducted a NIH-funded study called SPRINT in over 90 sites in the US including Puerto Rico, which helped answer this question.

SPRINT randomized over 9300 individuals to one of two systolic blood pressure goals: < 120 mm Hg (intensive treatment) or < 140 mm Hg (standard treatment). The primary outcome was the composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, and cardiovascular death.

The study was stopped early due to the significant benefit seen with intensive treatment. The systolic blood pressure achieved was about 121 mm Hg (intensive) versus 136 mm Hg (standard). Individuals took an average of 2.8 versus 1.8 blood pressure medications in the intensive and standard treatment groups, respectively. Intensive treatment resulted in a significantly lower rate of the primary outcome (1.65%/yr versus 2.17%/yr). The outcome was mostly driven by acute heart failure and cardiovascular death (HR 0.62 and HR 0.57, respectively). There were significant differences in the occurrence of serious adverse events due to hypotension (HR 1.67), syncope (HR 1.33), electrolyte abnormality (HR 1.35), and acute kidney injury (HR 1.66).

So does the SPRINT result apply to everyone? In an NEJM Perspective article, Chobanian from Boston University cautions that the “SPRINT results are not applicable to patients with diabetes, those with prior stroke, or institutionalized elderly people, all of whom were excluded from the study.” The previous ACCORD study in individuals with diabetes and high cardiovascular risk showed that treating to a systolic blood pressure to < 120 mm Hg had no cardiovascular benefit. However, in an editorial, Perkovic and Rodgers from the George Institute in Sydney, Australia argue that the benefits should be understood more broadly, and suggest that the results of SPRINT and ACCORD are actually consistent with significant benefit in both settings.

Should Mrs. Weymouth’s blood pressure be lowered? What factors do you consider in this decision? Read 2 experts’ opposing viewpoints on how low to target blood pressure in the Clinical Decisions and cast your vote and leave your comments.    

See also a new NEJM Quick Take on the SPRINT trial results.