Visit for the Latest on the Ebola Outbreak

Posted by Karen Buckley • August 14th, 2014

Be sure to visit the NEJM Infectious Disease page, which brings together new and recent articles on Ebola, and features a healthmap that tracks publicly-reported, confirmed and suspected cases of Ebola throughout the world. The map is automatically updated to provide up-to-the-minute data on the outbreak.

A new Perspective article from NIH’s Antony Fauci suggests we need sound public health practices, engagement with affected communities,  and considerable international assistance and global solidarity to defeat Ebola in West Africa.

Another Perspective article from NIAID’s Heinz Feldmann says the outbreak has demonstrated our public health systems’ limited ability to respond to rare, highly virulent communicable diseases.  A Brief Report looks at emergence of the outbreak of Ebola in Guinea back in March.

We’ll be posting more content in this space as it becomes available, so check back regularly.

A Salty Subject: Sodium Consumption and Cardiovascular Health

Posted by Rena Xu • August 13th, 2014

Salt has long been a staple of life.  Once upon a time, it was a form of currency; roads were built to transport it; cities arose to produce and trade it.  And, of course, people ate it.  Today, we continue to consume it the whole world over.

It’s hard to believe something so integral to the human experience, spanning centuries and civilizations, might be bad for the body.  But as the Mrs. Dashes of the world would have us know, salt consumption has been linked to high blood pressure, which in turn has been linked to heart disease — a reason, perhaps, to keep one’s salt intake in check.

Just how much salt are we consuming?  And how much damage can we attribute to the delicious granules that top our pretzels, coat our fries, and cure our meats?  A group of researchers from the Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NUTRICODE) used survey data and statistical models to estimate the sodium consumption of adults from 187 nations.  They also performed a meta-analysis of over a hundred randomized interventional studies to calculate the effects of sodium on blood pressure and analyzed pooled data from cohort studies to calculate the effects of high blood pressure, in turn, on cardiovascular mortality.

Their findings, published in this week’s NEJM, might make you think twice before reaching for the saltshaker.  In 2010, the average daily sodium consumption was 3.95 grams, well above the World Health Organization recommendation of 2 grams per day.  In fact, 181 out of the 187 nations — accounting for a whopping 99.2% of adults — exceeded the recommended intake level.  The consequence?  Nearly one in every ten deaths from cardiovascular causes in 2010, the authors estimated, could be attributed to excess sodium consumption.  That translated to 1.65 million deaths globally.  What’s worse, over 40% of these deaths occurred prematurely (i.e., in people younger than 70 years of age).

While no region of the world was spared, there was considerable variability across geographies in sodium-associated cardiovascular mortality rates.  The highest rates were in Central Asia and Eastern and Central Europe.  Among individual countries, Georgia had the highest rate (1967 deaths per 1 million adults per year), while Kenya had the lowest (4 deaths per 1 million adults per year).  Perhaps most striking, more than 80% of sodium-related cardiovascular deaths around the world — four out of every five — occurred in low- or middle-income countries.

There may be a silver lining.  The authors also found that reductions in sodium intake were linked proportionally to reductions in blood pressure (P<0.001 for a linear dose-response relationship).  For a white, normotensive 50-year-old, for instance, a reduction of 2.3 grams per day lowered systolic blood pressure by 3.74 mmHg (95% CI: 2.29 to 5.18).  The exact effect varied by age and race, with greater reductions in older people (vs. younger people), blacks (vs. whites), and people with hypertension (vs. without).

Does that mean low sodium intake translates to better health?  Not necessarily, according to two other articles published in this week’s NEJM.  The Prospective Urban Rural Epidemiology (PURE) study collected fasting morning urine specimens from over 100,000 adults, representing 18 different countries and a range of income levels, and calculated 24-hour urinary sodium excretion (a proxy of sorts for sodium consumption).  This was correlated with blood pressure.

The investigators found a non-linear relationship.  For people who excreted a lot of sodium (in this study, defined as over five grams per day), there was a strong association, meaning each additional gram of sodium was linked to a steep rise in blood pressure (2.58 mmHg per gram).  In contrast, for people with low sodium excretion (less than three grams per day), the association with blood pressure was not statistically significant (0.74 mmHg per gram; P=0.19).  Remarkably, only ten percent of study participants fell into this low-sodium category, and only four percent had sodium excretion levels consistent with the current U.S. guidelines for sodium intake.

Based on these results, Dr. Suzanne Oparil of the University of Alabama at Birmingham suggests in an accompanying editorial, a low-sodium diet might not be the most useful public health recommendation.  She writes, “The authors concluded from the findings that a very small proportion of the worldwide population consumes a low-sodium diet and that sodium intake is not related to blood pressure in these persons, calling into question the feasibility and usefulness of reducing dietary sodium as a population-based strategy for reducing blood pressure.”

The PURE study investigators also tested the correlation between sodium excretion and a composite outcome of death and major cardiovascular events (heart attacks, strokes, heart failure).  They observed that, compared to a reference sodium excretion range of four to six grams per day, a higher level of sodium excretion (seven or more grams per day) was linked to a greater risk of the composite outcome (odds ratio 1.15; 95% CI, 1.02 to 1.30).  But, when they looked at people with very low sodium excretion (below three grams per day), they found an increased risk as well (odds ratio, 1.27; 95% CI, 1.12 to 1.44).

Complicating matters further, the authors also looked at the urinary excretion of potassium.  Compared to a reference level of 1.5 grams per day, a higher potassium excretion level was linked to a reduced risk of the composite outcome.  “The alternative approach of recommending high-quality diets rich in potassium might achieve greater health benefits, including blood-pressure reduction, than aggressive sodium reduction alone,” Oparil writes.

To the scholars in us, these findings are an inspiration for further research.  But how should we apply this knowledge to our daily lives, when we’re sitting in diners wondering whether to shake or not to shake?  It may be presumptuous to read too much into the findings, to infer causality where it has yet to be established.  Still, as a species, we’re better equipped today than we’ve ever been to make smart choices about our diet.  And until more data become available, moderation may be the way to go.

The results of this new research are also summarized in a short animation.

View the latest NEJM Quick Take now.

A Gut Instinct

Posted by Sara Fazio • August 8th, 2014

In the latest Clinical Problem-Solving article, a 30-year-old female physician presented to the emergency department in mid-August, with a 4-day history of anorexia, nausea, vomiting, and diarrhea. She had no fever or respiratory symptoms but had mild abdominal discomfort.

Tuberculosis is a well-recognized occupational hazard for those involved in health care. In a systematic review that included 15 studies conducted in high-income countries, health care workers had a median annual risk of pulmonary tuberculosis infection of 1.1% (range, 0.2 to 12), as compared with a risk of 0.1 to 0.2% in the general population.

Clinical Pearls

How has the incidence of extrapulmonary tuberculosis changed in the United States?

There has been a steady decline in cases of tuberculosis in the United States, from 52.6 cases per 100,000 population in 1953 to 3.6 cases per 100,000 population in 2010. However, the proportion of cases of extrapulmonary tuberculosis per total cases of tuberculosis increased from 7.6% in 1962 to 20% or more since the late 1990s. The risk of extrapulmonary tuberculosis is reported to be increased among women, Asian and foreign-born persons, and health care workers.

What are the epidemiology and features of intraabdominal tuberculosis?

Intraabdominal tuberculosis, including peritoneal and mesenteric lymph-node involvement, is the sixth most common type of extrapulmonary tuberculosis reported in the United States. The diagnosis of intraabdominal tuberculosis is challenging, owing to its protean and nonspecific manifestations. In a large case series, up to two thirds of patients had negative tuberculin skin tests, and many did not have respiratory symptoms. Systemic and constitutional symptoms are frequent, as are abdominal pain and distention. The majority of patients with tuberculous peritonitis have ascites, which results from fluid exudation from peritoneal surfaces; only about 10% of patients present with the “dry type” of tuberculous peritonitis, characterized by a doughy abdomen, adhesions, fibrosis, and the absence of ascites. Often there is a long delay between symptom onset and diagnosis.

Morning Report Questions

Q: What is the reported sensitivity of tuberculin skin testing in cases of active tuberculosis?  

A: In the case of active tuberculosis, the reported sensitivity of tuberculin skin testing is highly variable and is generally estimated from culture-confirmed cases; false negative test results are reported in up to 25% of cases. Tuberculin skin tests should not be considered to be reliable tests for the diagnosis of active disease.

Q: What are the guidelines for treatment of extrapulmonary tuberculosis?        

A: Guidelines for the treatment of extrapulmonary tuberculosis closely mirror those for the treatment of pulmonary tuberculosis. Currently, for susceptible tuberculosis, four-drug therapy for 2 months is recommended, followed by two-drug therapy for 4 months or longer, depending on the extrapulmonary site (e.g., the meninges require longer therapy).

Kidney Transplantation in Children

Posted by Sara Fazio • August 8th, 2014

A new review discusses unique aspects of kidney transplantation in children that necessitate specialized approaches and have resulted in clinical advances leading to higher success rates in young children than in any other age group.

The most common primary causes of kidney failure are congenital or inherited disorders such as renal dysplasia, obstructive uropathies, or reflux nephropathy in young children and acquired glomerular diseases such as focal segmental glomerulosclerosis and lupus nephritis in older children. In contrast, the most common primary renal diseases that lead to end-stage kidney disease in adults are diabetic nephropathy, hypertension, and autosomal dominant polycystic kidney disease, which rarely cause end-stage kidney disease in children.

Clinical Pearls

• How should immunizations be handled in the pediatric transplant recipient?

Children require multiple vaccinations during early childhood to protect them from preventable infectious diseases. However, vaccines may not be effective if administered to an immunocompromised patient. Therefore, a vigorous effort to immunize children completely before transplantation is critical. Because children with end-stage kidney disease often have a suboptimal immune response and reduced duration of immunity, higher initial doses, extra doses, and antibody titer monitoring with booster doses of vaccines may be needed. In the period after transplantation, the administration of live vaccines is generally avoided, but other immunizations may be given after immunosuppressive medications have reached low maintenance levels, typically at 6 to 12 months after transplantation. Injectable influenza vaccine should be given annually.

• Is size and age matching required in pediatric kidney transplant recipients?

Unlike heart and liver allografts, the kidney allograft is placed in a different location from the failed native organ, and the native organ is often left in place. Thus, size and age matching is generally not required in kidney transplantation. In fact, matching very young donors to very young recipients was associated previously with a very high rate of graft loss, often due to thrombosis. On the basis of those adverse results, pediatric programs now transplant adult kidneys into small children once the recipient has reached a sufficient size, typically 6.5 to 10.0 kg of body weight. An infant’s peritoneal cavity has enough space to accommodate an adult kidney without compressing the allograft. However, the youngest pediatric recipients have an allograft-size mismatch that leads to a high glomerular filtration rate and makes interpretation of serum creatinine results more difficult, since acute rejection may initially occur without an elevation of the serum creatinine level. Kidneys from deceased donors who were very small children are no longer allocated to small children but are, in fact, now transplanted en bloc (both kidney together, attached to a single segment of the aorta and vena cava) into adults with excellent results.

Morning Report Questions

Q: What concerns are there about linear growth in children who have chronic kidney failure and receive a kidney transplant?

A: Children are in a state of active growth. Chronic kidney failure can lead to severe growth failure, often with associated loss of self-esteem. Children with kidney failure were once approximately 2.5 SD below the expected height for their age at the time of transplantation. Improved nutrition before transplantation and aggressive use of recombinant human growth hormone have reduced, although not eliminated, this height deficit. Renal transplantation generally improves linear growth but does not completely restore it. The greatest recovery in growth is seen in the youngest children, and   the least is seen in adolescents. The use of glucocorticoid withdrawal or avoidance protocols and the administration of growth hormone after transplantation may further improve growth recovery.

Q: What have clinical trials shown about pediatric immunosuppression, and how do medications differ from those given to adults?

A: Trials have shown that high doses of immunosuppressive drugs to compensate for glucocorticoid withdrawal can lead to unacceptable rates of post-transplantation lymphoproliferative disorder (PTLD), that glucocorticoid avoidance is not immunologically detrimental, although it does not ameliorate chronic histologic damage, and that tacrolimus is associated with a significantly lower rate of acute rejection at 6 months than is cyclosporine. Pharmacokinetic studies showed that cyclosporine has a shorter half-life in children than in adults and requires dosing three times daily. Similarly, sirolimus has a shorter half-life in children than in adults and often requires twice-daily dosing. The area under the curve of dose-normalized mycophenolic acid is higher in children than has been commonly observed in adults. In glucocorticoid-free protocols as compared with protocols that include glucocorticoids, the use of mycophenolate mofetil is associated with more frequent and severe leukopenia, anemia, and gastrointestinal disturbances. B-cell depletion with the lytic chimeric mouse-human anti-CD20 antibody rituximab is used increasingly in pediatric kidney-transplant recipients. Data have shown full recovery of the B-cell pool 15 months after rituximab treatment in children, whereas recovery began only at 24 months in adults and was never complete.

Novel Ways to Detect Creutzfeld-Jacob Disease?

Posted by Daniela Lamas • August 6th, 2014

Anyone who has eaten a burger has had a sneaking fear, however irrational: Could I have been exposed to mad cow? And how could I possibly find out before symptoms of the disease take hold?

As it is, the way to confirm the diagnosis of the fatal disease is by direct examination of brain tissue, which requires a brain biopsy, or by autopsy. But two studies in this week’s issue of NEJM report preliminary data for novel ways to detect the abnormally folded prion protein, in urine and nasal brushings of affected patients. They offer hope for non-invasive methods to diagnose both variant Creutzfeld-Jacob Disease (vCJD)– so-called ‘mad cow disease’—and the sporadic form of CJD.

In one study, Christina Orrú and colleagues investigated how accurate an amplification technique called “real-time quaking induced conversion” is to diagnose sporadic CJD in living patients. This technique is an assay that works by causing the diseased prion protein to react with recombinant prion protein to form amyloid, which is detected with a dye. The technique has shown promise for detecting CJD in cerebrospinal fluid samples, with a sensitivity of 80 to 90 percent. At the same time, the abnormal prion protein is known to accumulate in the olfactory epithelium of patients with CJD – leading investigators to question whether that might be an easier-to-reach diagnostic site.

With that background, the authors enrolled 31 patients with rapidly progressive dementia due to definite or probable CJD and 43 patients with other neurodegenerative disorders. The investigators took nasal brushing samples and CSF samples from these patients and found that the sensitivity to detect CJD was 97 percent in nasal brushings, compared to 77 percent in CSF samples. Both tests were highly specific for CJD.

And olfactory mucosa isn’t the only unexpected place to find the misfolded prion proteins, an accompanying paper in this week’s NEJM suggests. Fabio Moda and colleagues took urine samples from 14 patients with variant CJD and more than 200 patients with other neurologic diseases, including the sporadic form of CJD Using a technique that allows amplification of “minute” samples of prion protein, the authors detected abnormal prion proteins in 13 of the 14 variant CJD patients and none of the other patients with other diseases.

Although questions remain — for instance, how accurate will these tests prove to be in making the diagnosis and how early in the disease process can the prion protein be detected –  both studies suggest promise for new ways to diagnose both variant and sporadic CJD in affected patient’s olfactory mucosa and urine. These findings could point the way toward further research into a non-invasive way to establish a definitive diagnosis of this devastating disease.

For more on this topic, see the accompanying editorial from the University of Melbourne’s Dr. Colin Masters.

Brain Abscess

Posted by Sara Fazio • August 1st, 2014

Despite advances in diagnostic techniques and treatment, brain abscess remains a challenging clinical problem with substantial case fatality rates. Delays in diagnosis and treatment can result in a poor outcome. A new review summarizes current approaches to effective treatment.

Despite advances in imaging techniques, laboratory diagnostics, surgical interventions, and antimicrobial treatment, brain abscess remains a challenging clinical problem with substantial case fatality rates. Brain abscess can be caused by bacteria, mycobacteria, fungi, or parasites (protozoa and helminths), and the reported incidence ranges from 0.4 to 0.9 cases per 100,000 population. Rates are increased in immunosuppressed patients.

Clinical Pearls

What is the epidemiology of brain abscesses?

Severe immunocompromise, resulting from immunosuppressive therapy in patients who have undergone solid-organ or hematopoietic stem-cell transplantation or from HIV infection, is often associated with tuberculosis or nonbacterial causes of infection, such as fungi or parasites. HIV infection is associated with brain abscess caused by Toxoplasma gondii, but HIV infection also predisposes patients to infection with Mycobacterium tuberculosis. Patients who have received solid-organ transplants are at risk not only for nocardial brain abscess but also for fungal abscess (e.g., resulting from infection by aspergillus or candida species). Abscess formation may occur after neurosurgical procedures or head trauma. In these cases, infection is often caused by skin-colonizing bacteria, such as Staphylococcus aureus and S. epidermidis, or gram-negative bacilli. Brain abscess due to contiguous spread from parameningeal foci of infection (e.g., the middle ears, mastoids, and sinuses) is frequently caused by streptococcus species, but staphylococcal and polymicrobial abscesses (including those caused by anaerobes and gram-negative bacilli) also occur. Staphylococcus and streptococcus species are often identified in brain abscesses after hematogenous spread. The microbial flora of brain abscesses resulting from paranasal sinus or dental infection are often polymicrobial.

What is the typical presentation of a patient with a brain abscess?

The most frequent clinical manifestation of brain abscess is headache; fever and altered level of consciousness are frequently absent. Neurologic signs depend on the site of the abscess and can be subtle for days to weeks. Behavioral changes may occur in patients with abscesses in the frontal or right temporal lobes. Patients with abscesses in the brain stem or cerebellum may present with cranial-nerve palsy, gait disorder, or either headache or altered  mental status owing to hydrocephalus. Up to 25% of patients present  with seizures.

Morning Report Questions

Q: What are the most appropriate diagnostic tools in cases of suspected brain abscess?

A: Cranial imaging should be performed in all patients with suspected brain abscess. Computed tomographic (CT) scanning with contrast enhancement provides a rapid means of detecting the size, number, and localization of abscesses. Magnetic resonance imaging (MRI), combined with diffusion-weighted and apparent-diffusion-coefficient images, is a valuable diagnostic tool in differentiating brain abscess from primary, cystic, or necrotic tumors. One prospective study involving 115 patients with 147 cystic brain lesions, which included 97 patients with brain abscess, showed that diffusion-weighted imaging had a sensitivity and specificity for the differentiation of brain abscesses from primary or metastatic cancers of 96% (positive predictive value, 98%; negative predictive value, 92%). Cultures of blood and cerebrospinal fluid identify the causative pathogen in approximately one quarter of patients. Cultures of cerebrospinal fluid may be valuable in patients with coexisting meningitis.  However, the risk of brain herniation must be considered in these patients.

Figure 3. Imaging Studies of Brain Abscess. 

Q: How should a brain abscess be managed?

A: Since 27% of brain abscesses are polymicrobial, broad-spectrum antimicrobial therapy is advised until the results of culture of the abscess itself are known or until repeated aerobic and anaerobic cultures from blood or other sites of infection show no other pathogen. An abscess size of more than 2.5 cm in diameter has been recommended as an indication for neurosurgical intervention, but data from comparative studies are lacking, and this size cannot be regarded as a definitive indication for aspiration. Anticonvulsant treatment is not routinely indicated in patients with brain abscess. Focal neurologic deficits may develop in response to abscess growth or surrounding edema. Adjunctive glucocorticoid therapy may reduce cerebral edema and is used in about half of patients with brain abscess. Since data from randomized studies are lacking and glucocorticoids may reduce passage of antimicrobial agents into the central nervous system, their use should be limited to patients with profound edema that is likely to lead to cerebral herniation.

Scorpion Envenomation

Posted by Sara Fazio • August 1st, 2014

Each year more than a million cases of scorpion envenomation occur worldwide, causing substantial morbidity and, among children, a risk of death. A new brief review discusses the effects and treatment of scorpion envenomation. Every year, more than 1 million cases of scorpion envenomation are reported worldwide. Although the resultant mortality is lower than that from snake envenomation, there is substantial morbidity and, among children, a risk of death.

Clinical Pearls

What are the general characteristics of scorpion stings?

Most scorpion stings cause localized pain, whereas only an estimated 10% of stings, even from the most dangerous scorpions, result in severe systemic envenomation. Edema, erythema, paresthesias, muscle fasciculations, and numbness may occur at the site of the sting. It is often difficult to see the sting site or to identify inflammation at the site, despite substantial local pain. Most cases of severe envenomation occur in children. Systemic envenomation is characterized by neuromuscular abnormalities resulting from effects on the somatic and cranial nerves, both cholinergic and adrenergic excitation of the autonomic nervous system, pulmonary edema, and cardiac effects.

What are the autonomic effects of scorpion stings?

Excitation of the autonomic nervous system is characterized by both parasympathetic and sympathetic responses. Parasympathetic, cholinergic effects may include hypersalivation, profuse diaphoresis, lacrimation, miosis, diarrhea, vomiting, bradycardia, hypotension, increased respiratory secretions, and priapism. Sympathetic, adrenergic effects include tachycardia, hypertension, mydriasis, hyperthermia, hyperglycemia, agitation, and restlessness. Whereas most parasympathetic effects tend to occur early, sympathetic effects persist because of the release of catecholamines and are responsible for severe envenomation.

Morning Report Questions

Q: What are possible cardiovascular complications of scorpion envenomation?
A: A range of cardiac conduction abnormalities occur in about one third to one half of patients with systemic envenomation. These effects include atrial tachycardia, ventricular extrasystoles, T-wave inversion, ST-T wave changes, and, less frequently, bundle-branch block. Increased autonomic stimulation caused by increased vagal effects on the heart and sympathetic stimulation are the probable causes of these effects. Hypertension is common and occurs early in response to sympathetic stimulation. Hypotension is less common, occurs with the development of severe envenomation, and often requires intervention with vasopressors and fluid resuscitation. Many factors are at play in the development of hypotension, with cholinergic stimulation causing vasodilation, fluid loss, and myocardial depression. Cardiac dysfunction resulting from catecholamine-induced myocarditis and myocardial ischemia complicates severe envenomation from androctonus, buthus, mesobuthus, and tityus scorpions. This complication may result in pulmonary edema and cardiogenic shock.

Figure 1. Pathophysiological and Clinical Effects of Systemic Scorpion Envenomation.

Q: What are the principles of treatment for cases of severe scorpion envenomation?
A: The specific treatment is the administration of antivenom combined with symptomatic and supportive treatment, including prazosin and dobutamine in patients with cardiovascular toxic effects and benzodiazepines when there is neuromuscular involvement. Symptoms related to the site of the sting should be managed with appropriate analgesia with acetaminophen and antiinflammatory agents, depending on severity. Once severe envenomation has developed, the administration of antivenom may be less effective, since its primary therapeutic action is to bind toxins; it does not reverse established pathophysiological injury, such as excess levels of catecholamine, pulmonary edema, and cardiogenic shock.

Table 1. Treatment of Scorpion Stings According to Clinical Grade. 

The Future of Malaria: Rising Rates of Resistance and a Potential New Hope

Posted by Joshua Allen-Dicker • July 30th, 2014

What do Emperor Charles V, Thomas Jefferson, and King Tut all have in common?  Each historical figure is thought to have suffered from malaria at some point during his life.

Plasmodium, malaria’s causative organism, is known as much for its effects on great civilizations and their leaders as for its present world-wide disease burden.  Yearly, it is responsible for over 200 million cases of malaria and over 600 thousand malaria-related deaths.

In this week’s NEJM, two groups of researchers report important findings in the battle against malaria: one provides cause for concern, and the other, a potential hope.

For the last decade, artemisinin-combination therapy (ACT) has been the recommended first-line therapy for treatment of Plasmodium falciparum malaria.  However, resistance to artemisinin was identified in certain endemic areas as early as 2006.  This week’s article from the Tracking Resistance to Artemisinin Collaboration (TRAC) revealed concerning developments in the prevalence and geographic spread of artemisinin resistance.

TRAC enrolled patients with acute uncomplicated falciparum malaria and fever at 15 sites across Africa and Asia.  In an open-label randomized format, patients were treated with either 2mg/kg or 4mg/kg of artesunate, an artemisinin derivative, followed by a full standard 3-day course of an ACT regimen.  Parasite clearance rates were calculated for all participants.  While no significant difference in clearance rates were observed between treatment groups, rising rates of artemisinin resistance were documented in Eastern Myanmar, Western Cambodia and Thailand, and Southern Vietnam, and emerging resistance was documented in Myanmar, Southern Laos, and Northeastern Cambodia.

In this concerning context, the development of new antimalarial agents should generate significant excitement.  The second of the two publications reports on KAE609, a first-in-class novel antiparasitic that acts via inhibition of a plasmodium plasma-membrane sodium-ATPase.  In a phase II, open-label study, 21 patients with Plasmodium vivax or Plasmodium falciparum mono-infections were enrolled at three locations in Thailand.  Participants were given KAE609 (30mg/day) for 3 days, followed by a course of standard antimalarial therapy beginning on day five.  Blood samples were collected at regular intervals to allow for safety monitoring and calculation of parasite clearance times, defined as the interval from starting treatment to the first blood smear negative for parasites.

Following KAE609 administration, median time to parasite clearance was 12 hours.  There was no evidence of treatment failure.  Two serious adverse events (fever) were reported, but no reported adverse events led to treatment discontinuation.

In the face of rising prevalence and geographic spread of artemisinin resistance, what should those involved in malaria prevention and treatment do?  Firstly, all is not lost for ACT.  While TRAC authors found increasing prevalence and geographic spread of artemisinin resistance, this was only isolated to Southeast Asia and was not yet present in the Indian and African areas they surveyed.  Additionally, they found that resistant strains responded to prolonged artemisinin courses (6 days versus the standard 3 days).  Secondly, as exciting as the KAE609 findings are, the current data are limited and the drug is not yet ready for the limelight.  The large randomized control studies required to assess safety and efficacy for KAE609 and other novel drugs will take time.  In the meantime, interventions should focus on refining existing strategies.  The World Health Organization recently recommended that a single dose of primaquine be administered with ACT to limit the spread of artemisinin resistance.  In order to continue to achieve this goal, the organization will need to consider further innovations in the area of treatment (e.g. improving primaquine compliance, extending ACT dosing) and vector control.

As NEJM Deputy Editor Dr. Lindsey Baden notes, “Plasmodium falciparum continues to evolve and evade our therapeutic options. The potential loss of the artemisinin class is likely to have a substantial impact on current malaria control efforts. Hopefully the safety and activity of KAE609 can be shown in larger trials as novel therapies are needed.”

For more on this topic, see the accompanying editorial  from Brian Greenwood at the London School of Hygiene and Tropical Medicine, and Perspective article on the origins of antimalarial-drug resistance, including an audio interview with Randall Packard from Johns Hopkins School of Medicine.

Care of the Asplenic Patient

Posted by Sara Fazio • July 25th, 2014

Asplenic patients are at risk for rapidly progressive septicemia and death. Such patients should be vaccinated against pneumococci, H. influenzae type b, meningococci, and influenza virus, and if fever develops, they should receive empirical antimicrobial therapy immediately.  This is the topic of the latest Clinical Practice review.

Mortality among patients with postsplenectomy sepsis can be as high as 50%. Most commonly caused by Streptococcus pneumoniae, this infection often has a sudden onset and a fulminant course.

Clinical Pearls

What factors influence the risk of postsplenectomy sepsis?

The risk of postsplenectomy sepsis varies according to several factors, including the indication for splenectomy, the patient’s age at the time of the surgery, and the interval since plenectomy. With respect to indication, the risk is lowest among otherwise healthy persons who undergo splenectomy because of trauma, intermediate among patients with hereditary spherocytosis or immune thrombocytopenic purpura, and highest among surgically asplenic patients with   (beta)-thalassemia, sickle cell anemia, or portal hypertension. With respect to age, the risk of sepsis is highest among infants with surgical or congenital asplenia. Children younger than 5 years at the time of splenectomy have a higher risk than older children or adults, but this finding may in part reflect the increased risk associated with the underlying conditions that warranted splenectomy (e.g., thalassemia major and sickle cell anemia). With respect to the interval since splenectomy, the risks of sepsis and associated death are highest in the first year after splenectomy, at least among young children, but remain elevated for more than 10 years and probably for life.

What pathogen most commonly causes sepsis in patients who have undergone splenectomy?

The pathogen that most commonly causes sepsis in patients who have undergone splenectomy, as well as in children with sickle cell disease, is S. pneumoniae (pneumococcus). Another encapsulated bacteria, Haemophilus influenzae type b (Hib), which primarily affects children younger than 5 years of age, is now rare because of universal use of the Hib conjugate vaccine in the United States. Although Neisseria meningitidis, Escherichia coli, and Staphylococcus aureus each accounts for a small proportion of bloodstream isolates from asplenic persons, whether asplenia is actually a risk factor for infection with these pathogens has not been established.

Morning Report Questions

Q: What vaccines are recommended for patients who have undergone a splenectomy?

A: Several vaccines are available for some of the pathogens that cause postsplenectomy sepsis, specifically S. pneumoniae, Hib, and N. meningitidis. For prevention of pneumococcal infection, administration of PCV13 followed 8 weeks later by PPSV23 is recommended. The risk of invasive infection with Hib among adults and older children is very low. Therefore, it is reasonable to limit vaccination of adults or older children with the Hib vaccine to those who were not previously vaccinated. Quadrivalent meningococcal conjugate vaccine (MenACWY) has replaced quadrivalent meningococcal polysaccharide vaccine for patients without a spleen; a two-dose primary series is indicated for such patients. Annual vaccination against influenza virus is recommended because influenza infection confers a predisposition to bacterial pneumonia and sepsis caused by S. pneumoniae and S. aureus.

Table 1. Recommended Vaccinations for Asplenic Patients.

Q: How should fever in an asplenic patient be handled?

A: If fever develops in an asplenic patient, immediate administration of an antimicrobial agent is indicated, because fever can be the initial manifestation of a fulminant infection and prompt administration of an antimicrobial agent may prevent the development of clinical sepsis. Ceftriaxone administered intravenously or intramuscularly with or without vancomycin is a reasonable empirical choice. Ceftriaxone is active against most S. pneumoniae strains as well as H. influenzae, N. meningitidis, and many community-acquired gram-negative bacilli, including capnocytophaga.

Figure 1. Management of an Episode of Fever in an Asplenic Patient.

Fevers, Rash, Pancytopenia, and Abnormal Liver Function

Posted by Sara Fazio • July 25th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 41-year-old man was admitted to the hospital in midsummer because of fever, rash, pancytopenia, and abnormal results of liver-function tests. Two days before the onset of fever, he had returned from a 3-week trip to Europe. Diagnostic tests were performed.

The combination of fever, rash, and laboratory abnormalities is a common syndrome that is associated with a large differential diagnosis. Possible causes include reactions to medications, cancer (including leukemia) autoimmune disease, and infection.

Clinical Pearls

What are the typical features of anaplasmosis infection?

Anaplasmosis, a tickborne infection, has an incubation period of 5 to 21 days. Disease manifestations include fever, malaise, headache, cervical lymphadenopathy, elevated liver-function values, and cytopenias. Pulmonary infiltrates have been described. Rash is uncommon in patients with anaplasmosis; if a rash is present, it is usually macular and spares the face.

What is the usual presentation of acute human immunodeficiency (HIV) infection?

Patients with acute human immunodeficiency virus (HIV) infection can present with fever, rash, pharyngitis, lymphadenopathy, leukopenia, thrombocytopenia, and elevated liver-function values. The rash associated with an acute HIV infection usually starts on the trunk and spreads to the arms and legs, and the face is often spared; lymphadenopathy is usually diffuse. Acute HIV infection is characterized by high-level viremia.

Morning Report Questions

Q: Which viral syndromes are associated with fever and rash?

A: Fever and rash are the hallmark of many viral syndromes. Young adults and adolescents with infectious mononucleosis — caused primarily by Epstein-Barr virus (EBV) and less commonly by cytomegalovirus (CMV) — can present with pharyngitis, cervical lymphadenopathy, thrombocytopenia, elevated liver-function values, and atypical lymphocytes. However, rash is rare, usually spares the face, and is often associated with the administration of amoxicillin. A rash that starts on the face is relatively unusual for viral exanthems. Certain enteroviruses (especially types 6, 11, and 25) can cause fever and a morbilliform rash that starts on the face. However, hepatitis and thrombocytopenia would be unusual manifestations of these viruses, except in neonates. Parvovirus B19, which causes fifth disease in children, can cause a confluent rash over the cheeks (commonly referred to as “slapped cheek” rash). Cytopenias, especially anemia, are common in patients with this infection, but elevated liver-function values are unusual; in adults, the disease is typically mild and rarely requires hospitalization.

Q: What is the classic presentation of measles infection?

A: Measles is associated with a classic morbilliform rash. After an incubation period of 5 to 10 days, patients with measles typically present with a prodrome of fever, malaise, cough, conjunctivitis, and coryza. Koplik’s spots may be present, and lymphadenopathy has beeen described. Over time, leukopenia and thrombocytopenia can develop, and elevated liver-function values have been described in 56 to 66% of adult patients with measles. Fevers can be high, and pulmonary infiltrates are common. The rash associated with measles is classically maculopapular; it starts on the face and spreads to the neck, trunk, arms, legs, hands, and feet, sparing the palms and soles. Convalescence occurs approximately 48 hours after the rash appears.