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.

40-Year-Old Woman with Postpartum Dyspnea and Hypoxemia

Posted by Sara Fazio • July 18th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 40-year-old woman was admitted to this hospital 10 days post partum because of dyspnea and hypoxemia associated with leg edema and blood-tinged sputum. Diagnostic procedures were performed.

Causes of dyspnea and hypoxemia in the peripartum period are predominantly of pulmonary or cardiovascular origin, the latter generally associated with pulmonary edema. The peripartum period predisposes women to a number of pathologic conditions, including pulmonary embolism, amniotic-fluid embolism, infection, aspiration, preeclampsia, and peripartum cardiomyopathy.

Clinical Pearls

What are the clinical manifestations of an amniotic fluid embolism?

Amniotic-fluid embolism is a rare but catastrophic complication of pregnancy or labor. Patients with amniotic-fluid embolism usually present with cardiorespiratory collapse; this is typically accompanied by disseminated intravascular coagulation and systemic inflammatory responses. Delayed manifestation of amniotic-fluid embolism beyond 48 hours after delivery is extremely rare.

What is the epidemiology and what are the clinical manifestations of peripartum cardiomyopathy?

Peripartum cardiomyopathy is characterized by congestive heart failure and left ventricular systolic dysfunction toward the end of pregnancy or in the months after delivery, in the absence of other identifiable causes of cardiac disease. The ejection fraction on echocardiography is nearly always less than 45%. More than 90% of cases present in the first weeks post partum. The incidence varies from 1 in 300 live births to 1 in 3000 live births; two “hot spots” are Haiti and Nigeria. Peripartum cardiomyopathy is most common in women of African descent but is seen throughout the world. The manifestation is similar to that of other cardiomyopathies, including such signs and symptoms of venous congestion as dyspnea, orthopnea, edema, and, in extreme cases, hypoxemia.

Morning Report Questions

Q: What are the principles of management of peripartum cardiomyopathy?

A: As with other cardiomyopathies, management of peripartum cardiomyopathy should focus on reducing preload and afterload and interrupting the maladaptive neurohormonal response to systolic heart failure. Diuretic agents and itrates are the treatments of choice for volume overload, although caution is required with the use of these agents before delivery. Angiotensin-converting-enzyme inhibitors and angiotensin II-receptor blockers could be administered but would be contraindicated if the patient were still pregnant. In the setting of a low ejection fraction and in light of the hypercoagulability of the puerperium, anticoagulation may be advised for the prevention of systemic embolism. Implantation of an automatic implantable cardioverter-defibrillator, to prevent death from arrhythmia, is relatively contraindicated, because systolic function frequently recovers. If the patient were pregnant, neither premature discontinuation of pregnancy nor delivery by cesarean section would be indicated.

Q: What is the prognosis of peripartum cardiomyopathy?

A: As many as 50% of women with peripartum cardiomyopathy eventually recover cardiac function, but 25% have progression to advanced heart failure, which often leads to cardiac transplantation or death. A lower ejection fraction at presentation predicts a worse outcome and  delayed recovery. Peripartum cardiomyopathy usually recurs in subsequent pregnancies, so decisions about repeat pregnancies need to be considered on an individual basis.

Single-Pill Regimens for HIV-1 Infection

Posted by Sara Fazio • July 18th, 2014

In the latest Clinical Therapeutics review, a 52-year-old man with a history of HIV-1 infection and poor medication adherence presents for evaluation. A single-pill regimen is considered. For some patients with HIV-1 infection, combination regimens consisting of one pill to be taken daily can improve adherence.

With the advent and refinement of combination ART [antiretroviral therapy], the life expectancy of HIV-infected patients has risen dramatically. In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners. If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.

Clinical Pearls

• What are the currently available single-pill combinations marketed for HIV-1 treatment?

There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF-FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF-FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF-FTC combined with 150 mg of the integrase strand-transfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth single-pill combination has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir DTG).

• In which patient populations should single-pill combinations be generally avoided?

Single-pill combinations should be avoided in patients with clinically significant renal disease because TDF, TC, and FTC all require dose reductions or elimination when the estimated creatine clearance is less than 50 ml per minute. The inability to adjust the dose of individual drug components in patients with renal insufficiency is an important limitation of single-pill combinations. In addition, patients who have drug-resistant HIV-1 infection often require agents that are not included in single-pill combinations.

Morning Report Questions

Q: When should a regimen containing a protease inhibitor be used?

A: None of the current single-pill combinations contain protease inhibitors, which should be used in patients with known viral resistance to NNRTIs or INSTIs. In addition, because transmitted resistance to protease inhibitors is uncommon and resistance to this class emerges relatively slowly, protease inhibitors are often favored when treatment decisions are required before resistance-testing results are available — for example, in the case of patients with acute HIV-1 infection or opportunistic infections. Protease inhibitors are also sometimes considered in patients with inconsistent adherence because multiple viral mutations are required to compromise the activity of these agents.

Q: How do currently available anchor medications for once daily regimens compare?

A: EFV, the anchor drug in EFV-TDF-FTC, is potent and, in recent years, the drug to which every newly developed anchor antiretroviral agent has been compared. EFV may cause neuropsychiatric effects (e.g., vivid dreams, insomnia, somnolence, and depression) or rash, although symptoms typically diminish over time. EFV is the preferred NNRTI during pregnancy, when initiated 8 weeks after conception. Rilpivirine (RPV)-based regimens are not recommended for patients whose pretherapy HIV-1 RNA level is more than 100,000 copies per milliliter or whose CD4+ T-cell count is 200 per cubic millimeter or less. RPV must be taken with a solid meal (greater than or equal to 390 kcal) and requires stomach acid for adequate absorption, precluding the concomitant use of proton-pump inhibitors. In addition to its use in initial therapy, RPV-TDF-FTC may have a role in patients with virologic suppression during treatment with a protease inhibitor-containing regimen who have a reason to change medications: in a recent trial, switching such patients to RPV-TDF-FTC maintained high rates of virologic suppression and improved lipid levels. Cobicistat-boosted EVG does not have neuropsychiatric effects and does not commonly cause rash. However, cobicistat inhibits tubular secretion of creatinine without reducing the creatine clearance. As a result, patients may have a mild increase in the serum creatinine level, typically less than 0.4 mg per deciliter (35 micromoles per liter), with this medication initially.

Table 1. Considerations for the Use of Particular Single-Pill Combinations in the Management of HIV-1 infection.

Niacin with Laropiprant in High-Risk Patients

Posted by Daniela Lamas • July 16th, 2014

Your patient, a 70-year-old man with a history of a heart attack three years ago, sits across from you at his regular outpatient follow-up appointment.

He’s doing well. He’s exercising and taking the medications you prescribed, including his statin, but he’s wondering if there’s anything more he should be doing to lower his “bad,” or LDL cholesterol and raise the “good,” or HDL, cholesterol.

A friend’s doctor prescribed him niacin, your patient tells you. Shouldn’t he take it as well?

Your patient isn’t alone. In recent years, the use of niacin as an adjunct to standard statin therapy has been increasing in the U.S. But the data on effectiveness aren’t so clear. One recent study published in NEJM in 2011, AIM-HIGH, suggested that there was actually no benefit to adding niacin for patients who were already on statins. But with concerns about how well the study was powered to determine a difference in cardiovascular events in these two groups, the question of whether patients might benefit from adding niacin to a statin remained open.

This is the question that Martin J. Landray and colleagues set out to answer. The THRIVE study, published in this week’s NEJM, reports that while adding niacin can lower levels of LDL cholesterol and raise HDL cholesterol, this comes without any clinical benefit – and with a host of adverse events.

Those eligible for the study were similar to the patient in your office – men and women 50 to 80 years old with a prior heart attack, stroke or diabetes with coronary artery disease. After an enrollment period that included standardizing background statin therapy, and a trial on niacin to make sure that patients could tolerate the drug, nearly 26,000 patients entered the study cohort. These were patients with good lipid control, with an average starting LDL of 63 mg/dL and HDL of 44 mg/dL. All received simvastatin 40 mg daily in addition to a combination of niacin and laropiprant (a medication that decreases the adverse effects, particularly flushing, associated with niacin), or placebo.

Over the four year follow-up, patients randomly assigned to the niacin group did, indeed, have lower LDL cholesterol by an average of 10 mg/dl, and 6 mg/dL higher HDL in addition to lower triglyceride levels. But these changes did not translate into clinical benefit.  When the investigators looked at their primary outcomes – major vascular events like heart attack and stroke – they found no significant difference between patients who were taking niacin, and those who weren’t. Even in subgroups of patients who might have been thought to net the most good from added niacin, such as those with low HDL and high triglycerides, the risk of serious vascular events were the same.

But the risk wasn’t. Those randomly assigned to niacin suffered a higher rate of serious adverse events, most commonly related to worsening or new onset diabetes, gastrointestinal side effects like ulcers and diarrhea, muskoskeletal adverse events like myopathy and gout, and an increase in infections and bleeding. Ultimately, those randomly assigned to niacin had a nine percent increase in the risk of death, although that did not meet statistical significance.

Of note, patients didn’t receive niacin alone, as they had in the prior AIM-HIGH study. Instead, they were given a formulation of extended-release niacin and laropripant, a prostaglandin receptor antagonist used to decrease flushing (commonly seen with niacin). This opens the question of whether some of the unanticipated adverse events were actually not due to niacin, but to laropripant, or to the combination of drugs. In a letter to the editor, the authors of the AIM-HIGH trial note that the spectrum of adverse events they saw was not entirely consistent with that described by the THRIVE investigators and suggest that some of the events seen in the THRIVE study might actually be due to the combination of drugs, rather than niacin alone.

Whether due to niacin alone or in combination, the adverse event profile is troubling. And so in an accompanying editorial, cardiologist Donald M. Lloyd-Jones recommends that while niacin should still be considered for patients who are unable to tolerate statins, or those with persistently high levels of triglycerides, “On the basis of the weight of available evidence showing net clinical harm, niacin must be considered to have an unacceptable toxicity profile for the majority of patients, and it should not be used routinely.”

To your patient, then: Stick with your current meds and skip the niacin. For now, that’s the best answer we have.

Letrozole or Clomiphene for Infertility in PCOS

Posted by Sara Fazio • July 11th, 2014

This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.

The PCOS, which is diagnosed on the basis of hyperandrogenism, oligo-ovulation with associated oligomenorrhea, and polycystic ovaries on ultrasonography, affects 5 to 10% of reproductive-age women and is the most common cause of anovulatory infertility.

Clinical Pearls

What are the potential drawbacks to the use of clomiphene citrate for ovulation induction?

Clomiphene citrate, a selective estrogen-receptor modulator that antagonizes the negative feedback of estrogen at the hypothalamus with a consequent increase in ovarian stimulation by endogenous gonadotropin, has been used for this indication for decades.  Clomiphene has drawbacks, including its overall poor efficacy (only a 22% rate of live birth with up to six cycles of clomiphene in our previous study), a relatively high multiple-pregnancy rate (3 to 8%) as compared with the rate associated with unassisted conception   (<1%), and an undesirable side-effect profile, including mood changes and hot flashes.

What was the primary outcome of this study comparing clomiphene to letrozole for ovulation induction in infertile women with the polycystic ovary syndrome?

The group of women who received letrozole had more cumulative live births than the group of women who received clomiphene (103 of 374 women [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth with letrozole, 1.44; 95% confidence interval, 1.10 to 1.87).   There were no significant between-group differences in live-birth rates according to treatment cycle. The live-birth rates after an anovulatory cycle were similar with and without progestin-induced withdrawal bleeding in both treatment groups.

Table 2. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity.

Figure 1. Kaplan-Meier Curves for Live Birth.

Morning Report Questions

Q: What were secondary study outcomes?

A: The rates of pregnancy loss after conception were similar in the two treatment groups. The ovulation rate was significantly higher with letrozole than with clomiphene at each monthly visit (P<0.01 for all comparisons) beginning with the second visit. Among patients who ovulated, there was a significantly greater chance of singleton pregnancy with letrozole than with clomiphene (P=0.03). The sex ratio at birth favored girls.

Table 2. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity. 

Q: How did adverse events compare between the two treatment groups?

A: Three serious adverse events related to ovarian-cyst formation occurred during infertility treatment: two with letrozole (a ruptured corpus luteum cyst in one patient and hospitalization for the drainage and removal of an ovarian cyst in another patient) and one with clomiphene (ovarian torsion). Clomiphene was associated with a significantly higher incidence of hot flushes; letrozole was associated with significantly higher incidences of fatigue and dizziness. During pregnancy, the most common complication was gestational diabetes, followed by preeclampsia or eclampsia, preterm labor, and premature rupture of membranes, with no significant differences between treatment groups. There were five major congenital anomalies (four with letrozole and one with clomiphene); the between-group difference was not significant (P=0.65).

Table 3. All Serious Adverse Events, plus Other Adverse Events with Significant Differences between the Treatment Groups.

CNS Fungal Infections

Posted by Sara Fazio • July 11th, 2014

Molds are ubiquitous in soil, water, and decaying vegetation and can cause devastating infections that are difficult to treat. This review summarizes the epidemiologic profiles, clinical characteristics, and treatment of mold infections of the central nervous system.

Molds are ubiquitous organisms found in soil, water, and decaying vegetation. All have septate, angular, branching hyphae in tissue, with the exception of those in the order Mucorales, which have broad, ribbonlike, nonseptate or hyposeptate hyphae.

Clinical Pearls

What is the typical mechanism by which fungal infections reach the CNS?

The respiratory tract is usually the portal of entry, with subsequent hematogenous dissemination to the CNS. However, direct inoculation of CNS or paraspinal tissue as a result of surgery, trauma, intravenous drug use, or contaminated medical supplies may also occur in immunocompetent persons. Organisms may also spread to the CNS from adjacent structures, including the sinuses, mastoid, and orbit. Infection of the ethmoid sinuses may lead to cavernous sinus thrombosis as a result of invasion of the emissary veins that drain the sinuses. Hyphae can invade from the ethmoid sinuses through the lamina papyracea and into the periorbital space, thus threatening the eye, extraocular muscles, and posterior apical structures, including the optic nerve. Angioinvasion is common in immunocompromised patients and accounts for the hematogenous dissemination from the lungs that causes focal neurologic deficits.

What are the characteristics of CNS aspergillosis?

The risk factors for CNS aspergillosis include neutropenia, systemic glucocorticoid treatment, mastoidectomy, spinal anesthesia, and paraspinal glucocorticoid injections. Focal neurologic deficits and seizures caused by stroke or mass effect are the most common clinical manifestations of CNS aspergillosis. Meningeal signs are uncommon, and their presence is indicative of a subarachnoid hemorrhage. CNS aspergillosis should be high on the list of disorders in the differential diagnosis for patients with immunosuppression and focal brain lesions, especially those with characteristic pulmonary infiltrates in whom focal neurologic deficits or focal seizures develop. Recovery of aspergillus from pulmonary lesions with the use of bronchoalveolar lavage or fine-needle aspiration should be pursued when possible. An enzyme immunoassay for detection of galactomannan in serum or bronchoalveolar lavage fluid should be performed when feasible. Galactomannan and 1,3-(beta)-d-glucan may be found in the serum or CSF of patients with CNS aspergillosis. Voriconazole is the first-line treatment for CNS aspergillosis.

Morning Report Questions

Q: What are typical features of cerebral mucormycosis?

A: Cerebral mucormycosis, which is perhaps the most aggressive mold infection of the CNS, constitutes a medical emergency. Diabetes mellitus and iron-overload conditions are distinctive risk factors for the development of mucormycosis. In patients with neutropenia or patients receiving glucocorticoid therapy, mold infections of the CNS develop as sino-orbital infections or through hematogenous dissemination of pulmonary mucormycosis. In contrast, patients with diabetes mellitus usually present with sino-orbital mucormycosis and seldom present with pulmonary or disseminated infection. Among intravenous drug users, CNS mucormycosis is a relatively common cause of intracerebral fungal abscesses. Perhaps more than any other infection, mucormycosis of the ethmoid sinuses may involve all structures along its invasive path, including the orbit and eye, bone, and brain tissue. Because venous drainage of the ethmoid sinuses extends into the cavernous sinuses, ethmoidal mucormycosis carries a high risk of cavernous sinus thrombosis. Successful management of rhinocerebral mucormycosis depends not only on early diagnosis but also on primary antifungal therapy with amphotericin B, reversal of host impairments and timely surgical intervention, when indicated.

Q: What are the features of CNS infection with fusarium species?

A: CNS fusariosis develops predominantly in patients with prolonged neutropenia. These organisms are highly angioinvasive and cause hemorrhagic infarction with strokelike events. Portals of entry include the lungs, sinuses, vascular catheters, and distinctively, periungual lesions (paronychia in patients with neutropenia). Fusarium species are also most frequently associated with fungemia, multiple erythematous nodular cutaneous lesions, and septic arthritis. A definitive mycologic diagnosis can be rapidly established by biopsy and culture of cutaneous lesions. As compared with other mold infections of the CNS, disseminated fusariosis is more commonly associated with bilateral endophthalmitis, which may lead to blindness. Fusarium species vary in their susceptibility to antifungal agents. Voriconazole is licensed for second-line therapy; however, amphotericin B also has been used successfully.

Take the Case Challenge

Posted by Jennifer Zeis • July 10th, 2014

A 41-year-old man was admitted to the hospital in midsummer because of fever, rash, pancytopenia, and abnormal results of liver-function tests. What is the diagnosis? What diagnostic tests are indicated?

Read the case description for the next Case Record of the Massachusetts General Hospital, and then vote and comment now on NEJM.org. In a few days, find the answer in the full text of the Case Record to be published July 24.

Follow the conversation with #NEJMCases on Twitter or Facebook.

Dupilumab as a Treatment for Atopic Dermatitis

Posted by Rachel Wolfson • July 9th, 2014

For thousands of years, our knowledge of medications has largely been based on trial and error: we haphazardly used substances and learned from the effects. Within the last half a century, however, rational drug design slowly took to the forefront as scientific discoveries improved our understanding of the underlying pathogenesis of diseases. While there have not been many victories for rational drug design so far, dupilumab is a key one on a small but growing list. As a monoclonal antibody that targets cytokines involved in type 2 helper T cell (Th2) activation, dupilumab has already demonstrated preliminary efficacy for asthma, a disease which is known to be driven, at least in part, by Th2 activation. Furthermore, Th2 activation has also been implicated in the pathogenesis of atopic dermatitis, a disease characterized by skin barrier abnormalities, Th2 immune responses, and pruritis.

To evaluate the importance of Th2 activation in the pathogenesis of atopic dermatitis and the efficacy of dupilumab as a treatment, Beck and colleagues conducted four randomized, double-blinded, placebo-controlled clinical trials and reported their results in this week’s NEJM. Two of the trials (studies M4A and M4B) were originally designed primarily for safety analysis but the clinical effects were striking. The patients were randomly assigned to four weeks of treatment with either dupilumab or placebo. Another trial (study M12) followed 109 patients for 12 weeks after initiating monotherapy with either dupilumab or placebo. The primary objective was to assess clinical efficacy. Finally, a fourth trial (study C4) compared dupilumab in combination with topical glucocorticosteroids to placebo with topical glucocorticosteroids. The primary endpoints after four weeks of combination therapy were the incidence and severity of adverse events.

In studies M4A and M4B, patients treated with dupilumab showed rapid and dose dependent improvements in all clinical outcomes that were tested, such as pruritis scale rating and improvement in eczema area. This improvement was also seen in patients treated with dupilumab at the four-week point in study M12, and this treatment group continued to improve throughout the entire 12-week course. Similarly, in study C4, patients treated with dupilumab in combination with topical glucocorticosteroids had better improvements in clinical outcomes than those treated with placebo and topical glucocorticosteroids. Finally, in terms of safety measures, there were more mild to moderate adverse events in the patients treated with dupilumab (i.e. nasopharyngitis and headache), but there were more serious adverse events in the placebo group, mostly due to skin infections and atopic dermatitis.

Overall, the data provide solid evidence for the key role of Th2 activation in the pathogenesis of the disease; these trials cannot address the clinical utility of the treatment. This advance reflects the importance of studying the molecular underpinning of diseases, because if we can truly understand the biology, we will find effective therapies for even the most stubborn illnesses.