12-Year-Old Girl with Irritability and Insomnia

Posted by Sara Fazio • May 24th, 2013

In the latest Case Record of the Massachusetts General Hospital, a 12-year-old girl with a history of celiac disease, anxiety, and depression was seen in the outpatient psychiatry clinic of this hospital because of irritability, hypersomnia, and multiple somatic symptoms. Psychotherapy and the administration of antidepressants were begun.

Pediatric patients with somatization are likely to have psychopathological symptoms, family dysfunction, and poor performance and attendance at school. Children with abdominal pain who have a negative medical workup may have been exposed to a traumatic event and may have underlying anxiety.

Clinical Pearls

• What are the manifestations and risk factors for childhood depression?           

Criteria for a major depressive episode includes persistent irritable mood for two or more weeks and five or more of the following neurovegetative symptoms: low energy, decreased appetite, hypersomnia, diminished interest in daily activities, psychomotor retardation, and decreased concentration. Children often have trouble recognizing and reporting their emotional state. Alexithymia (the inability to express one’s feelings) does not rule out depression.  Child psychiatrists base their diagnoses on observation and on reports from parents, as well as on the child’s self-report.  Prepubertal patients with depression commonly present with somatic symptoms, irritability, or social withdrawal, whereas adolescents are more likely to have hypersomnia or psychomotor retardation. Risk factors for a major depressive disorder include a family history of depression, the presence of another nonaffective psychiatric disorder predating the depression, female sex (after puberty), and multiple major life stressors. The more risk factors a patient has, the more likely it is that depression will develop.

• Which selective serotonin-reuptake inhibitors (SSRIs) are currently approved by the Food and Drug Administration (FDA) to treat childhood depression?      

Only two SSRIs are approved by the FDA — fluoxetine for the treatment of children 8 years of age or older, and escitalopram for the treatment of children 12 years of age or older. The FDA issued a black-box warning in 2004 that some children, adolescents, and young adults may have an increased risk of suicidal thoughts or behavior while taking antidepressants. One meta-analysis showed that the increased risk in suicidal thoughts was between 1% and 3%. Another meta-analysis concluded that the clinical benefits associated with the use of antidepressants in children with depression outweighed the risks.

Morning Report Questions

Q: What are the clinical and laboratory features of adrenal insufficiency?   

A: Features of adrenal insufficiency include chronic weakness, fatigue, anorexia, nausea, vomiting, abdominal pain, dizziness, weight loss, hyperpigmentation, hypotension, hyponatremia, hyperkalemia, hypercalcemia, anemia, and eosinophilia. The diagnosis of Addison’s disease is often missed for some time. In one study, only 47% of the cases were diagnosed within 1 year after initial symptoms and more than 20% were diagnosed more than 5 years after initial symptoms.

Q: What laboratory values are consistent with a diagnosis of autoimmune primary adrenal failure?               

A: Undetectable plasma cortisol levels, elevated plasma corticotrophin level, elevated plasma renin activity, and elevated 21-hydroxylase antibody level are diagnostic of autoimmune primary adrenal failure. This results in a loss of adrenal glucocorticoid, mineralocorticoid, and androgen production because of destruction of the adrenal cortex by autoreactive T cells. As a result of the loss of negative feedback of cortisol on the hypothalamus and pituitary, corticotropin levels rise dramatically and levels of thyrotropin can rise mildly. Because of the loss of the effects of mineralocorticoids on salt and water balance, there is decreased renal perfusion pressure, which drives the production of plasma renin activity.

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Lung-Cancer Screening

Posted by Sara Fazio • May 24th, 2013

In participants who underwent initial screening in the National Lung Cancer Screening Trial, low-dose CT scanning showed positive results three times as frequently as did chest radiography (27% vs. 9%) and detected more than twice as many stage I cancers (158 vs. 70).

Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer.

Clinical Pearls

• What was the differential benefit in this trial between low-dose CT scanning versus chest radiography in the detection of lung cancer?         

In more than 50,000 participants who underwent the initial screening in the National Lung Cancer Screening Trial, low-dose CT scanning was positive three times as frequently as chest radiography (27% vs. 9%).  For low-dose CT, all noncalcified nodules with long-axis diameters of 4 mm or greater in the axial plane were considered to be positive for lung cancer per study guidelines.

• What was the calculated sensitivity and specificity of each of the screening modalities?   

In the low-dose CT group, 270 (92.5%) of the participants with lung cancer had a positive screening result (a true positive result), 18 (6.2%) had a negative screening result (a false negative result), and 4 (1.4%) missed the screening visit. In the radiography group, 136 (71.6%) of the participants with lung cancer had a positive screening result (a true positive result), 49 (25.8%) had a negative screening result (a false negative result), and 5 (2.6%) missed the screening visit. The sensitivity and specificity were 93.8% (270 of 288) and  73.4% (19,043 of 25,954), respectively, for low-dose CT and 73.5% (136 of 185) and 91.3% (23,547 of 25,790), respectively, for chest radiography.

Morning Report Questions

Q: What was the positive predictive value in both study groups?          

A: In the low-dose CT group, the positive predictive value for any positive finding that led to a biopsy procedure was 52.9% (265 of 501), but the positive predictive value for positive findings overall was only 3.8% (270 of 718). The positive predictive value for pulmonary nodules 4 mm or more in the longest diameter was 3.8% (267 of 7010); the value increased from 0.5% to 41.3% as the diameter of the nodule increased from 4 to 6 mm to more than 30 mm. The positive predictive value for noncalcified hilar or mediastinal adenopathy was 18.5% (51 of 276). Overall, with low-dose CT, the negative predictive value was 99.9% (19,043 of 19,061). In the radiography group, the positive predictive value was 70.2% (132 of 188) for a positive finding that led to a biopsy procedure but only 5.7% (136 of 2379) for positive findings overall. The positive predictive value for pulmonary nodules 4 mm or more in the longest diameter was 5.8% (123 of 2105); the value increased from 1.0% to 39.3% as the diameter of the nodule increased from 4 to 6 mm to more than 30 mm.

Table 2. Frequency and Positive Predictive Value of Positive Screening Results, According to Study Group.

Q: What effect did low-dose CT have on detection of cancers in various stages?

A: There were 292 cases of diagnosed lung cancer in the low-dose CT group and 190 in the radiography group, with the difference nearly  completely accounted for by the higher incidence of stage IA cancer in the low-dose CT group (132 cases, vs. 46 in the radiography group). There was no significant difference in the total number of lung cancers in stages IIB through IV between the low-dose CT group and the radiography group (120 vs. 112). There were many more bronchioloalveolar carcinomas and adenocarcinomas in the low-dose CT group than in the chest-radiography group (38 vs. 8 and 123 vs. 71, respectively), but the frequencies of other histologic features were similar in the two groups.

Table 4. Stage and Histologic Features of Lung Cancers, According to Study Group and Screening Result.

 

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Take the Case Challenge!

Posted by Karen Buckley • May 23rd, 2013

 

The case description for next week’s Case Records of the Massachusetts General Hospital is now available.  We’re asking you to evaluate the case and tell us what you think.  What is the diagnosis? What diagnostic test is most likely to be helpful?

A 56-year-old woman with diabetes mellitus was admitted to the hospital because of hyperglycemia and chest pain.

Read the full case description, then vote and comment on NEJM.org.

 

Is the diagnosis…

…Small-cell lung cancer?

…Tuberculosis with adrenal-gland involvement?

…Carcinoid tumor with ectopic production of corticotrophin?

…Glucagonoma?

…Cushing’s disease?

…Pancreatic cancer?

The correct diagnosis, along with the full description of the case and the procedures performed, can be found in the full text of the case, to be published on May 30.

Look for the next Case Challenge on July 17th.

 

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Hepatitis C Virus Infection

Posted by Sara Fazio • May 17th, 2013

Only 20 years after the discovery of the hepatitis C virus, a cure is now likely for most people with chronic infection. The latest review in our Drug Therapy series considers current therapy and the present landscape of drug development for hepatitis C.

The hepatitis C virus (HCV) carries a substantial disease burden, not only in the United States but also worldwide. The recent approval of two direct-acting antiviral agents that specifically inhibit viral replication has dramatically increased the viral clearance rate, from less than 10% with the initial regimen of interferon monotherapy to more than 70% with current therapy.

Clinical Pearls

• What are the current CDC recommendations for screening for HCV?

Because most infected persons are unaware of their diagnosis, the Centers for Disease Control and Prevention recently recommended screening for HCV all persons born between 1945 and 1965. It is anticipated that in the course of such a screening process, a large number of persons will be found to be infected with the virus; whether it will be possible to treat all these people is unclear.

• What is the endpoint of successful therapy for HCV infection?  

The goal of therapy for chronic hepatitis C is eradication of the virus, which should limit or prevent the development of complications. The end point of successful therapy is a sustained virologic response, defined as undetectable HCV RNA in serum 24 weeks after treatment has been stopped. This outcome is predictive of long-term eradication of the virus and correlates with a reduction in symptoms and improvement in clinical outcomes.

Morning Report Questions

Q: How has the treatment of HCV infection changed over the past five years?     

A: The combination of peginterferon and ribavirin has been the standard of care for patients with chronic hepatitis C, regardless of the strain of the virus (genotype 1, 2, 3, 4, 5, or 6). This regimen results in rates of sustained virologic response of 70 to 80% among patients with HCV genotype 2 or 3 infection and rates of 45 to 70% among patients with any of the other genotypes. The approval of boceprevir and telaprevir has led to triple therapy for HCV genotype 1 infection — one of these two protease inhibitors in combination with peginterferon and ribavirin. These two triple-therapy regimens result in similar response rates but differ greatly with respect to the timing of administration (both when they should be administered and for how long). The combination of peginterferon and ribavirin remains the recommended therapy for HCV genotypes 2, 3, 4, 5, and 6 infection. Preliminary results of a study of a polymerase inhibitor (sofosbuvir) in combination with ribavirin, administered for 12 weeks, showed a 100% rate of sustained virologic response among patients with HCV genotype 2 or 3 infection. As reported in this issue of the Journal, two phase 3 trials of the same oral combination showed similar response rates among patients with genotype 2 infection (93% and 97% in the two studies) but much lower response rates among patients with genotype 3 infection (56% and 61% in the two studies).

Figure 3. Treatment Algorithm for HCV Infection, According to Genotype.  

Q: What are the challenges of triple therapy regimens for HCV with protease inhibitors? 

A: Although the approved triple-therapy regimens are more efficacious than a regimen of peginterferon and ribavirin without a protease inhibitor, they have additional side effects and are quite complex to adhere to because patients must take an increased number of pills and the schedule requires pills to be taken every 8 hours. The most common side effects with boceprevir are anemia, neutropenia, and dysgeusia (altered taste sensation), and the most common side effects with telaprevir are anemia, rash, and anorectal discomfort. Anemia (a hemoglobin level of <10 g per deciliter) occurs in 36 to 50% of cases and is the most challenging complication to manage. Drug-drug interactions are a major issue, and antiviral resistance is another major concern and may develop as early as 4 days after initiation of the drug when these agents are used as monotherapy.

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Fever and Altered Mental Status

Posted by Sara Fazio • May 17th, 2013

In the latest Case Record of the Massachusetts General Hospital, 76-year-old man with chronic renal disease was admitted to this hospital because of fever, worsening renal function, and confusion. Brain imaging revealed a small amount of material with restricted diffusion layering in the occipital horns of the lateral ventricles.

Typical bacterial organisms that commonly cause acute meningitis in older patients are Streptococcus pneumoniae, Neisseria meningitidis, Hemophilus influenzae, and Listeria monocytogenes. The administration of empirical antimicrobial agents should be started before results of blood tests and culture of the cerebrospinal fluid are available.

Clinical Pearls

• What tickborne infections are in the differential diagnosis of altered mentation?

Infection with B. burgdorferi is more commonly associated with central nervous system infection than human granulocytic anaplasmosis (infection with Anaplasma phagocytophilum) or human monocytic ehrlichiosis (infection with Ehrlichia chaffeensis). Early disseminated Lyme disease typically occurs several weeks to months after the tick bite, and lymphocytic meningitis can be accompanied by cranial-nerve palsy. Rocky Mountain spotted fever (infection with Rickettsia rickettsii) can cause fever, thrombocytopenia, and lymphocytic meningitis. Most patients with this disease present with a rash, but the absence of a rash does not rule out the diagnosis, although it makes it less likely.

• What are the clinical manifestations of West Nile virus infection?

Although 60 to 80% of patients infected with West Nile virus remain asymptomatic, West Nile fever develops in approximately 20% and is characterized by typical influenza-like symptoms of fever, myalgias, malaise, and anorexia. A maculopapular rash can appear in a quarter to half of patients and portends a lower risk for neuroinvasive disease. Patients with neurologic symptoms may have encephalitis, meningitis, or flaccid paralysis. Physical examination may reveal a coarse tremor, myoclonus, or such parkinsonian features as rigidity and cogwheeling.

Morning Report Questions

Q: How is West Nile virus infection diagnosed?

A: A brief, low-level viremia occurs early in the course of many arboviral infections in humans; however, viremia is typically of short duration and overlaps with the asymptomatic period of clinical incubation. As a result, direct detection of arbovirus by nucleic acid testing is often no longer possible by the time a patient comes to the attention of clinicians. Therefore, serologic tests are the mainstay of diagnosis. Serum IgM is frequently detectable by the time patients with arboviral infections present for clinical care, and several days later, the IgG level becomes elevated. Patients may be seronegative if tested very early in the course of infection, so repeat testing of a convalescent-phase serum sample may be necessary if the diagnosis is strongly suspected. For patients with neuroinvasive disease, detection of virus-specific IgM in the cerebrospinal fluid (CSF) is also very useful; since IgM does not readily diffuse across the blood-brain barrier, finding it in the CSF suggests that antibody is being synthesized intrathecally in response to viral antigen that is present in the central nervous system.

Q: What is the most common viral cause of meningoencephalitis?

A: In general, herpes simplex virus type 1 is likely the most common viral infection leading to encephalitis. Depending on the season, arboviruses are not an uncommon cause of infection. During mosquito season in the eastern United States, West Nile virus, eastern equine encephalitis virus, St. Louis encephalitis virus, and La Crosse virus are in circulation. The largest outbreak of West Nile infection in recent U.S. history occurred in 2012, and approximately half of the cases were classified as neuroinvasive and 236 deaths were attributed to the virus that year. Typically, enteroviruses cause meningitis, but some types have been associated with encephalitis. Less common viral causes of encephalitis include human immunodeficiency virus, varicella zoster virus, and the mumps and measles viruses.

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The role of nurse practitioners in primary care

Posted by Jamie Colbert • May 16th, 2013

Sara is a 31-year-old healthy female professional living in Boston who gets her medical care at a large, multi-provider primary care clinic. When Sara goes to the clinic for a routine visit, she sees a nurse practitioner (NP) about 75% of the time.  Sara says that she chooses to see the NP rather than an MD for a number of reasons:  “For primary care I usually find that it is easier to get an appointment with an NP. I also feel like the NP spends a little more time with me and does not seem to be in as much of a hurry to get through the visit. I’ve been very satisfied by the care I’ve received from the NPs that I have seen.” However, when asked about whether she would prefer to see a NP for all of her clinic visits, she hesitates: “If I had a more serious illness or a complex medical problem, I would feel more confident being evaluated by an MD who has received more years of training and has broader overall medical knowledge.”

Sara’s experience is not unique. In the United States an estimated 60,000 nurse practitioners are currently working in the primary care setting, yet there is no clear consensus as to what role NPs should play in delivering care. A 2010 report from the Institute of Medicine recommended that NPs “should be able to practice to the full extent of their education and training.” But, how do we determine what activities fulfill this mandate? Should NPs be given free range to prescribe all medications including controlled substances? Should NPs have their own panel of primary care patients, or should they only see patients as part of a care team led by an MD?

This week’s issue of NEJM features a Special Article by Donelan et. al describing the findings from the 2012 National Survey of Primary Care Nurse Practitioners (PCNPs) and Physicians. The authors surveyed nearly 1000 primary care nurse practitioners and physicians to learn what attitudes they had on the scope of practice of NPs as well as to learn what services NPs are currently performing in the primary care setting. While the majority of MDs and PCNPs surveyed agree that NPs should practice to the full extent of their education and training, the responses to most other questions were widely divergent.

The survey showed that on average, PCNPs work fewer hours, see fewer patients, and are paid less than their MD colleagues.  While 83% of PCNPs felt that they should be able to lead primary care medical homes, only 17% of MDs agreed. Similarly, 64% of PCNPs felt that they should be paid equally to MDs for the provision of the same services, but only 4% of MDs agreed. When asked about the effect of increasing the supply of PCNPs in the US, more than three-fourths of PCNPs felt that such an expansion of the workforce would improve patient safety, primary care effectiveness, and lower health costs. However, only about one-quarter of MDs surveyed felt that a larger supply of PCNPs would result in better safety, effectiveness or improvement in costs. Finally, there exists a disconnect in perceived quality of care provided – as two-thirds of MDs felt that they provide a higher quality examination and consultation, while fewer than 10% of PCNPs agreed.

Despite these differences of opinion and attitude, the fact remains that primary care in the US is currently under enormous strain. Other surveys have shown that primary care physicians today feel overworked, underpaid, and have lower job satisfaction than those in other specialties. In many cities, waits for new appointments with primary care providers can reach six months or more. And with roll out of the Accountable Care Act, as many as 35 million uninsured Americans may finally gain health insurance – yet who will take care of them? Many health policy experts have suggested expanding the role of non-MDs in the primary care space, yet this report raises significant concerns about how such a move would be received by those MDs currently practicing primary care. Recent attempts to expand the scope-of-practice of NPs to allow them to practice more independently have met with opposition from physician groups, including the AMA, AAFP, and American Academy of Pediatrics. The Robert Wood Johnson Foundation has recently taken the lead in working to bring the nursing and physician communities together to create consensus on this issue. As we move towards new models of care delivery in which physicians and nurses provide team-based primary care, one can only hope that such interprofessional collaboration will eventually result in agreement on how best to define the role of advanced nurse practitioners in the primary care clinic.

Connect with Dr. Colbert on Twitter: @jcolbertMD

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Global Health Author Q&A: George Institute’s Robyn Norton

Posted by Jennifer Zeis • May 15th, 2013

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

Answers from Robyn Norton, Ph.D., M.P.H., of the George Institute for Global Health, Oxford, UK.

Dr. Norton is a co-author of the May 2 article, “Injuries.”

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

Recognition of the current and increasing significance of non-communicable diseases for the global health agenda – and especially recognition of the potential threats to health and economic development in low and middle-income countries as a result of these conditions.

This recognition is perhaps best exemplified by the holding of the UN high-level meeting on non-communicable diseases in New York in September 2011 – only the second time in the history of the UN that the general Assembly has met on a health issue (the previous issue discussed was AIDS).

lack of knowledge of the challenges ahead can no longer be no excuse for inaction

While recognition of an issue is no guarantee that action will follow, lack of knowledge of the challenges ahead can no longer be no excuse for inaction.

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

The implementation of evidence-based prevention initiatives will be essential in efforts to stem the growing burden of non-communicable diseases.

Equally important, though, will be the need for healthcare systems to manage the growing numbers of individuals who require treatment for non-communicable diseases and in particular for chronic conditions and disabilities that require ongoing care.  However, healthcare systems in most low and middle-income countries are not designed to provide care for such conditions.

As a consequence, these systems will need to be radically redesigned if they are to provide safe, effective and importantly, affordable healthcare for all who require it.  A strengthened evidence-base on how best to redesign healthcare delivery systems within limited resources, therefore warrants increased attention and awareness in the coming decade.

Of course, the prevention and management of injuries, especially road traffic injuries, will also required increased attention, given increasing levels of motorization in most low and middle-income countries.  Adolescents in particular must be a key focus of that attention.

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

Given the paucity of highly skilled healthcare workers in many low and middle-income countries, the revolution in IT must be harnessed in such a way that healthcare workers with minimal levels of training, supported by IT, can provide care that is safe, effective and affordable.

Such workers should be able to access technology that would allow them to screen and identify high-risk individuals, access electronic decision support systems to enable them to manage simple conditions and refer individuals with complex conditions to more highly skilled clinicians for further management.  The use of IT should also enable quality control of all aspects of this patient and healthcare worker interface.

In high-income countries too, the revolution in IT should be harnessed to maximize quality control of all aspects of the patient and health worker interface, especially as a means to reduce variations in care and improve health outcomes.

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

The view that involvement in global health requires spending significant time abroad is in many ways an old-fashioned view of global health.  Building local capacity within countries, to manage local health problems, arguably seems a more appropriate approach to finding solutions to the health challenges in low and middle-income countries.

Consequently, for American physicians, engaging in and supporting training initiatives that enable healthcare workers in these countries to develop the necessary skills to address their country’s health problems, seems a more appropriate contribution.

Developing relationships with like-minded colleagues in low and middle-income countries and together undertaking collaborative research, for example, provides opportunities where the skills and expertise of American physicians can complement the interests and local knowledge of non-American physicians.

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Vaginal Bleeding

Posted by Sara Fazio • May 10th, 2013

In the latest Case Record of the Massachusetts General Hospital, a 70-year-old woman was seen in this hospital because of vaginal bleeding. An endometrial-biopsy specimen showed a poorly differentiated malignant neoplasm that was suggestive of mixed müllerian tumor (carcinosarcoma). A diagnostic and therapeutic procedure was performed.

The underlying cause of abnormal vaginal bleeding is age-dependent. Ten percent of premenopausal women with abnormal bleeding have a malignant tumor. In contrast, 75% of women over 70 years of age with postmenopausal bleeding have cancer, and the risk rises with age in postmenopausal women.

Clinical Pearls

• What is the typical presentation of carcinosarcoma of the uterus?

Postmenopausal vaginal bleeding is the most common manifestation of carcinosarcoma. Patients with carcinosarcoma also frequently present with the classic triad of painful postmenopausal bleeding, an enlarged uterus, and prolapsed tumor visible at the cervical os.

• Under what circumstances is surgery not the primary treatment for uterine cancer?

In only a few circumstances is surgery not the primary treatment for uterine cancer — when there is a desire to preserve fertility, high operative risk, and unresectable disease. The goals of surgical treatment are excision of all disease with at least a 1-cm margin and staging of the tumor. The initial spread is to regional lymph nodes; therefore, standard treatment is a radical total abdominal hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy. Endometrial cancers have several potential patterns of spread: direct invasion and expansion of the primary tumor, lymphatic invasion, hematogenous spread, and intraperitoneal dissemination. Because metastasis is common, preoperative combination positron-emission tomography and computed tomography (PET-CT) and a meticulous exploratory laparotomy are standard practice.

Morning Report Questions

Q: What features affect the overall prognosis of patients with carcinosarcoma?

A: Diagnostic features of malignant mixed mullerian tumor (carcinosarcoma) include the finding of a biphasic malignant tumor that is composed of high-grade carcinoma (most commonly endometrioid or serous) and sarcoma and is typically homologous (arising from mesenchymal tissue normally found in the uterus), although in up to 50% of cases, the tumor has a heterologous component (most commonly rhabdomyosarcoma or chondrosarcoma). There is no transition between the two components. Tumor stage is the most important prognostic factor in these tumors, although histologic features also affect outcome. The finding of serous or clear-cell carcinoma is associated with a more aggressive course. Sarcomatous components adversely affect the overall prognosis of patients with stage I tumors (5-year survival is 30% among patients with heterologous elements as compared with 80% among patients with homologous elements); myometrial and lymphovascular invasion are also associated with a poor prognosis.

Q: What are the treatment options for carcinosarcoma?

A: Carcinosarcoma is thought to require multiple methods of treatment. Radiation therapy has been shown to reduce the rates of local recurrence in the pelvis but does not increase the survival benefit among patients with carcinosarcoma. Adjuvant chemotherapy has not been shown to have an effect on recurrence rates or progression-free or overall survival among patients with carcinosarcoma. Hormonal therapy is of no use, since estrogen and progesterone receptors do not control tumor growth, even though they are typically present in patients with carcinosarcoma.

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Enteropathogens in Returning Travelers

Posted by Sara Fazio • May 10th, 2013

Chronic gastrointestinal illness sometimes develops after international travel. The latest review article in our Current Concepts series covers the diagnosis of the major enteropathogens and provides recommendations for treatment.

In a recent study that analyzed data from the GeoSentinel Surveillance Network (which consists of 42 specialized travel or tropical-medicine sites located around the world) on 25,867 returned travelers over a 9-year period (from 1996 to 2005), of the 2902 clinically significant pathogens that were isolated, approximately 65% were parasitic, 31% bacterial, and 3% viral. Six organisms (giardia, campylobacter, Entamoeba histolytica, shigella, strongyloides, and salmonella species) accounted for 70% of the gastrointestinal burden.

Clinical Pearls

• What are the clinical manifestations of Giardia lamblia infection?

Giardia lamblia (also called Giardia intestinalis or Giardia duodenalis) is highly contagious (ingestion of as few as 10 to 25 cysts may cause disease), with persons becoming infected through the ingestion of cysts in contaminated food or water. However, person-to-person transmission is possible. The clinical manifestations range from mild intestinal problems that resolve spontaneously to complex symptoms that last up to several weeks, such as protein-losing enteropathy, postinfectious fatigue, chronic diarrhea, abdominal pain, nausea, and weight loss. In children, the disease can cause growth and cognitive impairment as a result of iron and micronutrient deficiencies.

• What is the natural history, typical clinical course, and methods to diagnose amebiasis?

E. histolytica and E. moshkovskii are pathogenic in humans, causing amebiasis. The parasite is acquired through the ingestion of food or water contaminated with fecal cysts. After it has been ingested, the cyst emerges in the terminal ileum as an active trophozoite, which migrates to the colon where it colonizes the mucus layer. Invasion may take days to years after the initial infection and is characterized by fever, abdominal pain, and bloody dark-brown diarrhea. However, 90% of cases are asymptomatic and self-limiting. Symptomatic disease occurs when trophozoites invade the mucosa and submucosa, and some trophozoites enter the portal circulation and disperse to the liver and other soft organs. Disease of the right colon is common and is associated with the following serious complications: strictures, rectovaginal fistulas, bowel obstruction, toxic megacolon, perforation, peritonitis, and death. Only 1% of clinical cases of amebiasis involve the liver. Several stool antigen assays specific for E. histolytica are commercially available to make an accurate diagnosis of intestinal or hepatic amebiasis on the basis of the Gal/GalNAc lectin. Microscopic examination of the stool is no longer performed for amebiasis because of its low sensitivity and specificity; with microscopy, it is easy to confuse E. histolytica with the identically appearing and much more common nonpathogenic parasite E. dispar.

Morning Report Questions

Q: What are the manifestations of strongyloides infection?

A: Strongyloides stercoralis (threadworm) is the most dominant species causing infection in humans. Third-stage filariform larvae penetrate the skin (usually the foot) of the human host, reach the lungs via the blood circulation, and enter respiratory pathways. From there, they migrate upward through the trachea, are swallowed, and finally reach the small intestine, where they mature into adult egg-laying female worms. Female worms embed in the submucosa of the duodenum, where they produce dozens of eggs per day. These hatch in the gut lumen, and the first-stage rhabditiform larvae either are passed out in the feces and develop into infective third-stage larvae or remain in the gastrointestinal tract of the human host and start a new infection cycle (autoinfection). Autoinfection can result in persistent infection for decades. More than 50% of patients with a chronic infection are asymptomatic. For a subset of patients with disease, the symptoms include erythematous pruritus, skin eruptions, larva currens, abdominal pain, diarrhea, and weight loss. In travelers presenting with eosinophilia or elevated IgE levels, strongyloides should be considered in the differential diagnosis. In immunocompromised persons, strongyloidiasis can cause a hyperinfection syndrome owing to the reproductive capacity of the parasite inside the host. In cases of dissemination disease, the hyperinfection syndrome can be associated with a mortality rate of close to 90%.

Q: What is the natural history and clinical presentation of schistosomiasis?

A: Schistosomiasis is a common chronic helminth disease caused by intravascular parasitic schistosoma trematode worms. The three most important species in humans are Schistosoma hematobium, S. mansoni, and S. japonicum. Schistosome transmission requires the contamination of water by egg-containing feces or urine, a specific freshwater snail as intermediate host, and human contact with water inhabited by the intermediate host snails. Schistosome larvae (cercariae) emerge from the snails and penetrate human skin, thereby instigating infection. A maculopapular eruption consisting of discrete erythematous, raised lesions that vary in size from 1 to 3 cm may arise at the site of percutaneous penetration by the cercariae. Patients with acute schistosomiasis, or Katayama fever, which usually begins with the deposition of schistosome eggs into host tissues, can present with fever, malaise, myalgia, fatigue, nonproductive cough, diarrhea (with or without blood), hematuria (S. hematobium), and right-upper-quadrant pain. A skin reaction may develop within a few hours after infection in migrants or tourists infected for the first time, although a rash may appear as much as a week later. In cases of infection with S. mansoni and S. japonicum, a T-cell-mediated granulomatous reaction to schistosome eggs leads to fibrosis and chronic disease of the human liver, resulting in the development of severe hepatosplenic schistosomiasis; in cases of S. hematobium, this reaction leads to fibrosis and calcification of the bladder and ureters, which can result in bladder cancer.

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Global Health Author Q&A: Carter Center’s Donald Hopkins

Posted by Jennifer Zeis • May 9th, 2013

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

Donald Hopkins, the Carter Center (Credit: The Carter Center/L. Gubb)

Answers from Donald R. Hopkins, M.D., M.P.H., of the Carter Center, Atlanta.

Dr. Hopkins is author of the January 3 article, “Disease Eradication.”

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

Dramatically increased distribution of bed nets to prevent malaria and lymphatic filariasis in Africa, and increased availability of treatment for HIV/AIDS infections.

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

More attention to education and mobilization of local communities to participate actively in measures to improve their health and well-being.

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

Work with local officials, communities and citizens to discover useful IT applications.

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

Work with U.S.-based organizations that allow them to spend lesser time abroad physically, conduct relevant research, help teach relevant skills, and/or help support others who do work abroad.

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