In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

A 50-year-old man who returned from a business trip to Nigeria 24 days ago presents with complaints of the sudden onset of fever, diarrhea, myalgia, and headache. He reports 10 bowel movements per day and has seen bloody stools.

During his trip he flew in to Murtala Muhammed International Airport in Lagos, ate meals only in his hotel, and attended meetings in Lagos central business district. He had no exposure to animals, mosquitoes, ticks, or sick people, and no sexual activity. After returning home, he felt well for the first 3 weeks.

The patient has a history of hypertension. He does not smoke, drink alcohol, or use injection drugs. He is married, works with commercial banks and financial institutions, and lives in Cleveland, OH.

On physical examination his temperature is 100.0˚F (37.8˚C), pulse 98, respirations 15, blood pressure 105/70 mm Hg, and weight 78 kg (172 lb). He appears comfortable but is a little diaphoretic. His abdomen is tender to palpation in the epigastrium and slightly to the right; he has no signs of peritonitis. His skin is without rash, bleeding, or bruising. The remainder of the examination is normal.

His white blood cell count is 17 × 10⁹/L, hemoglobin 15 g/dL, hematocrit 41%, and platelet count 172 × 10⁹/L. His sodium level is 126 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, carbon dioxide 20 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.7 mg/dL, and glucose 130 mg/dL. His aminotransferase and alkaline phosphatase levels are normal.

Could this patient have Ebola virus disease?

With Ebola virus disease on the rise in West Africa, physicians who encounter patients like this one need to include it in the differential diagnosis. Because the disease is new, many questions are raised for which we as yet have no answers. Here, I will review what we know and do not know in an effort to remove some of the fear and uncertainty.

A NEW DISEASE

Ebola virus disease is a severe hemorrhagic fever caused by negative-sense single-stranded RNA viruses classified by the International Committee on Taxonomy of Viruses as belonging to the genus Ebolavirus in the family Filoviridae. Filoviruses get their name from the Latin filum, or thread-like structure.

The family Filoviridae was discovered in 1967 after inadvertent importation of infected monkeys from Uganda into Yugoslavia and Marburg, Germany. Outbreaks of severe illness occurred in workers at a vaccine plant who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production.

Ebola virus was discovered in 1976 by Peter Piot, who was working at the Institute of Tropical Medicine in Antwerp, Belgium. The blood of a Belgian woman who had been working in what is now the Democratic Republic of the Congo (formerly Zaire) had been sent to the institute; she and Mabalo Lokela, a school headmaster and the first recorded victim of Ebola virus, had been working near Yambuku, about 96 km from the Ebola River.

Before the 2014 outbreak, all known outbreaks had caused fewer than 2,400 cases across a dozen African countries over 3 decades.

Five species of Ebola virus

The genus Ebolavirus contains five species, each associated with a consistent case-fatality rate and a more or less well-identified endemic area.¹

Zaire ebolavirus was recognized in 1976; it has caused multiple outbreaks, with high case-fatality rates.

Sudan ebolavirus was seen first in the 1970s; it has a 50% case-fatality rate.

Tai Forest ebolavirus has been found in only one person, an ethologist working with deceased chimpanzees.

Bundibugyo ebolavirus emerged in 2007 and has a 30% case-fatality rate.

Reston ebolavirus is maintained in an animal reservoir in the Philippines and is not found in Africa. It caused an outbreak of lethal infection in macaques imported into the United States in 1989. There is evidence that Reston ebolavirus can cause asymptomatic infection in humans. None of the caretakers of the macaques became ill, nor did farmers working with infected pigs, although both groups seroconverted.

A reservoir in bats?

A reservoir in nonhuman primates was initially suspected. However, studies subsequently showed that monkeys are susceptible to rapidly lethal filoviral disease, precluding any role as a host for persistent viral infection. It is likely that Ebola virus is maintained in small animals that serve as a source of infection for both humans and wild primates. A prominent suspect is fruit bats, which are consumed in soup in West Africa.

Transmission is person-to-person or nosocomial

Ebola virus is transmitted by direct contact with body fluids such as blood, urine, sweat, vomitus, semen, and breast milk. Filoviruses can initiate infection via ingestion, inhalation (although probably not Ebola), or passage through breaks in the skin. Droplet inoculation into the mouth or eyes has been shown to result from inadvertent transfer of virus from contaminated hands. Patients transmit the virus while febrile and through later stages of disease, as well as postmortem through contact with the body during funeral preparations. The virus has been isolated in semen for as many as 61 days after illness onset.

One primary human case generates only one to three secondary cases on average, but the case-fatality rate is high

Ebola virus can also be spread nosocomially. In 1976, a 44-year-old teacher sought care for fever at the Yambuku Mission Hospital. He was given parenteral chloroquine as empiric treatment for presumed malaria, which was routine for all febrile patients. However, he had unrecognized Ebola virus infection. Moreover, syringes were rinsed in the same pan of water and reused, which spread the infection to nearly 100 people, all of whom developed fulminant Ebola virus disease and died. Infection then spread to family caregivers, the hospital staff, and those who prepared the bodies for burial.

Nosocomial transmission was also responsible for an outbreak of Lake Victoria Marburg virus in Uige Province in northern Angola in 2005, with 374 putative cases and 329 deaths. When teams from Médecins Sans Frontières started setting up the Marburg ward, there were five patients with hemorrhagic fever in a makeshift isolation room in the hospital, together with corpses that the hospital staff had been too afraid to remove. Healers found in many rural African communities were administering injections in homes or in makeshift clinics with reused needles or syringes.²

There is no evidence that filoviruses are carried by mosquitoes or other biting arthropods. Also, the risk of transmission via fomites appears to be low when currently recommended infection-control guidelines for the viral hemorrhagic fevers are followed.³ One primary human case generates only one to three secondary cases on average.

EBOLA IS AN IMMUNODEFICIENCY VIRUS

The main targets of infection are endothelial cells, mononuclear phagocytes, and hepatocytes. Ebola virus replicates at an unusually high rate. Macrophages infected with Zaire ebolavirus produce tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, macrophage chemotactic protein 1, and nitric oxide. Virus-infected macrophages synthesize cell-surface tissue factor, triggering the extrinsic coagulation pathway.

Ebola is an immunodeficiency virus. Dendritic cells, which initiate adaptive immune responses, are a major site of filoviral replication. Infected cells cannot present antigens to naïve lymphocytes. Patients who die of Ebola virus disease do not develop antibodies to the virus. Lymphocytes remain uninfected, but undergo “bystander” apoptosis induced by inflammatory mediators.

CLINICAL MANIFESTATIONS

The incubation period is generally 5 to 7 days (range 2 to 28 days), during which the patient is not infectious. Symptoms begin abruptly, with fever, chills, general malaise, weakness, severe headache, and myalgia. By the time of case detection in West Africa, most patients also had nausea, vomiting, diarrhea, and abdominal pain. Once symptoms arise, patients have high levels of the virus in their blood and fluids and are infectious. Hemorrhagic symptoms have apparently been uncommon in West Africa, occurring in 1.0% to 5.7%, but “unexplained bleeding” has been documented in 18% of cases.⁴ Among those in whom the disease enters its hemorrhagic terminal phase, there is characteristic internal and subcutaneous bleeding, vomiting of blood, and subconjunctival hemorrhage.⁴

Laboratory findings include lymphocytopenia (often with counts as low as 1.0 × 10⁹/L), thrombocytopenia (with counts in the range of 50 to 100 × 10⁹/L), elevated aminotransferase levels (including aspartate aminotransferase levels 7 to 12 times higher than alanine aminotransferase in fatal cases), low total protein (due to capillary leak), and disseminated intravascular coagulation. Those who survive begin to improve in the second week, during which viremia resolves in association with the appearance of virus-specific antibodies.⁴

DIAGNOSIS

In symptomatic patients, Ebola virus infection is diagnosed by detection in blood or body fluids of viral antigens by enzyme-linked immunosorbent assay, or RNA sequences by reverse transcriptase polymerase chain reaction. The diagnosis is confirmed with cell culture (in a BSL-4 containment laboratory) showing characteristic viral particles by electron microscopy.

CARING FOR PATIENTS

The most detailed descriptions of the care of patients with Ebola virus disease have come from Dr. Bruce Ribner, of Emory University Hospital, in an October 2014 report of his experience caring for Ebola-infected patients at Emory University Hospital in Atlanta, GA.⁵ He described fluid losses of 5 to 10 L/day, profound hyponatremia, hypokalemia, and hypocalcemia, which were associated with cardiac arrhythmias and the need for intravenous and oral electrolyte repletion and hemodialysis. Intensive one-to-one nursing was critical, as was the coordination of many medical subspecialties. The Emory team arranged point-of-care testing near the unit and generally kept laboratory testing to a minimum. The team was surprised to learn that commercial carriers refused to transport specimens even when they were licensed for category A agents. Difficulties with the local water authority and waste disposal contractor required the hospital to dedicate an autoclave to process all materials used in clinical care.

TREATMENT: SUPPORTIVE AND EXPERIMENTAL

Treatment is supportive to maintain circulatory function and blood pressure and to correct coagulopathy. However, a variety of vaccines, antibodies, small-molecule agents, and antiviral agents are undergoing testing, mostly in animals at this point.

Vaccines. A therapeutic vaccine that worked only slightly was a live-attenuated recombinant vesicular stomatitis virus expressing Ebola virus transmembrane glycoproteins, which was tested in mice, guinea pigs, and rhesus macaques who had been exposed to Ebola virus.⁶

Incubation is about 5–7 days, during which the patient is not infectious

A preventive vaccine worked better. Stanley et al⁷ evaluated a replication-defective chimpanzee adenovirus 3-vectored vaccine that also contained Ebola virus glycoprotein. They gave macaques a single injection of this vaccine, and then 5 weeks later gave them a lethal dose of Ebola virus. All the vaccinated animals survived the infection, and half (2 of 4) survived when challenged 10 months later. With a prime-boost strategy (modified vaccinia virus Ankara, a poxvirus), all survived when challenged 10 months later.

KZ52, a neutralizing antibody, did not work. Oswald et al⁸ gave a human IgG monoclonal antibody against Zaire Ebola virus, designated KZ52, to four rhesus macaques, challenged them with the virus 24 hours later, and administered a second shot of KZ52 on day 4. All of them died.

ZMAb is a combination of three murine monoclonal antibodies, designated 1H3, 2G4, and 4G7. Ad-IFN is a human adenovirus, serotype 5, that expresses human interferon alpha. Qui et al⁹ gave ZMAb and Ad-IFN to macaques in several experiments. In experiment 1, eight macaques were infected and then were given ZMAb and Ad-IFN 3 days later, and ZMAb again on days 6 and 9. Seven of the eight survived. In a second experiment, Ad-IFN was given first, when the viral load was still less than the limit of detection of known assays, and then ZMAb was given upon detection of viremia and fever. Two of four macaques survived. Control animals had undetectable levels of IgG, whereas Ebola virus GP–specific IgG levels were detected in all survivors. IFN-gamma ELISpots showed high EBOV-GP–specific T-cell response in all survivors.

ZMapp is another cocktail of monoclonal antibodies, containing two from ZMab (2G4 and 4G7), plus a third, c13C6. In experiments in rhesus macaques, three groups of six animals each received three doses of ZMapp at varying times after being infected with Ebola virus: at 3, 6, and 9 days; at 4, 7, and 10 days, and at 5, 8, and 11 days. All 18 macaques treated with ZMapp survived. Thus, Zmapp extended the treatment window to 5 days postexposure.¹⁰ One of the American health care workers who contracted Ebola virus in Liberia received this medication.

HSPA5-PMO. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5) is instrumental in the maturation of envelope proteins in hepatitis C and influenza A virus. It plays a role in viral entry for coxsackievirus A9 and dengue virus serotype 2, and it may be involved in Ebola viral budding. Phosphorodiamidate morpholino oligomers (PMOs) are a class of antisense DNA nucleotide analogs.

Reid et al¹¹ reported that mice treated with HSPA5–PMO were completely protected from lethal Ebola challenge. Therefore, HSPA5 appears to be a promising target for the development of antifilovirus countermeasures.

Favipiravir, an antiviral agent also known as T-705, is a pyrazinecarboxamide derivative. Invented in 2002 by Toyama Chemicals as an inhibitor of influenza virus replication, it acts as a nucleotide analog, selectively inhibiting the viral RNA-dependent RNA polymerase, or causes lethal mutagenesis upon incorporation into the virus RNA. Favipiravir suppresses Ebola virus replication by 4 log₁₀ units in cell culture.¹²

Mice were challenged with intranasal inoculation of 1,000 focus-forming units of Ebola virus diluted in phosphate-buffered saline. Until the first day of treatment (postinfection day 6), all mice in the T-705 group lost weight similarly to control mice, developed viremia, and showed elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Within 4 days of T-705 treatment (post-infection day 10), the animals had cleared the virus from blood. Surviving mice developed Ebola virus-specific antibodies and CD8+ T cells specific for the viral nucleoprotein.¹²

The authors hypothesized that suppression of virus replication by T-705 allowed the host to mount a virus-specific adaptive immune response, and concluded that T-705 was 100% effective in the treatment of Zaire Ebola virus infection up to postinfection day 6 but was hardly beneficial at the terminal stage of disease.¹² Of note, favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan.

THE CURRENT OUTBREAK

The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.¹³

The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.¹⁴

As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.¹⁵

Favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan

But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.

Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.¹

LIMITED CAPACITY, EVEN IN THE UNITED STATES

A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.

QUESTIONS, ANSWERS—AND MORE QUESTIONS

(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)

Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al¹⁶ analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.

Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown¹⁷ that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.

Mutations are occurring but are not changing the characteristics of the Ebola virus

Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.

Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.

Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.

Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.

Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.

Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.

Q: How long does the virus remain viable outside the body? A: In one study,¹⁸ Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,¹⁹ Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.

Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.³

Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.

Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.

Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.

Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.¹⁴

BACK TO OUR PATIENT

The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.

A 50-year-old man who returned from a business trip to Nigeria 24 days ago presents with complaints of the sudden onset of fever, diarrhea, myalgia, and headache. He reports 10 bowel movements per day and has seen bloody stools.

During his trip he flew in to Murtala Muhammed International Airport in Lagos, ate meals only in his hotel, and attended meetings in Lagos central business district. He had no exposure to animals, mosquitoes, ticks, or sick people, and no sexual activity. After returning home, he felt well for the first 3 weeks.

The patient has a history of hypertension. He does not smoke, drink alcohol, or use injection drugs. He is married, works with commercial banks and financial institutions, and lives in Cleveland, OH.

On physical examination his temperature is 100.0˚F (37.8˚C), pulse 98, respirations 15, blood pressure 105/70 mm Hg, and weight 78 kg (172 lb). He appears comfortable but is a little diaphoretic. His abdomen is tender to palpation in the epigastrium and slightly to the right; he has no signs of peritonitis. His skin is without rash, bleeding, or bruising. The remainder of the examination is normal.

His white blood cell count is 17 × 10⁹/L, hemoglobin 15 g/dL, hematocrit 41%, and platelet count 172 × 10⁹/L. His sodium level is 126 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, carbon dioxide 20 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.7 mg/dL, and glucose 130 mg/dL. His aminotransferase and alkaline phosphatase levels are normal.

Could this patient have Ebola virus disease?

With Ebola virus disease on the rise in West Africa, physicians who encounter patients like this one need to include it in the differential diagnosis. Because the disease is new, many questions are raised for which we as yet have no answers. Here, I will review what we know and do not know in an effort to remove some of the fear and uncertainty.

A NEW DISEASE

Ebola virus disease is a severe hemorrhagic fever caused by negative-sense single-stranded RNA viruses classified by the International Committee on Taxonomy of Viruses as belonging to the genus Ebolavirus in the family Filoviridae. Filoviruses get their name from the Latin filum, or thread-like structure.

The family Filoviridae was discovered in 1967 after inadvertent importation of infected monkeys from Uganda into Yugoslavia and Marburg, Germany. Outbreaks of severe illness occurred in workers at a vaccine plant who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production.

Ebola virus was discovered in 1976 by Peter Piot, who was working at the Institute of Tropical Medicine in Antwerp, Belgium. The blood of a Belgian woman who had been working in what is now the Democratic Republic of the Congo (formerly Zaire) had been sent to the institute; she and Mabalo Lokela, a school headmaster and the first recorded victim of Ebola virus, had been working near Yambuku, about 96 km from the Ebola River.

Before the 2014 outbreak, all known outbreaks had caused fewer than 2,400 cases across a dozen African countries over 3 decades.

Five species of Ebola virus

The genus Ebolavirus contains five species, each associated with a consistent case-fatality rate and a more or less well-identified endemic area.¹

Zaire ebolavirus was recognized in 1976; it has caused multiple outbreaks, with high case-fatality rates.

Sudan ebolavirus was seen first in the 1970s; it has a 50% case-fatality rate.

Tai Forest ebolavirus has been found in only one person, an ethologist working with deceased chimpanzees.

Bundibugyo ebolavirus emerged in 2007 and has a 30% case-fatality rate.

Reston ebolavirus is maintained in an animal reservoir in the Philippines and is not found in Africa. It caused an outbreak of lethal infection in macaques imported into the United States in 1989. There is evidence that Reston ebolavirus can cause asymptomatic infection in humans. None of the caretakers of the macaques became ill, nor did farmers working with infected pigs, although both groups seroconverted.

A reservoir in bats?

A reservoir in nonhuman primates was initially suspected. However, studies subsequently showed that monkeys are susceptible to rapidly lethal filoviral disease, precluding any role as a host for persistent viral infection. It is likely that Ebola virus is maintained in small animals that serve as a source of infection for both humans and wild primates. A prominent suspect is fruit bats, which are consumed in soup in West Africa.

Transmission is person-to-person or nosocomial

Ebola virus is transmitted by direct contact with body fluids such as blood, urine, sweat, vomitus, semen, and breast milk. Filoviruses can initiate infection via ingestion, inhalation (although probably not Ebola), or passage through breaks in the skin. Droplet inoculation into the mouth or eyes has been shown to result from inadvertent transfer of virus from contaminated hands. Patients transmit the virus while febrile and through later stages of disease, as well as postmortem through contact with the body during funeral preparations. The virus has been isolated in semen for as many as 61 days after illness onset.

One primary human case generates only one to three secondary cases on average, but the case-fatality rate is high

Ebola virus can also be spread nosocomially. In 1976, a 44-year-old teacher sought care for fever at the Yambuku Mission Hospital. He was given parenteral chloroquine as empiric treatment for presumed malaria, which was routine for all febrile patients. However, he had unrecognized Ebola virus infection. Moreover, syringes were rinsed in the same pan of water and reused, which spread the infection to nearly 100 people, all of whom developed fulminant Ebola virus disease and died. Infection then spread to family caregivers, the hospital staff, and those who prepared the bodies for burial.

Nosocomial transmission was also responsible for an outbreak of Lake Victoria Marburg virus in Uige Province in northern Angola in 2005, with 374 putative cases and 329 deaths. When teams from Médecins Sans Frontières started setting up the Marburg ward, there were five patients with hemorrhagic fever in a makeshift isolation room in the hospital, together with corpses that the hospital staff had been too afraid to remove. Healers found in many rural African communities were administering injections in homes or in makeshift clinics with reused needles or syringes.²

There is no evidence that filoviruses are carried by mosquitoes or other biting arthropods. Also, the risk of transmission via fomites appears to be low when currently recommended infection-control guidelines for the viral hemorrhagic fevers are followed.³ One primary human case generates only one to three secondary cases on average.

EBOLA IS AN IMMUNODEFICIENCY VIRUS

The main targets of infection are endothelial cells, mononuclear phagocytes, and hepatocytes. Ebola virus replicates at an unusually high rate. Macrophages infected with Zaire ebolavirus produce tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, macrophage chemotactic protein 1, and nitric oxide. Virus-infected macrophages synthesize cell-surface tissue factor, triggering the extrinsic coagulation pathway.

Ebola is an immunodeficiency virus. Dendritic cells, which initiate adaptive immune responses, are a major site of filoviral replication. Infected cells cannot present antigens to naïve lymphocytes. Patients who die of Ebola virus disease do not develop antibodies to the virus. Lymphocytes remain uninfected, but undergo “bystander” apoptosis induced by inflammatory mediators.

CLINICAL MANIFESTATIONS

The incubation period is generally 5 to 7 days (range 2 to 28 days), during which the patient is not infectious. Symptoms begin abruptly, with fever, chills, general malaise, weakness, severe headache, and myalgia. By the time of case detection in West Africa, most patients also had nausea, vomiting, diarrhea, and abdominal pain. Once symptoms arise, patients have high levels of the virus in their blood and fluids and are infectious. Hemorrhagic symptoms have apparently been uncommon in West Africa, occurring in 1.0% to 5.7%, but “unexplained bleeding” has been documented in 18% of cases.⁴ Among those in whom the disease enters its hemorrhagic terminal phase, there is characteristic internal and subcutaneous bleeding, vomiting of blood, and subconjunctival hemorrhage.⁴

Laboratory findings include lymphocytopenia (often with counts as low as 1.0 × 10⁹/L), thrombocytopenia (with counts in the range of 50 to 100 × 10⁹/L), elevated aminotransferase levels (including aspartate aminotransferase levels 7 to 12 times higher than alanine aminotransferase in fatal cases), low total protein (due to capillary leak), and disseminated intravascular coagulation. Those who survive begin to improve in the second week, during which viremia resolves in association with the appearance of virus-specific antibodies.⁴

DIAGNOSIS

In symptomatic patients, Ebola virus infection is diagnosed by detection in blood or body fluids of viral antigens by enzyme-linked immunosorbent assay, or RNA sequences by reverse transcriptase polymerase chain reaction. The diagnosis is confirmed with cell culture (in a BSL-4 containment laboratory) showing characteristic viral particles by electron microscopy.

CARING FOR PATIENTS

The most detailed descriptions of the care of patients with Ebola virus disease have come from Dr. Bruce Ribner, of Emory University Hospital, in an October 2014 report of his experience caring for Ebola-infected patients at Emory University Hospital in Atlanta, GA.⁵ He described fluid losses of 5 to 10 L/day, profound hyponatremia, hypokalemia, and hypocalcemia, which were associated with cardiac arrhythmias and the need for intravenous and oral electrolyte repletion and hemodialysis. Intensive one-to-one nursing was critical, as was the coordination of many medical subspecialties. The Emory team arranged point-of-care testing near the unit and generally kept laboratory testing to a minimum. The team was surprised to learn that commercial carriers refused to transport specimens even when they were licensed for category A agents. Difficulties with the local water authority and waste disposal contractor required the hospital to dedicate an autoclave to process all materials used in clinical care.

TREATMENT: SUPPORTIVE AND EXPERIMENTAL

Treatment is supportive to maintain circulatory function and blood pressure and to correct coagulopathy. However, a variety of vaccines, antibodies, small-molecule agents, and antiviral agents are undergoing testing, mostly in animals at this point.

Vaccines. A therapeutic vaccine that worked only slightly was a live-attenuated recombinant vesicular stomatitis virus expressing Ebola virus transmembrane glycoproteins, which was tested in mice, guinea pigs, and rhesus macaques who had been exposed to Ebola virus.⁶

Incubation is about 5–7 days, during which the patient is not infectious

A preventive vaccine worked better. Stanley et al⁷ evaluated a replication-defective chimpanzee adenovirus 3-vectored vaccine that also contained Ebola virus glycoprotein. They gave macaques a single injection of this vaccine, and then 5 weeks later gave them a lethal dose of Ebola virus. All the vaccinated animals survived the infection, and half (2 of 4) survived when challenged 10 months later. With a prime-boost strategy (modified vaccinia virus Ankara, a poxvirus), all survived when challenged 10 months later.

KZ52, a neutralizing antibody, did not work. Oswald et al⁸ gave a human IgG monoclonal antibody against Zaire Ebola virus, designated KZ52, to four rhesus macaques, challenged them with the virus 24 hours later, and administered a second shot of KZ52 on day 4. All of them died.

ZMAb is a combination of three murine monoclonal antibodies, designated 1H3, 2G4, and 4G7. Ad-IFN is a human adenovirus, serotype 5, that expresses human interferon alpha. Qui et al⁹ gave ZMAb and Ad-IFN to macaques in several experiments. In experiment 1, eight macaques were infected and then were given ZMAb and Ad-IFN 3 days later, and ZMAb again on days 6 and 9. Seven of the eight survived. In a second experiment, Ad-IFN was given first, when the viral load was still less than the limit of detection of known assays, and then ZMAb was given upon detection of viremia and fever. Two of four macaques survived. Control animals had undetectable levels of IgG, whereas Ebola virus GP–specific IgG levels were detected in all survivors. IFN-gamma ELISpots showed high EBOV-GP–specific T-cell response in all survivors.

ZMapp is another cocktail of monoclonal antibodies, containing two from ZMab (2G4 and 4G7), plus a third, c13C6. In experiments in rhesus macaques, three groups of six animals each received three doses of ZMapp at varying times after being infected with Ebola virus: at 3, 6, and 9 days; at 4, 7, and 10 days, and at 5, 8, and 11 days. All 18 macaques treated with ZMapp survived. Thus, Zmapp extended the treatment window to 5 days postexposure.¹⁰ One of the American health care workers who contracted Ebola virus in Liberia received this medication.

HSPA5-PMO. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5) is instrumental in the maturation of envelope proteins in hepatitis C and influenza A virus. It plays a role in viral entry for coxsackievirus A9 and dengue virus serotype 2, and it may be involved in Ebola viral budding. Phosphorodiamidate morpholino oligomers (PMOs) are a class of antisense DNA nucleotide analogs.

Reid et al¹¹ reported that mice treated with HSPA5–PMO were completely protected from lethal Ebola challenge. Therefore, HSPA5 appears to be a promising target for the development of antifilovirus countermeasures.

Favipiravir, an antiviral agent also known as T-705, is a pyrazinecarboxamide derivative. Invented in 2002 by Toyama Chemicals as an inhibitor of influenza virus replication, it acts as a nucleotide analog, selectively inhibiting the viral RNA-dependent RNA polymerase, or causes lethal mutagenesis upon incorporation into the virus RNA. Favipiravir suppresses Ebola virus replication by 4 log₁₀ units in cell culture.¹²

Mice were challenged with intranasal inoculation of 1,000 focus-forming units of Ebola virus diluted in phosphate-buffered saline. Until the first day of treatment (postinfection day 6), all mice in the T-705 group lost weight similarly to control mice, developed viremia, and showed elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Within 4 days of T-705 treatment (post-infection day 10), the animals had cleared the virus from blood. Surviving mice developed Ebola virus-specific antibodies and CD8+ T cells specific for the viral nucleoprotein.¹²

The authors hypothesized that suppression of virus replication by T-705 allowed the host to mount a virus-specific adaptive immune response, and concluded that T-705 was 100% effective in the treatment of Zaire Ebola virus infection up to postinfection day 6 but was hardly beneficial at the terminal stage of disease.¹² Of note, favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan.

THE CURRENT OUTBREAK

The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.¹³

The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.¹⁴

As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.¹⁵

Favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan

But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.

Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.¹

LIMITED CAPACITY, EVEN IN THE UNITED STATES

A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.

QUESTIONS, ANSWERS—AND MORE QUESTIONS

(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)

Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al¹⁶ analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.

Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown¹⁷ that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.

Mutations are occurring but are not changing the characteristics of the Ebola virus

Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.

Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.

Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.

Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.

Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.

Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.

Q: How long does the virus remain viable outside the body? A: In one study,¹⁸ Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,¹⁹ Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.

Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.³

Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.

Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.

Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.

Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.¹⁴

BACK TO OUR PATIENT

The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.

A 50-year-old man who returned from a business trip to Nigeria 24 days ago presents with complaints of the sudden onset of fever, diarrhea, myalgia, and headache. He reports 10 bowel movements per day and has seen bloody stools.

During his trip he flew in to Murtala Muhammed International Airport in Lagos, ate meals only in his hotel, and attended meetings in Lagos central business district. He had no exposure to animals, mosquitoes, ticks, or sick people, and no sexual activity. After returning home, he felt well for the first 3 weeks.

The patient has a history of hypertension. He does not smoke, drink alcohol, or use injection drugs. He is married, works with commercial banks and financial institutions, and lives in Cleveland, OH.

On physical examination his temperature is 100.0˚F (37.8˚C), pulse 98, respirations 15, blood pressure 105/70 mm Hg, and weight 78 kg (172 lb). He appears comfortable but is a little diaphoretic. His abdomen is tender to palpation in the epigastrium and slightly to the right; he has no signs of peritonitis. His skin is without rash, bleeding, or bruising. The remainder of the examination is normal.

His white blood cell count is 17 × 10⁹/L, hemoglobin 15 g/dL, hematocrit 41%, and platelet count 172 × 10⁹/L. His sodium level is 126 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, carbon dioxide 20 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.7 mg/dL, and glucose 130 mg/dL. His aminotransferase and alkaline phosphatase levels are normal.

Could this patient have Ebola virus disease?

With Ebola virus disease on the rise in West Africa, physicians who encounter patients like this one need to include it in the differential diagnosis. Because the disease is new, many questions are raised for which we as yet have no answers. Here, I will review what we know and do not know in an effort to remove some of the fear and uncertainty.

A NEW DISEASE

Ebola virus disease is a severe hemorrhagic fever caused by negative-sense single-stranded RNA viruses classified by the International Committee on Taxonomy of Viruses as belonging to the genus Ebolavirus in the family Filoviridae. Filoviruses get their name from the Latin filum, or thread-like structure.

The family Filoviridae was discovered in 1967 after inadvertent importation of infected monkeys from Uganda into Yugoslavia and Marburg, Germany. Outbreaks of severe illness occurred in workers at a vaccine plant who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production.

Ebola virus was discovered in 1976 by Peter Piot, who was working at the Institute of Tropical Medicine in Antwerp, Belgium. The blood of a Belgian woman who had been working in what is now the Democratic Republic of the Congo (formerly Zaire) had been sent to the institute; she and Mabalo Lokela, a school headmaster and the first recorded victim of Ebola virus, had been working near Yambuku, about 96 km from the Ebola River.

Before the 2014 outbreak, all known outbreaks had caused fewer than 2,400 cases across a dozen African countries over 3 decades.

Five species of Ebola virus

The genus Ebolavirus contains five species, each associated with a consistent case-fatality rate and a more or less well-identified endemic area.¹

Zaire ebolavirus was recognized in 1976; it has caused multiple outbreaks, with high case-fatality rates.

Sudan ebolavirus was seen first in the 1970s; it has a 50% case-fatality rate.

Tai Forest ebolavirus has been found in only one person, an ethologist working with deceased chimpanzees.

Bundibugyo ebolavirus emerged in 2007 and has a 30% case-fatality rate.

Reston ebolavirus is maintained in an animal reservoir in the Philippines and is not found in Africa. It caused an outbreak of lethal infection in macaques imported into the United States in 1989. There is evidence that Reston ebolavirus can cause asymptomatic infection in humans. None of the caretakers of the macaques became ill, nor did farmers working with infected pigs, although both groups seroconverted.

A reservoir in bats?

A reservoir in nonhuman primates was initially suspected. However, studies subsequently showed that monkeys are susceptible to rapidly lethal filoviral disease, precluding any role as a host for persistent viral infection. It is likely that Ebola virus is maintained in small animals that serve as a source of infection for both humans and wild primates. A prominent suspect is fruit bats, which are consumed in soup in West Africa.

Transmission is person-to-person or nosocomial

Ebola virus is transmitted by direct contact with body fluids such as blood, urine, sweat, vomitus, semen, and breast milk. Filoviruses can initiate infection via ingestion, inhalation (although probably not Ebola), or passage through breaks in the skin. Droplet inoculation into the mouth or eyes has been shown to result from inadvertent transfer of virus from contaminated hands. Patients transmit the virus while febrile and through later stages of disease, as well as postmortem through contact with the body during funeral preparations. The virus has been isolated in semen for as many as 61 days after illness onset.

One primary human case generates only one to three secondary cases on average, but the case-fatality rate is high

Ebola virus can also be spread nosocomially. In 1976, a 44-year-old teacher sought care for fever at the Yambuku Mission Hospital. He was given parenteral chloroquine as empiric treatment for presumed malaria, which was routine for all febrile patients. However, he had unrecognized Ebola virus infection. Moreover, syringes were rinsed in the same pan of water and reused, which spread the infection to nearly 100 people, all of whom developed fulminant Ebola virus disease and died. Infection then spread to family caregivers, the hospital staff, and those who prepared the bodies for burial.

Nosocomial transmission was also responsible for an outbreak of Lake Victoria Marburg virus in Uige Province in northern Angola in 2005, with 374 putative cases and 329 deaths. When teams from Médecins Sans Frontières started setting up the Marburg ward, there were five patients with hemorrhagic fever in a makeshift isolation room in the hospital, together with corpses that the hospital staff had been too afraid to remove. Healers found in many rural African communities were administering injections in homes or in makeshift clinics with reused needles or syringes.²

There is no evidence that filoviruses are carried by mosquitoes or other biting arthropods. Also, the risk of transmission via fomites appears to be low when currently recommended infection-control guidelines for the viral hemorrhagic fevers are followed.³ One primary human case generates only one to three secondary cases on average.

EBOLA IS AN IMMUNODEFICIENCY VIRUS

The main targets of infection are endothelial cells, mononuclear phagocytes, and hepatocytes. Ebola virus replicates at an unusually high rate. Macrophages infected with Zaire ebolavirus produce tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, macrophage chemotactic protein 1, and nitric oxide. Virus-infected macrophages synthesize cell-surface tissue factor, triggering the extrinsic coagulation pathway.

Ebola is an immunodeficiency virus. Dendritic cells, which initiate adaptive immune responses, are a major site of filoviral replication. Infected cells cannot present antigens to naïve lymphocytes. Patients who die of Ebola virus disease do not develop antibodies to the virus. Lymphocytes remain uninfected, but undergo “bystander” apoptosis induced by inflammatory mediators.

CLINICAL MANIFESTATIONS

The incubation period is generally 5 to 7 days (range 2 to 28 days), during which the patient is not infectious. Symptoms begin abruptly, with fever, chills, general malaise, weakness, severe headache, and myalgia. By the time of case detection in West Africa, most patients also had nausea, vomiting, diarrhea, and abdominal pain. Once symptoms arise, patients have high levels of the virus in their blood and fluids and are infectious. Hemorrhagic symptoms have apparently been uncommon in West Africa, occurring in 1.0% to 5.7%, but “unexplained bleeding” has been documented in 18% of cases.⁴ Among those in whom the disease enters its hemorrhagic terminal phase, there is characteristic internal and subcutaneous bleeding, vomiting of blood, and subconjunctival hemorrhage.⁴

Laboratory findings include lymphocytopenia (often with counts as low as 1.0 × 10⁹/L), thrombocytopenia (with counts in the range of 50 to 100 × 10⁹/L), elevated aminotransferase levels (including aspartate aminotransferase levels 7 to 12 times higher than alanine aminotransferase in fatal cases), low total protein (due to capillary leak), and disseminated intravascular coagulation. Those who survive begin to improve in the second week, during which viremia resolves in association with the appearance of virus-specific antibodies.⁴

DIAGNOSIS

In symptomatic patients, Ebola virus infection is diagnosed by detection in blood or body fluids of viral antigens by enzyme-linked immunosorbent assay, or RNA sequences by reverse transcriptase polymerase chain reaction. The diagnosis is confirmed with cell culture (in a BSL-4 containment laboratory) showing characteristic viral particles by electron microscopy.

CARING FOR PATIENTS

The most detailed descriptions of the care of patients with Ebola virus disease have come from Dr. Bruce Ribner, of Emory University Hospital, in an October 2014 report of his experience caring for Ebola-infected patients at Emory University Hospital in Atlanta, GA.⁵ He described fluid losses of 5 to 10 L/day, profound hyponatremia, hypokalemia, and hypocalcemia, which were associated with cardiac arrhythmias and the need for intravenous and oral electrolyte repletion and hemodialysis. Intensive one-to-one nursing was critical, as was the coordination of many medical subspecialties. The Emory team arranged point-of-care testing near the unit and generally kept laboratory testing to a minimum. The team was surprised to learn that commercial carriers refused to transport specimens even when they were licensed for category A agents. Difficulties with the local water authority and waste disposal contractor required the hospital to dedicate an autoclave to process all materials used in clinical care.

TREATMENT: SUPPORTIVE AND EXPERIMENTAL

Treatment is supportive to maintain circulatory function and blood pressure and to correct coagulopathy. However, a variety of vaccines, antibodies, small-molecule agents, and antiviral agents are undergoing testing, mostly in animals at this point.

Vaccines. A therapeutic vaccine that worked only slightly was a live-attenuated recombinant vesicular stomatitis virus expressing Ebola virus transmembrane glycoproteins, which was tested in mice, guinea pigs, and rhesus macaques who had been exposed to Ebola virus.⁶

Incubation is about 5–7 days, during which the patient is not infectious

A preventive vaccine worked better. Stanley et al⁷ evaluated a replication-defective chimpanzee adenovirus 3-vectored vaccine that also contained Ebola virus glycoprotein. They gave macaques a single injection of this vaccine, and then 5 weeks later gave them a lethal dose of Ebola virus. All the vaccinated animals survived the infection, and half (2 of 4) survived when challenged 10 months later. With a prime-boost strategy (modified vaccinia virus Ankara, a poxvirus), all survived when challenged 10 months later.

KZ52, a neutralizing antibody, did not work. Oswald et al⁸ gave a human IgG monoclonal antibody against Zaire Ebola virus, designated KZ52, to four rhesus macaques, challenged them with the virus 24 hours later, and administered a second shot of KZ52 on day 4. All of them died.

ZMAb is a combination of three murine monoclonal antibodies, designated 1H3, 2G4, and 4G7. Ad-IFN is a human adenovirus, serotype 5, that expresses human interferon alpha. Qui et al⁹ gave ZMAb and Ad-IFN to macaques in several experiments. In experiment 1, eight macaques were infected and then were given ZMAb and Ad-IFN 3 days later, and ZMAb again on days 6 and 9. Seven of the eight survived. In a second experiment, Ad-IFN was given first, when the viral load was still less than the limit of detection of known assays, and then ZMAb was given upon detection of viremia and fever. Two of four macaques survived. Control animals had undetectable levels of IgG, whereas Ebola virus GP–specific IgG levels were detected in all survivors. IFN-gamma ELISpots showed high EBOV-GP–specific T-cell response in all survivors.

ZMapp is another cocktail of monoclonal antibodies, containing two from ZMab (2G4 and 4G7), plus a third, c13C6. In experiments in rhesus macaques, three groups of six animals each received three doses of ZMapp at varying times after being infected with Ebola virus: at 3, 6, and 9 days; at 4, 7, and 10 days, and at 5, 8, and 11 days. All 18 macaques treated with ZMapp survived. Thus, Zmapp extended the treatment window to 5 days postexposure.¹⁰ One of the American health care workers who contracted Ebola virus in Liberia received this medication.

HSPA5-PMO. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5) is instrumental in the maturation of envelope proteins in hepatitis C and influenza A virus. It plays a role in viral entry for coxsackievirus A9 and dengue virus serotype 2, and it may be involved in Ebola viral budding. Phosphorodiamidate morpholino oligomers (PMOs) are a class of antisense DNA nucleotide analogs.

Reid et al¹¹ reported that mice treated with HSPA5–PMO were completely protected from lethal Ebola challenge. Therefore, HSPA5 appears to be a promising target for the development of antifilovirus countermeasures.

Favipiravir, an antiviral agent also known as T-705, is a pyrazinecarboxamide derivative. Invented in 2002 by Toyama Chemicals as an inhibitor of influenza virus replication, it acts as a nucleotide analog, selectively inhibiting the viral RNA-dependent RNA polymerase, or causes lethal mutagenesis upon incorporation into the virus RNA. Favipiravir suppresses Ebola virus replication by 4 log₁₀ units in cell culture.¹²

Mice were challenged with intranasal inoculation of 1,000 focus-forming units of Ebola virus diluted in phosphate-buffered saline. Until the first day of treatment (postinfection day 6), all mice in the T-705 group lost weight similarly to control mice, developed viremia, and showed elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Within 4 days of T-705 treatment (post-infection day 10), the animals had cleared the virus from blood. Surviving mice developed Ebola virus-specific antibodies and CD8+ T cells specific for the viral nucleoprotein.¹²

The authors hypothesized that suppression of virus replication by T-705 allowed the host to mount a virus-specific adaptive immune response, and concluded that T-705 was 100% effective in the treatment of Zaire Ebola virus infection up to postinfection day 6 but was hardly beneficial at the terminal stage of disease.¹² Of note, favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan.

THE CURRENT OUTBREAK

The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.¹³

The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.¹⁴

As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.¹⁵

Favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan

But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.

Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.¹

LIMITED CAPACITY, EVEN IN THE UNITED STATES

A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.

QUESTIONS, ANSWERS—AND MORE QUESTIONS

(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)

Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al¹⁶ analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.

Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown¹⁷ that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.

Mutations are occurring but are not changing the characteristics of the Ebola virus

Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.

Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.

Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.

Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.

Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.

Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.

Q: How long does the virus remain viable outside the body? A: In one study,¹⁸ Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,¹⁹ Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.

Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.³

Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.

Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.

Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.

Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.¹⁴

BACK TO OUR PATIENT

The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.

Among the items featured in Dr David Henry’s monthly podcast for The Journal of Community and Supportive Oncology, are reports on congestive heart failure during induction with anthracycline-based therapy in patients with acute promyelocytic leukemia and on the impact of aprepitant on emesis control, dose intensity, and recurrence-free survival in head and neck cancer patients on cisplatin chemotherapy. Two articles focus on patient quality of life: one examines peripheral neuropathy and its impact on QoL after chemotherapy and another looks at QoL and symptoms after stereotactic body radiotherapy in early-stage lung cancer. There’s also a Case Report about a patient with superior vena cava syndrome as an initial presentation of low-grade follicular lymphoma, a feature article on choice of anesthesia during cancer surgery and patient outcomes, and a comprehensive and informative round-up of ASCO’s 2013-2014 guideline releases, updates, and endorsements.

Among the items featured in Dr David Henry’s monthly podcast for The Journal of Community and Supportive Oncology, are reports on congestive heart failure during induction with anthracycline-based therapy in patients with acute promyelocytic leukemia and on the impact of aprepitant on emesis control, dose intensity, and recurrence-free survival in head and neck cancer patients on cisplatin chemotherapy. Two articles focus on patient quality of life: one examines peripheral neuropathy and its impact on QoL after chemotherapy and another looks at QoL and symptoms after stereotactic body radiotherapy in early-stage lung cancer. There’s also a Case Report about a patient with superior vena cava syndrome as an initial presentation of low-grade follicular lymphoma, a feature article on choice of anesthesia during cancer surgery and patient outcomes, and a comprehensive and informative round-up of ASCO’s 2013-2014 guideline releases, updates, and endorsements.

Among the items featured in Dr David Henry’s monthly podcast for The Journal of Community and Supportive Oncology, are reports on congestive heart failure during induction with anthracycline-based therapy in patients with acute promyelocytic leukemia and on the impact of aprepitant on emesis control, dose intensity, and recurrence-free survival in head and neck cancer patients on cisplatin chemotherapy. Two articles focus on patient quality of life: one examines peripheral neuropathy and its impact on QoL after chemotherapy and another looks at QoL and symptoms after stereotactic body radiotherapy in early-stage lung cancer. There’s also a Case Report about a patient with superior vena cava syndrome as an initial presentation of low-grade follicular lymphoma, a feature article on choice of anesthesia during cancer surgery and patient outcomes, and a comprehensive and informative round-up of ASCO’s 2013-2014 guideline releases, updates, and endorsements.

Thrombus

Credit: Andre E.X. Brown

Health Canada has expanded the indication for the oral anticoagulant apixaban (Eliquis).

The direct factor Xa inhibitor can now be used to prevent venous thromboembolism (VTE) in adult patients who have undergone elective total hip surgery or knee replacement surgery.

The drug was already approved in Canada to treat and prevent recurrent VTE and for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

“The development of VTE or pulmonary embolism is an important risk for patients having major orthopedic surgery such as total knee or hip replacement,” said John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

“The approval of apixaban gives Canadian surgeons a new option to help prevent VTE in these patients. As an oral option for patients in hospital and once they return home after surgery, where most clotting complications can take place after they are discharged from hospital, apixaban offers patients an alternative to an injected anticoagulant.”

Health Canada’s approval of apixaban is based on results of the ADVANCE clinical trials. In these trials, researchers randomized 11,659 patients and assessed the efficacy and safety of apixaban compared to enoxaparin.

The primary efficacy endpoint of the trials was the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure was the composite of major and clinically relevant nonmajor bleeding.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

Apixaban is under development in Canada by Bristol-Myers Squibb and Pfizer Canada Inc. For more details on the drug, see the product monograph.

Thrombus

Credit: Andre E.X. Brown

Health Canada has expanded the indication for the oral anticoagulant apixaban (Eliquis).

The direct factor Xa inhibitor can now be used to prevent venous thromboembolism (VTE) in adult patients who have undergone elective total hip surgery or knee replacement surgery.

The drug was already approved in Canada to treat and prevent recurrent VTE and for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

“The development of VTE or pulmonary embolism is an important risk for patients having major orthopedic surgery such as total knee or hip replacement,” said John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

“The approval of apixaban gives Canadian surgeons a new option to help prevent VTE in these patients. As an oral option for patients in hospital and once they return home after surgery, where most clotting complications can take place after they are discharged from hospital, apixaban offers patients an alternative to an injected anticoagulant.”

Health Canada’s approval of apixaban is based on results of the ADVANCE clinical trials. In these trials, researchers randomized 11,659 patients and assessed the efficacy and safety of apixaban compared to enoxaparin.

The primary efficacy endpoint of the trials was the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure was the composite of major and clinically relevant nonmajor bleeding.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

Apixaban is under development in Canada by Bristol-Myers Squibb and Pfizer Canada Inc. For more details on the drug, see the product monograph.

Thrombus

Credit: Andre E.X. Brown

Health Canada has expanded the indication for the oral anticoagulant apixaban (Eliquis).

The direct factor Xa inhibitor can now be used to prevent venous thromboembolism (VTE) in adult patients who have undergone elective total hip surgery or knee replacement surgery.

The drug was already approved in Canada to treat and prevent recurrent VTE and for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

“The development of VTE or pulmonary embolism is an important risk for patients having major orthopedic surgery such as total knee or hip replacement,” said John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

“The approval of apixaban gives Canadian surgeons a new option to help prevent VTE in these patients. As an oral option for patients in hospital and once they return home after surgery, where most clotting complications can take place after they are discharged from hospital, apixaban offers patients an alternative to an injected anticoagulant.”

Health Canada’s approval of apixaban is based on results of the ADVANCE clinical trials. In these trials, researchers randomized 11,659 patients and assessed the efficacy and safety of apixaban compared to enoxaparin.

The primary efficacy endpoint of the trials was the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure was the composite of major and clinically relevant nonmajor bleeding.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

Apixaban is under development in Canada by Bristol-Myers Squibb and Pfizer Canada Inc. For more details on the drug, see the product monograph.

Anopheles albimanus mosquito

Credit: James Gathany

Two studies comparing mosquito genomes have begun to provide answers to a century-old mystery: why only some Anopheles mosquitoes transmit human malaria.

There are more than 400 species of Anopheles mosquitoes, but only about 60 transmit parasites that cause malaria in humans.

Variation in the ability to transmit malaria, or “vectorial capacity,” is determined by many factors, including feeding and breeding preferences, as well as immune responses to infections.

Much of our understanding of such processes is derived from the sequencing of the Anopheles gambiae genome in 2002, which facilitated large-scale functional studies that have offered insights into how this mosquito became highly specialized to live among and feed upon humans.

The lack of such genomic resources for other Anopheles species limited comparisons to small-scale studies of individual genes with no genome-wide data to investigate key attributes that impact the mosquitoes’ ability to transmit parasites.

In an attempt to change that, Daniel Neafsey, PhD, of the Broad Institute in Cambridge, Massachusetts, and his colleagues sequenced the genomes of 16 anopheline mosquito species.

A second team of researchers—Michael Fontaine, PhD, of the University of Notre Dame in Indiana, and his colleagues—leveraged the 16 reference sequences to uncover additional information.

Both groups described their work in Science Express.

The researchers performed comparative genomics analyses among the Anopheles species and Drosophila (one of the most closely related genera for which equivalent genomic resources exist). This revealed significant genetic differences that make certain Anopheles species particularly adept at inflicting life-threatening infections.

Anopheles species had high rates of gene gain and loss, about 5 times higher than in Drosophila. Some genes, such as those involved in reproduction or those that encode proteins secreted into the mosquito saliva, have very high rates of sequence evolution and are only found in subsets of the most closely related species.

“These dynamic changes may offer clues to understanding the diversification of Anopheles mosquitoes: why some breed in salty water while others need temporary or permanent pools of fresh water, or why some are attracted to livestock while others will only feed on humans,” said Nora Besansky, PhD, a professor at the University of Notre Dame and senior author of both studies.

The genome sequences also provided conclusive evidence of the true relations among several species that are very closely related to Anopheles gambiae but show different traits that affect their vectorial capacity.

“The question of the true species phylogeny has been a highly contentious issue in the field,” Dr Besansky said. “Our results show that the most efficient vectors are not necessarily the most closely related species, and that traits enhancing vectorial capacity may be gained by gene flow between species.”

The researchers found that gene flow is much more extensive in anophelines than in Drosophila, largely because of a process called introgression, whereby a gene from one species enters the gene pool of another. The process allows for a much more rapid transfer of genes than would arise simply by waiting for new mutations to crop up.

The high degree of anopheline gene flow provides a source of genetic variation on which natural selection can act—paving the way for traits that make mosquitoes highly effective vectors for malaria (like insecticide resistance or tolerance of more malaria parasites) to be fixed in certain anophelines.

Anopheles albimanus mosquito

Credit: James Gathany

Two studies comparing mosquito genomes have begun to provide answers to a century-old mystery: why only some Anopheles mosquitoes transmit human malaria.

There are more than 400 species of Anopheles mosquitoes, but only about 60 transmit parasites that cause malaria in humans.

Variation in the ability to transmit malaria, or “vectorial capacity,” is determined by many factors, including feeding and breeding preferences, as well as immune responses to infections.

Much of our understanding of such processes is derived from the sequencing of the Anopheles gambiae genome in 2002, which facilitated large-scale functional studies that have offered insights into how this mosquito became highly specialized to live among and feed upon humans.

The lack of such genomic resources for other Anopheles species limited comparisons to small-scale studies of individual genes with no genome-wide data to investigate key attributes that impact the mosquitoes’ ability to transmit parasites.

In an attempt to change that, Daniel Neafsey, PhD, of the Broad Institute in Cambridge, Massachusetts, and his colleagues sequenced the genomes of 16 anopheline mosquito species.

A second team of researchers—Michael Fontaine, PhD, of the University of Notre Dame in Indiana, and his colleagues—leveraged the 16 reference sequences to uncover additional information.

Both groups described their work in Science Express.

The researchers performed comparative genomics analyses among the Anopheles species and Drosophila (one of the most closely related genera for which equivalent genomic resources exist). This revealed significant genetic differences that make certain Anopheles species particularly adept at inflicting life-threatening infections.

Anopheles species had high rates of gene gain and loss, about 5 times higher than in Drosophila. Some genes, such as those involved in reproduction or those that encode proteins secreted into the mosquito saliva, have very high rates of sequence evolution and are only found in subsets of the most closely related species.

“These dynamic changes may offer clues to understanding the diversification of Anopheles mosquitoes: why some breed in salty water while others need temporary or permanent pools of fresh water, or why some are attracted to livestock while others will only feed on humans,” said Nora Besansky, PhD, a professor at the University of Notre Dame and senior author of both studies.

The genome sequences also provided conclusive evidence of the true relations among several species that are very closely related to Anopheles gambiae but show different traits that affect their vectorial capacity.

“The question of the true species phylogeny has been a highly contentious issue in the field,” Dr Besansky said. “Our results show that the most efficient vectors are not necessarily the most closely related species, and that traits enhancing vectorial capacity may be gained by gene flow between species.”

The researchers found that gene flow is much more extensive in anophelines than in Drosophila, largely because of a process called introgression, whereby a gene from one species enters the gene pool of another. The process allows for a much more rapid transfer of genes than would arise simply by waiting for new mutations to crop up.

The high degree of anopheline gene flow provides a source of genetic variation on which natural selection can act—paving the way for traits that make mosquitoes highly effective vectors for malaria (like insecticide resistance or tolerance of more malaria parasites) to be fixed in certain anophelines.

Anopheles albimanus mosquito

Credit: James Gathany

Two studies comparing mosquito genomes have begun to provide answers to a century-old mystery: why only some Anopheles mosquitoes transmit human malaria.

There are more than 400 species of Anopheles mosquitoes, but only about 60 transmit parasites that cause malaria in humans.

Variation in the ability to transmit malaria, or “vectorial capacity,” is determined by many factors, including feeding and breeding preferences, as well as immune responses to infections.

Much of our understanding of such processes is derived from the sequencing of the Anopheles gambiae genome in 2002, which facilitated large-scale functional studies that have offered insights into how this mosquito became highly specialized to live among and feed upon humans.

The lack of such genomic resources for other Anopheles species limited comparisons to small-scale studies of individual genes with no genome-wide data to investigate key attributes that impact the mosquitoes’ ability to transmit parasites.

In an attempt to change that, Daniel Neafsey, PhD, of the Broad Institute in Cambridge, Massachusetts, and his colleagues sequenced the genomes of 16 anopheline mosquito species.

A second team of researchers—Michael Fontaine, PhD, of the University of Notre Dame in Indiana, and his colleagues—leveraged the 16 reference sequences to uncover additional information.

Both groups described their work in Science Express.

The researchers performed comparative genomics analyses among the Anopheles species and Drosophila (one of the most closely related genera for which equivalent genomic resources exist). This revealed significant genetic differences that make certain Anopheles species particularly adept at inflicting life-threatening infections.

Anopheles species had high rates of gene gain and loss, about 5 times higher than in Drosophila. Some genes, such as those involved in reproduction or those that encode proteins secreted into the mosquito saliva, have very high rates of sequence evolution and are only found in subsets of the most closely related species.

“These dynamic changes may offer clues to understanding the diversification of Anopheles mosquitoes: why some breed in salty water while others need temporary or permanent pools of fresh water, or why some are attracted to livestock while others will only feed on humans,” said Nora Besansky, PhD, a professor at the University of Notre Dame and senior author of both studies.

The genome sequences also provided conclusive evidence of the true relations among several species that are very closely related to Anopheles gambiae but show different traits that affect their vectorial capacity.

“The question of the true species phylogeny has been a highly contentious issue in the field,” Dr Besansky said. “Our results show that the most efficient vectors are not necessarily the most closely related species, and that traits enhancing vectorial capacity may be gained by gene flow between species.”

The researchers found that gene flow is much more extensive in anophelines than in Drosophila, largely because of a process called introgression, whereby a gene from one species enters the gene pool of another. The process allows for a much more rapid transfer of genes than would arise simply by waiting for new mutations to crop up.

The high degree of anopheline gene flow provides a source of genetic variation on which natural selection can act—paving the way for traits that make mosquitoes highly effective vectors for malaria (like insecticide resistance or tolerance of more malaria parasites) to be fixed in certain anophelines.

University of Delaware

 

A newly developed injectable material can prevent blood loss from serious internal injuries, according to research published in ACS Nano.

This biodegradable hydrogel is embedded with silicate nanoplatelets that aid in coagulation.

Once injected, the material locks into place at the site of the injury and decreases clotting time.

In experiments, the hydrogel decreased clotting time by 77% in vitro and promoted life-saving hemostasis in vivo.

Though it’s still in early testing, the researchers envision the material being preloaded into syringes that soldiers can carry with them into combat situations.

If a soldier experiences a penetrating, incompressible injury, he or she could inject the hydrogel into the wound site, where it would trigger rapid coagulation and, ideally, provide enough time to get to a medical facility for treatment.

“The time to get to a medical facility can take a half hour to an hour, and this hour is crucial; it can decide life and death,” said study author Akhilesh Gaharwar, PhD, of Texas A&M University in College Station, Texas.

“Our material’s combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency situations.”

Unlike some injectable solutions, which pose the risk of flowing to other parts of the body and forming unintended and potentially harmful clots, the material designed by Dr Gaharwar and his colleagues solidifies at the site of the wound and begins promoting coagulation in the targeted area.

To engineer the material, the researchers inserted 2-dimensional synthetic silicate nanoplatelets into hydrogels. The structure, composition, and arrangement of the nanoplatelets result in both positive and negative charges on each particle.

These charges cause the platelets to interact with the hydrogel in a unique way. The interaction causes the gel to temporarily undergo a change in its viscosity when mechanical force is applied. This allows the hydrogel to be injected and regain its shape once inside the body.

In addition to changing the mechanical properties of the hydrogel, these disc-shaped nanoplatelets interact with blood to promote clotting.

Animal models showed clot formation occurring in about 1 minute as opposed to 5 minutes without the presence of these nanoparticles. Animal models also demonstrated the formation of life-saving clots with the hydrogel.

“These 2D, silicate nanoparticles are unprecedented in the biomedical field,” Dr Gaharwar said. “And their use promises to lead to both conceptual and therapeutic advances in the important and emerging field of tissue engineering, drug delivery, cancer therapies, and immune engineering.”

The researchers plan to further enhance the biomaterial so it can initiate regeneration of damaged tissues through the formation of new blood vessels. The result could be a 2-pronged wound treatment—one that not only aids in damage control but also assists the body’s natural healing process.

University of Delaware

 

A newly developed injectable material can prevent blood loss from serious internal injuries, according to research published in ACS Nano.

This biodegradable hydrogel is embedded with silicate nanoplatelets that aid in coagulation.

Once injected, the material locks into place at the site of the injury and decreases clotting time.

In experiments, the hydrogel decreased clotting time by 77% in vitro and promoted life-saving hemostasis in vivo.

Though it’s still in early testing, the researchers envision the material being preloaded into syringes that soldiers can carry with them into combat situations.

If a soldier experiences a penetrating, incompressible injury, he or she could inject the hydrogel into the wound site, where it would trigger rapid coagulation and, ideally, provide enough time to get to a medical facility for treatment.

“The time to get to a medical facility can take a half hour to an hour, and this hour is crucial; it can decide life and death,” said study author Akhilesh Gaharwar, PhD, of Texas A&M University in College Station, Texas.

“Our material’s combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency situations.”

Unlike some injectable solutions, which pose the risk of flowing to other parts of the body and forming unintended and potentially harmful clots, the material designed by Dr Gaharwar and his colleagues solidifies at the site of the wound and begins promoting coagulation in the targeted area.

To engineer the material, the researchers inserted 2-dimensional synthetic silicate nanoplatelets into hydrogels. The structure, composition, and arrangement of the nanoplatelets result in both positive and negative charges on each particle.

These charges cause the platelets to interact with the hydrogel in a unique way. The interaction causes the gel to temporarily undergo a change in its viscosity when mechanical force is applied. This allows the hydrogel to be injected and regain its shape once inside the body.

In addition to changing the mechanical properties of the hydrogel, these disc-shaped nanoplatelets interact with blood to promote clotting.

Animal models showed clot formation occurring in about 1 minute as opposed to 5 minutes without the presence of these nanoparticles. Animal models also demonstrated the formation of life-saving clots with the hydrogel.

“These 2D, silicate nanoparticles are unprecedented in the biomedical field,” Dr Gaharwar said. “And their use promises to lead to both conceptual and therapeutic advances in the important and emerging field of tissue engineering, drug delivery, cancer therapies, and immune engineering.”

The researchers plan to further enhance the biomaterial so it can initiate regeneration of damaged tissues through the formation of new blood vessels. The result could be a 2-pronged wound treatment—one that not only aids in damage control but also assists the body’s natural healing process.

University of Delaware

 

A newly developed injectable material can prevent blood loss from serious internal injuries, according to research published in ACS Nano.

This biodegradable hydrogel is embedded with silicate nanoplatelets that aid in coagulation.

Once injected, the material locks into place at the site of the injury and decreases clotting time.

In experiments, the hydrogel decreased clotting time by 77% in vitro and promoted life-saving hemostasis in vivo.

Though it’s still in early testing, the researchers envision the material being preloaded into syringes that soldiers can carry with them into combat situations.

If a soldier experiences a penetrating, incompressible injury, he or she could inject the hydrogel into the wound site, where it would trigger rapid coagulation and, ideally, provide enough time to get to a medical facility for treatment.

“The time to get to a medical facility can take a half hour to an hour, and this hour is crucial; it can decide life and death,” said study author Akhilesh Gaharwar, PhD, of Texas A&M University in College Station, Texas.

“Our material’s combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency situations.”

Unlike some injectable solutions, which pose the risk of flowing to other parts of the body and forming unintended and potentially harmful clots, the material designed by Dr Gaharwar and his colleagues solidifies at the site of the wound and begins promoting coagulation in the targeted area.

To engineer the material, the researchers inserted 2-dimensional synthetic silicate nanoplatelets into hydrogels. The structure, composition, and arrangement of the nanoplatelets result in both positive and negative charges on each particle.

These charges cause the platelets to interact with the hydrogel in a unique way. The interaction causes the gel to temporarily undergo a change in its viscosity when mechanical force is applied. This allows the hydrogel to be injected and regain its shape once inside the body.

In addition to changing the mechanical properties of the hydrogel, these disc-shaped nanoplatelets interact with blood to promote clotting.

Animal models showed clot formation occurring in about 1 minute as opposed to 5 minutes without the presence of these nanoparticles. Animal models also demonstrated the formation of life-saving clots with the hydrogel.

“These 2D, silicate nanoparticles are unprecedented in the biomedical field,” Dr Gaharwar said. “And their use promises to lead to both conceptual and therapeutic advances in the important and emerging field of tissue engineering, drug delivery, cancer therapies, and immune engineering.”

The researchers plan to further enhance the biomaterial so it can initiate regeneration of damaged tissues through the formation of new blood vessels. The result could be a 2-pronged wound treatment—one that not only aids in damage control but also assists the body’s natural healing process.

Pill production

Credit: FDA

New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.

When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.

Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.

The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.

These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.

To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.

The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.

Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.

Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.

Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.

The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.

An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.

Pill production

Credit: FDA

New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.

When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.

Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.

The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.

These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.

To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.

The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.

Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.

Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.

Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.

The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.

An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.

Pill production

Credit: FDA

New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.

When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.

Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.

The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.

These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.

To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.

The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.

Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.

Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.

Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.

The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.

An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.

VANCOUVER – Morcellation is an effective, lifesaving tool in gynecologic surgery when used appropriately and should not be abandoned despite recent concerns about the dissemination of occult cancers, according to an expert panel that weighed in on this issue at a meeting sponsored by AAGL.

Panelists presented new data to inform the intense debate over this procedure, which has culminated in the Food and Drug Administration (FDA) recommending against the use of power morcellators during fibroid removal by hysterectomy or myomectomy for most women.

Earlier this year, AAGL convened the Tissue Extraction Task Force to study this issue and respond to the controversy. The association presented a statement to the FDA on power morcellation and published the task force findings that morcellation can be done safely and effectively when performed by trained and experienced surgeons in informed, carefully screened premenopausal women (J. Minim. Invasive Gynecol. 2014;21:517-30).

Abandoning it may raise mortality

“The priority of this entire discussion needs to focus on the patient’s welfare,” contended panelist Dr. Jubilee Brown, an associate professor in the department of gynecologic oncology and reproductive medicine, University of Texas M.D. Anderson Cancer Center, Houston. “For every piece of data that we look at, we need to keep that in the back of our minds as we analyze this.”

In a new study, she and her colleagues retrospectively studied outcomes in 808 consecutive patients with planned laparoscopic supracervical hysterectomy with morcellation who had at least 5 years of follow-up. The leading indications for surgery were menorrhagia and leiomyomata.

Only a single woman had a leiomyosarcoma; she was converted to an open procedure without morcellation but nonetheless died from the disease. “What hasn’t shown up in much of the literature is the wisdom of the operating surgeon, who identified that this uterus looked abnormal and called our group in,” commented Dr. Brown, who is also AAGL’s designated spokesperson on tissue extraction. “Unfortunately, what’s also missed in much of the literature is that leiomyosarcoma is an aggressive and often deadly disease. … In her case, as in so many cases, the problem was not the surgery, the problem was the cancer.”

Among the 778 women who underwent the planned laparoscopic hysterectomy with morcellation, 16 were found to have endometrial hyperplasia, two had adenocarcinoma, and one had an endometrial stromal sarcoma – but reassuringly, none had evidence of disease at follow-up.

“I think that what this tells us is that we need to be absolutely meticulous in our preoperative evaluation of patients in whom we are considering morcellation,” Dr. Brown said. The findings “speak to our obligation to educate our membership and everybody performing preoperative sampling on these patients.”

A decision analysis study also reported at the meeting by first author Dr. R. Wendel Naumann, Carolinas Medical Center in Charlotte, N.C., showed that mortality from laparoscopic hysterectomy with power morcellation – even accounting for possible dissemination of undiagnosed leiomyosarcomas – was 0.077%, still less than the 0.085% mortality from abdominal hysterectomy. “Though it is a small difference, it is an absolute difference in favor of laparoscopic hysterectomy with power morcellation. In fact, if all women were converted to an open hysterectomy, 17 more women each year would die of open hysterectomy than of power morcellation,” Dr. Brown commented.

“Power morcellation is an important tool,” she concluded, reiterating AAGL’s position that its use should be improved, not abandoned.

Low risk of leiomyosarcomas

Panelist Dr. Marit Lieng, an associate professor and consultant in the gynecology department of Oslo University Hospital, and her coinvestigators retrospectively studied 4,765 women who underwent surgery at the hospital for uterine fibroids between 2000 and 2013.

There were 26 cases of leiomyosarcoma (the majority in postmenopausal women), for an incidence of 0.54%, or 1 in 183 women.

However, only a single patient with leiomyosarcoma had laparoscopic supracervical hysterectomy with morcellation, because the tumor was identified or suspected preoperatively or intraoperatively in the rest, reported Dr. Lieng, who is also with the Institute of Clinical Medicine at the University of Oslo.

Therefore, the risk of unintended morcellation of an undiagnosed leiomyosarcoma was just 1 in 4,765 women, or 0.02%.

“I think the findings of our study support the conclusions of the AAGL expert group. … You can do power morcellation in selected patients,” Dr. Lieng commented. “Given a thorough preoperative evaluation, including a cervical cytology, endometrial biopsy, and evaluation of the myometrium by ultrasound or MRI, the risk of unintended morcellation of a uterine leiomyosarcoma in premenopausal women appears to be very low.”

Leiomyosarcomas best removed en bloc

“When you are creating public health care policy, decision analysis must begin with scientifically valid evidence,” asserted panelist Dr. Elizabeth Pritts, medical director of the Wisconsin Fertility Institute, Middleton.

She and her colleagues undertook a comprehensive new meta-analysis assessing the prevalence of occult leiomyosarcomas at hysterectomy or myomectomy for presumed uterine fibroids, including 133 original articles describing 30,193 women having explicit pathology.

Analysis of all prospective data showed that the predicted prevalence rate of occult leiomyosarcoma was 0.12 per 1,000 operations for presumed benign fibroids.

The corresponding 1 in 8,300 operations needed to find a leiomyosarcoma in this new meta-analysis differs greatly from the 1 in 498 found in an FDA meta-analysis, mainly because of the differing evidence base, Dr. Pritts maintained. “It really has to do with initial search criteria,” she said, noting, for example, that the FDA’s search strategy missed studies in which no cancer was found and studies in languages other than English.

Dr. Pritts and her colleagues also conducted a new systematic review looking at outcomes after morcellation of an unsuspected leiomyosarcoma, which was recently published (J. Minim. Invasive Gynecol. 2014 Sept. 2 [doi: 10.1016/j.jmig.2014.08.781]).

Main analyses here were based on six papers that compared morcellation with en bloc removal of leiomyosarcomas, most of which found worse survival for women whose tumors were morcellated.

“Now this is not great evidence, but remember, in evidence-based medicine, you’ve got to look at the very best available evidence. This is it,” Dr. Pritts maintained. “En bloc removal confers benefit—don’t cut into these.”

On closer inspection, only 3 of the 81 cases of morcellation reported were confirmed to be power morcellation. Comparisons of outcome with power versus hand morcellation, albeit limited by small numbers, suggested no difference in survival or upstaging.

“There are no data to suggest that any type of morcellation is better or worse than another type, even when including simple tumor biopsies,” Dr. Pritts concluded.

Dr. Brown, Dr. Lieng, and Dr. Pritts disclosed that they had no relevant conflicts of interest.

VANCOUVER – Morcellation is an effective, lifesaving tool in gynecologic surgery when used appropriately and should not be abandoned despite recent concerns about the dissemination of occult cancers, according to an expert panel that weighed in on this issue at a meeting sponsored by AAGL.

Panelists presented new data to inform the intense debate over this procedure, which has culminated in the Food and Drug Administration (FDA) recommending against the use of power morcellators during fibroid removal by hysterectomy or myomectomy for most women.

Earlier this year, AAGL convened the Tissue Extraction Task Force to study this issue and respond to the controversy. The association presented a statement to the FDA on power morcellation and published the task force findings that morcellation can be done safely and effectively when performed by trained and experienced surgeons in informed, carefully screened premenopausal women (J. Minim. Invasive Gynecol. 2014;21:517-30).

Abandoning it may raise mortality

“The priority of this entire discussion needs to focus on the patient’s welfare,” contended panelist Dr. Jubilee Brown, an associate professor in the department of gynecologic oncology and reproductive medicine, University of Texas M.D. Anderson Cancer Center, Houston. “For every piece of data that we look at, we need to keep that in the back of our minds as we analyze this.”

In a new study, she and her colleagues retrospectively studied outcomes in 808 consecutive patients with planned laparoscopic supracervical hysterectomy with morcellation who had at least 5 years of follow-up. The leading indications for surgery were menorrhagia and leiomyomata.

Only a single woman had a leiomyosarcoma; she was converted to an open procedure without morcellation but nonetheless died from the disease. “What hasn’t shown up in much of the literature is the wisdom of the operating surgeon, who identified that this uterus looked abnormal and called our group in,” commented Dr. Brown, who is also AAGL’s designated spokesperson on tissue extraction. “Unfortunately, what’s also missed in much of the literature is that leiomyosarcoma is an aggressive and often deadly disease. … In her case, as in so many cases, the problem was not the surgery, the problem was the cancer.”

Among the 778 women who underwent the planned laparoscopic hysterectomy with morcellation, 16 were found to have endometrial hyperplasia, two had adenocarcinoma, and one had an endometrial stromal sarcoma – but reassuringly, none had evidence of disease at follow-up.

“I think that what this tells us is that we need to be absolutely meticulous in our preoperative evaluation of patients in whom we are considering morcellation,” Dr. Brown said. The findings “speak to our obligation to educate our membership and everybody performing preoperative sampling on these patients.”

A decision analysis study also reported at the meeting by first author Dr. R. Wendel Naumann, Carolinas Medical Center in Charlotte, N.C., showed that mortality from laparoscopic hysterectomy with power morcellation – even accounting for possible dissemination of undiagnosed leiomyosarcomas – was 0.077%, still less than the 0.085% mortality from abdominal hysterectomy. “Though it is a small difference, it is an absolute difference in favor of laparoscopic hysterectomy with power morcellation. In fact, if all women were converted to an open hysterectomy, 17 more women each year would die of open hysterectomy than of power morcellation,” Dr. Brown commented.

“Power morcellation is an important tool,” she concluded, reiterating AAGL’s position that its use should be improved, not abandoned.

Low risk of leiomyosarcomas

Panelist Dr. Marit Lieng, an associate professor and consultant in the gynecology department of Oslo University Hospital, and her coinvestigators retrospectively studied 4,765 women who underwent surgery at the hospital for uterine fibroids between 2000 and 2013.

There were 26 cases of leiomyosarcoma (the majority in postmenopausal women), for an incidence of 0.54%, or 1 in 183 women.

However, only a single patient with leiomyosarcoma had laparoscopic supracervical hysterectomy with morcellation, because the tumor was identified or suspected preoperatively or intraoperatively in the rest, reported Dr. Lieng, who is also with the Institute of Clinical Medicine at the University of Oslo.

Therefore, the risk of unintended morcellation of an undiagnosed leiomyosarcoma was just 1 in 4,765 women, or 0.02%.

“I think the findings of our study support the conclusions of the AAGL expert group. … You can do power morcellation in selected patients,” Dr. Lieng commented. “Given a thorough preoperative evaluation, including a cervical cytology, endometrial biopsy, and evaluation of the myometrium by ultrasound or MRI, the risk of unintended morcellation of a uterine leiomyosarcoma in premenopausal women appears to be very low.”

Leiomyosarcomas best removed en bloc

“When you are creating public health care policy, decision analysis must begin with scientifically valid evidence,” asserted panelist Dr. Elizabeth Pritts, medical director of the Wisconsin Fertility Institute, Middleton.

She and her colleagues undertook a comprehensive new meta-analysis assessing the prevalence of occult leiomyosarcomas at hysterectomy or myomectomy for presumed uterine fibroids, including 133 original articles describing 30,193 women having explicit pathology.

Analysis of all prospective data showed that the predicted prevalence rate of occult leiomyosarcoma was 0.12 per 1,000 operations for presumed benign fibroids.

The corresponding 1 in 8,300 operations needed to find a leiomyosarcoma in this new meta-analysis differs greatly from the 1 in 498 found in an FDA meta-analysis, mainly because of the differing evidence base, Dr. Pritts maintained. “It really has to do with initial search criteria,” she said, noting, for example, that the FDA’s search strategy missed studies in which no cancer was found and studies in languages other than English.

Dr. Pritts and her colleagues also conducted a new systematic review looking at outcomes after morcellation of an unsuspected leiomyosarcoma, which was recently published (J. Minim. Invasive Gynecol. 2014 Sept. 2 [doi: 10.1016/j.jmig.2014.08.781]).

Main analyses here were based on six papers that compared morcellation with en bloc removal of leiomyosarcomas, most of which found worse survival for women whose tumors were morcellated.

“Now this is not great evidence, but remember, in evidence-based medicine, you’ve got to look at the very best available evidence. This is it,” Dr. Pritts maintained. “En bloc removal confers benefit—don’t cut into these.”

On closer inspection, only 3 of the 81 cases of morcellation reported were confirmed to be power morcellation. Comparisons of outcome with power versus hand morcellation, albeit limited by small numbers, suggested no difference in survival or upstaging.

“There are no data to suggest that any type of morcellation is better or worse than another type, even when including simple tumor biopsies,” Dr. Pritts concluded.

Dr. Brown, Dr. Lieng, and Dr. Pritts disclosed that they had no relevant conflicts of interest.

VANCOUVER – Morcellation is an effective, lifesaving tool in gynecologic surgery when used appropriately and should not be abandoned despite recent concerns about the dissemination of occult cancers, according to an expert panel that weighed in on this issue at a meeting sponsored by AAGL.

Panelists presented new data to inform the intense debate over this procedure, which has culminated in the Food and Drug Administration (FDA) recommending against the use of power morcellators during fibroid removal by hysterectomy or myomectomy for most women.

Earlier this year, AAGL convened the Tissue Extraction Task Force to study this issue and respond to the controversy. The association presented a statement to the FDA on power morcellation and published the task force findings that morcellation can be done safely and effectively when performed by trained and experienced surgeons in informed, carefully screened premenopausal women (J. Minim. Invasive Gynecol. 2014;21:517-30).

Abandoning it may raise mortality

“The priority of this entire discussion needs to focus on the patient’s welfare,” contended panelist Dr. Jubilee Brown, an associate professor in the department of gynecologic oncology and reproductive medicine, University of Texas M.D. Anderson Cancer Center, Houston. “For every piece of data that we look at, we need to keep that in the back of our minds as we analyze this.”

In a new study, she and her colleagues retrospectively studied outcomes in 808 consecutive patients with planned laparoscopic supracervical hysterectomy with morcellation who had at least 5 years of follow-up. The leading indications for surgery were menorrhagia and leiomyomata.

Only a single woman had a leiomyosarcoma; she was converted to an open procedure without morcellation but nonetheless died from the disease. “What hasn’t shown up in much of the literature is the wisdom of the operating surgeon, who identified that this uterus looked abnormal and called our group in,” commented Dr. Brown, who is also AAGL’s designated spokesperson on tissue extraction. “Unfortunately, what’s also missed in much of the literature is that leiomyosarcoma is an aggressive and often deadly disease. … In her case, as in so many cases, the problem was not the surgery, the problem was the cancer.”

Among the 778 women who underwent the planned laparoscopic hysterectomy with morcellation, 16 were found to have endometrial hyperplasia, two had adenocarcinoma, and one had an endometrial stromal sarcoma – but reassuringly, none had evidence of disease at follow-up.

“I think that what this tells us is that we need to be absolutely meticulous in our preoperative evaluation of patients in whom we are considering morcellation,” Dr. Brown said. The findings “speak to our obligation to educate our membership and everybody performing preoperative sampling on these patients.”

A decision analysis study also reported at the meeting by first author Dr. R. Wendel Naumann, Carolinas Medical Center in Charlotte, N.C., showed that mortality from laparoscopic hysterectomy with power morcellation – even accounting for possible dissemination of undiagnosed leiomyosarcomas – was 0.077%, still less than the 0.085% mortality from abdominal hysterectomy. “Though it is a small difference, it is an absolute difference in favor of laparoscopic hysterectomy with power morcellation. In fact, if all women were converted to an open hysterectomy, 17 more women each year would die of open hysterectomy than of power morcellation,” Dr. Brown commented.

“Power morcellation is an important tool,” she concluded, reiterating AAGL’s position that its use should be improved, not abandoned.

Low risk of leiomyosarcomas

Panelist Dr. Marit Lieng, an associate professor and consultant in the gynecology department of Oslo University Hospital, and her coinvestigators retrospectively studied 4,765 women who underwent surgery at the hospital for uterine fibroids between 2000 and 2013.

There were 26 cases of leiomyosarcoma (the majority in postmenopausal women), for an incidence of 0.54%, or 1 in 183 women.

However, only a single patient with leiomyosarcoma had laparoscopic supracervical hysterectomy with morcellation, because the tumor was identified or suspected preoperatively or intraoperatively in the rest, reported Dr. Lieng, who is also with the Institute of Clinical Medicine at the University of Oslo.

Therefore, the risk of unintended morcellation of an undiagnosed leiomyosarcoma was just 1 in 4,765 women, or 0.02%.

“I think the findings of our study support the conclusions of the AAGL expert group. … You can do power morcellation in selected patients,” Dr. Lieng commented. “Given a thorough preoperative evaluation, including a cervical cytology, endometrial biopsy, and evaluation of the myometrium by ultrasound or MRI, the risk of unintended morcellation of a uterine leiomyosarcoma in premenopausal women appears to be very low.”

Leiomyosarcomas best removed en bloc

“When you are creating public health care policy, decision analysis must begin with scientifically valid evidence,” asserted panelist Dr. Elizabeth Pritts, medical director of the Wisconsin Fertility Institute, Middleton.

She and her colleagues undertook a comprehensive new meta-analysis assessing the prevalence of occult leiomyosarcomas at hysterectomy or myomectomy for presumed uterine fibroids, including 133 original articles describing 30,193 women having explicit pathology.

Analysis of all prospective data showed that the predicted prevalence rate of occult leiomyosarcoma was 0.12 per 1,000 operations for presumed benign fibroids.

The corresponding 1 in 8,300 operations needed to find a leiomyosarcoma in this new meta-analysis differs greatly from the 1 in 498 found in an FDA meta-analysis, mainly because of the differing evidence base, Dr. Pritts maintained. “It really has to do with initial search criteria,” she said, noting, for example, that the FDA’s search strategy missed studies in which no cancer was found and studies in languages other than English.

Dr. Pritts and her colleagues also conducted a new systematic review looking at outcomes after morcellation of an unsuspected leiomyosarcoma, which was recently published (J. Minim. Invasive Gynecol. 2014 Sept. 2 [doi: 10.1016/j.jmig.2014.08.781]).

Main analyses here were based on six papers that compared morcellation with en bloc removal of leiomyosarcomas, most of which found worse survival for women whose tumors were morcellated.

“Now this is not great evidence, but remember, in evidence-based medicine, you’ve got to look at the very best available evidence. This is it,” Dr. Pritts maintained. “En bloc removal confers benefit—don’t cut into these.”

On closer inspection, only 3 of the 81 cases of morcellation reported were confirmed to be power morcellation. Comparisons of outcome with power versus hand morcellation, albeit limited by small numbers, suggested no difference in survival or upstaging.

“There are no data to suggest that any type of morcellation is better or worse than another type, even when including simple tumor biopsies,” Dr. Pritts concluded.

Dr. Brown, Dr. Lieng, and Dr. Pritts disclosed that they had no relevant conflicts of interest.

Acne vulgaris is a diagnosis common to all primary care physicians, and the No. 1 concern for most adolescents. Referral wait times to a dermatologist can be anywhere from 3 to 6 months; if you’re lucky, dermatologists have a physician assistant or nurse practitioner who can see patients sooner. But the majority of acne cases – even complex ones – can successfully be treated by a primary care physician. Not only would you be improving patient satisfaction because the patient can be treated immediately, you also would increase your revenue.

Acne care is a billion dollar industry. Prescription medications are a $2 billion industry, and nonprescription medications are three to four times that (Semin. Cutan. Med. Surg. 2008;27:170). Yet, the average primary care physician will start treatment, then refer to the dermatologist.

The scope of acne care is not that broad; this should decrease your anxiety about being more aggressive with the treatment. Acne begins when there is follicular hyperproliferation, which leads to the obstruction of the follicle. This is followed by an increase in the sebum, by inflammation, and then by colonization with bacteria. Topical retinoids (tretinoin, adapalene, and tazarotene) normalize the follicular hyperproliferation and decrease inflammation. Antibiotics kill the bacteria. So, with implementation of topical retinoids, antibiotics, and a good home regimen, the vast majority of acne cases can be successfully treated without a referral.

When a patient presents with either concerns about acne or obvious full-blown acne, an assessment of the condition should be done. Realizing that there is gender gap in the treatment of acne is crucial. Males are much less likely to admit that they are bothered by their acne or adhere to treatment because they think it’s “girly” to use products on the face or follow a cleansing regimen. But, it is well documented that acne is associated with lower self-esteem, being bullied, depression, and anxiety. The patient assessment should identify acne type (comedonal, inflammatory, nodular), severity, scarring, menstrual history in girls, and the psychological impact on the patient.

Also review past treatments and what worked, what didn’t work, and why. Most patients upon presentation have used the over-the-counter preparations, which usually consist of benzoyl peroxide and salicylic acid.

Managing patients’ expectations is another key component to successful treatment. Most of the topical treatments have undesirable side effects like drying and reddening and hyperpigmentation of the skin. Informing them that irritations will lessen and will improve over time can aid in adherence to the regimen.

If a patient has dry skin, cream formulations will be less irritating; more oily skin will respond better to gels that tend to be more drying. The percentage of benzoyl peroxide also contributes to the discomfort. One study showed that the 2.5% was as effective as the 10% formulation, but resulted in less irritation (Br. J. Dermatol .2014;170:557). Salicylic acid is a good alternative if benzoyl peroxide is not tolerated.

Antibiotics are an essential part of acne treatment. Topicals such as erythromycin, clindamycin, and dapsone reduce Propionibacterium acnes, which also reduces inflammation. Oral antibiotics have similar efficacy, but are associated with more rapid clinical improvement. Another consideration in using oral antibiotics is the side effects. Photosensitivity and gastrointestinal upset are significant issues that arise with their use. Doxycycline monohydrate tends to have fewer GI side effects and is preferred over doxycycline hyclate. Minocycline has fewer GI effects and less photosensitivity, but tends to be more expensive and is associated with vertigo and serum sickness (Arch. Dermatol. 1982;118:989-92). Prolonged use of either topical or oral antibiotics increases the risk of resistant strains of P. acnes. Other antibiotics are available for use, such as trimethoprim-sulfamethoxazole, clindamycin, and erythromycin, but all have either significant side effects associated with them or higher levels of resistance.

Combination therapy is superior to monotherapy. Whether combining benzoyl peroxide with a topical retinoid, antibiotic, or both, improved outcomes have been shown. Studies also confirm that use of benzoyl peroxide with antibiotics lowers the risk of P. acne’s resistance (Dermatol. Clin. 2009;27:25-31).

Now, how do you make acne care work for your business model? It’s easier than you may think. Other highly effective, inexpensive, and efficient treatments can be implemented with little investment.

Establishing and marketing an acne program and dedicating a few hours a week to an acne clinic can add significant revenue to your practice. Educate the patient on cleansing and diet; information can be found at www.acne.com. Beyond using the traditional acne treatments, consider adding peels and a light-based therapy to the regimen. Salicylic acid peels are easy to apply and give great results. Treatments are done monthly for five to six treatments at a cost of $140-$250 per treatment. The application process takes 15-20 minutes.

Light therapy is also easy to implement. With the purchase of a lamp that costs less than $1,000, you can offer this treatment. Patients can come twice a week for 15-minute sessions for a total of eight sessions. The average cost for these treatments is $50-$75 per treatment. Combinations of peels and light therapy have great results with minimal risk and prevent families from having to wait the 3-6 months it takes to get to see the dermatologist.

Lastly, consider cosmeceuticals. There is no great mystery as to what is in the acne medications. You can create your own line using a compounding pharmacy such as MasterPharm or University Compounding Pharmacy . Or use a cosmeceuticals company that will provide you quality products at wholesale prices. Many of them don’t require you to stock the product. SkinMedica and SkinCeuticals ( are popular ones, but there are several more. As opposed to your patient going to the local pharmacy and guessing at which product is best, you can provide a full line of products that will give the best results.

Without compromising care, you can provide complete skin care to your patients and increase your revenue and your patient’s satisfaction.

Dr. Pearce is a pediatrician in Frankfort, Ill. Dr. Pearce had no relevant financial disclosures. E-mail her at [email protected].

Acne vulgaris is a diagnosis common to all primary care physicians, and the No. 1 concern for most adolescents. Referral wait times to a dermatologist can be anywhere from 3 to 6 months; if you’re lucky, dermatologists have a physician assistant or nurse practitioner who can see patients sooner. But the majority of acne cases – even complex ones – can successfully be treated by a primary care physician. Not only would you be improving patient satisfaction because the patient can be treated immediately, you also would increase your revenue.

Acne care is a billion dollar industry. Prescription medications are a $2 billion industry, and nonprescription medications are three to four times that (Semin. Cutan. Med. Surg. 2008;27:170). Yet, the average primary care physician will start treatment, then refer to the dermatologist.

The scope of acne care is not that broad; this should decrease your anxiety about being more aggressive with the treatment. Acne begins when there is follicular hyperproliferation, which leads to the obstruction of the follicle. This is followed by an increase in the sebum, by inflammation, and then by colonization with bacteria. Topical retinoids (tretinoin, adapalene, and tazarotene) normalize the follicular hyperproliferation and decrease inflammation. Antibiotics kill the bacteria. So, with implementation of topical retinoids, antibiotics, and a good home regimen, the vast majority of acne cases can be successfully treated without a referral.

When a patient presents with either concerns about acne or obvious full-blown acne, an assessment of the condition should be done. Realizing that there is gender gap in the treatment of acne is crucial. Males are much less likely to admit that they are bothered by their acne or adhere to treatment because they think it’s “girly” to use products on the face or follow a cleansing regimen. But, it is well documented that acne is associated with lower self-esteem, being bullied, depression, and anxiety. The patient assessment should identify acne type (comedonal, inflammatory, nodular), severity, scarring, menstrual history in girls, and the psychological impact on the patient.

Also review past treatments and what worked, what didn’t work, and why. Most patients upon presentation have used the over-the-counter preparations, which usually consist of benzoyl peroxide and salicylic acid.

Managing patients’ expectations is another key component to successful treatment. Most of the topical treatments have undesirable side effects like drying and reddening and hyperpigmentation of the skin. Informing them that irritations will lessen and will improve over time can aid in adherence to the regimen.

If a patient has dry skin, cream formulations will be less irritating; more oily skin will respond better to gels that tend to be more drying. The percentage of benzoyl peroxide also contributes to the discomfort. One study showed that the 2.5% was as effective as the 10% formulation, but resulted in less irritation (Br. J. Dermatol .2014;170:557). Salicylic acid is a good alternative if benzoyl peroxide is not tolerated.

Antibiotics are an essential part of acne treatment. Topicals such as erythromycin, clindamycin, and dapsone reduce Propionibacterium acnes, which also reduces inflammation. Oral antibiotics have similar efficacy, but are associated with more rapid clinical improvement. Another consideration in using oral antibiotics is the side effects. Photosensitivity and gastrointestinal upset are significant issues that arise with their use. Doxycycline monohydrate tends to have fewer GI side effects and is preferred over doxycycline hyclate. Minocycline has fewer GI effects and less photosensitivity, but tends to be more expensive and is associated with vertigo and serum sickness (Arch. Dermatol. 1982;118:989-92). Prolonged use of either topical or oral antibiotics increases the risk of resistant strains of P. acnes. Other antibiotics are available for use, such as trimethoprim-sulfamethoxazole, clindamycin, and erythromycin, but all have either significant side effects associated with them or higher levels of resistance.

Combination therapy is superior to monotherapy. Whether combining benzoyl peroxide with a topical retinoid, antibiotic, or both, improved outcomes have been shown. Studies also confirm that use of benzoyl peroxide with antibiotics lowers the risk of P. acne’s resistance (Dermatol. Clin. 2009;27:25-31).

Now, how do you make acne care work for your business model? It’s easier than you may think. Other highly effective, inexpensive, and efficient treatments can be implemented with little investment.

Establishing and marketing an acne program and dedicating a few hours a week to an acne clinic can add significant revenue to your practice. Educate the patient on cleansing and diet; information can be found at www.acne.com. Beyond using the traditional acne treatments, consider adding peels and a light-based therapy to the regimen. Salicylic acid peels are easy to apply and give great results. Treatments are done monthly for five to six treatments at a cost of $140-$250 per treatment. The application process takes 15-20 minutes.

Light therapy is also easy to implement. With the purchase of a lamp that costs less than $1,000, you can offer this treatment. Patients can come twice a week for 15-minute sessions for a total of eight sessions. The average cost for these treatments is $50-$75 per treatment. Combinations of peels and light therapy have great results with minimal risk and prevent families from having to wait the 3-6 months it takes to get to see the dermatologist.

Lastly, consider cosmeceuticals. There is no great mystery as to what is in the acne medications. You can create your own line using a compounding pharmacy such as MasterPharm or University Compounding Pharmacy . Or use a cosmeceuticals company that will provide you quality products at wholesale prices. Many of them don’t require you to stock the product. SkinMedica and SkinCeuticals ( are popular ones, but there are several more. As opposed to your patient going to the local pharmacy and guessing at which product is best, you can provide a full line of products that will give the best results.

Without compromising care, you can provide complete skin care to your patients and increase your revenue and your patient’s satisfaction.

Dr. Pearce is a pediatrician in Frankfort, Ill. Dr. Pearce had no relevant financial disclosures. E-mail her at [email protected].

Acne vulgaris is a diagnosis common to all primary care physicians, and the No. 1 concern for most adolescents. Referral wait times to a dermatologist can be anywhere from 3 to 6 months; if you’re lucky, dermatologists have a physician assistant or nurse practitioner who can see patients sooner. But the majority of acne cases – even complex ones – can successfully be treated by a primary care physician. Not only would you be improving patient satisfaction because the patient can be treated immediately, you also would increase your revenue.

Acne care is a billion dollar industry. Prescription medications are a $2 billion industry, and nonprescription medications are three to four times that (Semin. Cutan. Med. Surg. 2008;27:170). Yet, the average primary care physician will start treatment, then refer to the dermatologist.

The scope of acne care is not that broad; this should decrease your anxiety about being more aggressive with the treatment. Acne begins when there is follicular hyperproliferation, which leads to the obstruction of the follicle. This is followed by an increase in the sebum, by inflammation, and then by colonization with bacteria. Topical retinoids (tretinoin, adapalene, and tazarotene) normalize the follicular hyperproliferation and decrease inflammation. Antibiotics kill the bacteria. So, with implementation of topical retinoids, antibiotics, and a good home regimen, the vast majority of acne cases can be successfully treated without a referral.

When a patient presents with either concerns about acne or obvious full-blown acne, an assessment of the condition should be done. Realizing that there is gender gap in the treatment of acne is crucial. Males are much less likely to admit that they are bothered by their acne or adhere to treatment because they think it’s “girly” to use products on the face or follow a cleansing regimen. But, it is well documented that acne is associated with lower self-esteem, being bullied, depression, and anxiety. The patient assessment should identify acne type (comedonal, inflammatory, nodular), severity, scarring, menstrual history in girls, and the psychological impact on the patient.

Also review past treatments and what worked, what didn’t work, and why. Most patients upon presentation have used the over-the-counter preparations, which usually consist of benzoyl peroxide and salicylic acid.

Managing patients’ expectations is another key component to successful treatment. Most of the topical treatments have undesirable side effects like drying and reddening and hyperpigmentation of the skin. Informing them that irritations will lessen and will improve over time can aid in adherence to the regimen.

If a patient has dry skin, cream formulations will be less irritating; more oily skin will respond better to gels that tend to be more drying. The percentage of benzoyl peroxide also contributes to the discomfort. One study showed that the 2.5% was as effective as the 10% formulation, but resulted in less irritation (Br. J. Dermatol .2014;170:557). Salicylic acid is a good alternative if benzoyl peroxide is not tolerated.

Antibiotics are an essential part of acne treatment. Topicals such as erythromycin, clindamycin, and dapsone reduce Propionibacterium acnes, which also reduces inflammation. Oral antibiotics have similar efficacy, but are associated with more rapid clinical improvement. Another consideration in using oral antibiotics is the side effects. Photosensitivity and gastrointestinal upset are significant issues that arise with their use. Doxycycline monohydrate tends to have fewer GI side effects and is preferred over doxycycline hyclate. Minocycline has fewer GI effects and less photosensitivity, but tends to be more expensive and is associated with vertigo and serum sickness (Arch. Dermatol. 1982;118:989-92). Prolonged use of either topical or oral antibiotics increases the risk of resistant strains of P. acnes. Other antibiotics are available for use, such as trimethoprim-sulfamethoxazole, clindamycin, and erythromycin, but all have either significant side effects associated with them or higher levels of resistance.

Combination therapy is superior to monotherapy. Whether combining benzoyl peroxide with a topical retinoid, antibiotic, or both, improved outcomes have been shown. Studies also confirm that use of benzoyl peroxide with antibiotics lowers the risk of P. acne’s resistance (Dermatol. Clin. 2009;27:25-31).

Now, how do you make acne care work for your business model? It’s easier than you may think. Other highly effective, inexpensive, and efficient treatments can be implemented with little investment.

Establishing and marketing an acne program and dedicating a few hours a week to an acne clinic can add significant revenue to your practice. Educate the patient on cleansing and diet; information can be found at www.acne.com. Beyond using the traditional acne treatments, consider adding peels and a light-based therapy to the regimen. Salicylic acid peels are easy to apply and give great results. Treatments are done monthly for five to six treatments at a cost of $140-$250 per treatment. The application process takes 15-20 minutes.

Light therapy is also easy to implement. With the purchase of a lamp that costs less than $1,000, you can offer this treatment. Patients can come twice a week for 15-minute sessions for a total of eight sessions. The average cost for these treatments is $50-$75 per treatment. Combinations of peels and light therapy have great results with minimal risk and prevent families from having to wait the 3-6 months it takes to get to see the dermatologist.

Lastly, consider cosmeceuticals. There is no great mystery as to what is in the acne medications. You can create your own line using a compounding pharmacy such as MasterPharm or University Compounding Pharmacy . Or use a cosmeceuticals company that will provide you quality products at wholesale prices. Many of them don’t require you to stock the product. SkinMedica and SkinCeuticals ( are popular ones, but there are several more. As opposed to your patient going to the local pharmacy and guessing at which product is best, you can provide a full line of products that will give the best results.

Without compromising care, you can provide complete skin care to your patients and increase your revenue and your patient’s satisfaction.

Dr. Pearce is a pediatrician in Frankfort, Ill. Dr. Pearce had no relevant financial disclosures. E-mail her at [email protected].