Closer to home, general internists and other primary care providers can use the awareness of global health concerns to the health advantage of our patients, including the young and healthy, who generally eschew preventive health visits to their physicians, and busy traveling executives, who only see a doctor for (hopefully) quick resolution to intermittent problems.

In this issue of the Journal, Powell and Ford offer a general primer on travel medicine, highlighting specific concerns that should be addressed to facilitate our patients’ safe and uninterrupted travels. But often, a pretravel visit is also a good time to introduce concepts of preventive health to patients who might not otherwise be accessible or amenable.

Just as the preoperative medical consultation can provide a “teaching moment” to address smoking cessation or reversible cardiac risks to a captive audience, the visit regarding “What shots do I need to go to Thailand?” can open the door for talk about general vaccinations (see the article by Campos-Outcalt of this issue), venereal disease, air-travel-associated thrombosis, excessive alcohol use, and perhaps other wellness issues. Creating a travel advisory service within most practices will not supplant the benefits of having travelers review the CDC travel Web site or the need to refer some patients to travel medicine experts regarding specific diseases and vaccinations. But it may create the opportunity for interaction, dialogue, and even a blood pressure check with patients who might not otherwise have the time or see the need to schedule a visit with a physician in the absence of an acute medical concern.

Closer to home, general internists and other primary care providers can use the awareness of global health concerns to the health advantage of our patients, including the young and healthy, who generally eschew preventive health visits to their physicians, and busy traveling executives, who only see a doctor for (hopefully) quick resolution to intermittent problems.

In this issue of the Journal, Powell and Ford offer a general primer on travel medicine, highlighting specific concerns that should be addressed to facilitate our patients’ safe and uninterrupted travels. But often, a pretravel visit is also a good time to introduce concepts of preventive health to patients who might not otherwise be accessible or amenable.

Just as the preoperative medical consultation can provide a “teaching moment” to address smoking cessation or reversible cardiac risks to a captive audience, the visit regarding “What shots do I need to go to Thailand?” can open the door for talk about general vaccinations (see the article by Campos-Outcalt of this issue), venereal disease, air-travel-associated thrombosis, excessive alcohol use, and perhaps other wellness issues. Creating a travel advisory service within most practices will not supplant the benefits of having travelers review the CDC travel Web site or the need to refer some patients to travel medicine experts regarding specific diseases and vaccinations. But it may create the opportunity for interaction, dialogue, and even a blood pressure check with patients who might not otherwise have the time or see the need to schedule a visit with a physician in the absence of an acute medical concern.

Closer to home, general internists and other primary care providers can use the awareness of global health concerns to the health advantage of our patients, including the young and healthy, who generally eschew preventive health visits to their physicians, and busy traveling executives, who only see a doctor for (hopefully) quick resolution to intermittent problems.

In this issue of the Journal, Powell and Ford offer a general primer on travel medicine, highlighting specific concerns that should be addressed to facilitate our patients’ safe and uninterrupted travels. But often, a pretravel visit is also a good time to introduce concepts of preventive health to patients who might not otherwise be accessible or amenable.

Just as the preoperative medical consultation can provide a “teaching moment” to address smoking cessation or reversible cardiac risks to a captive audience, the visit regarding “What shots do I need to go to Thailand?” can open the door for talk about general vaccinations (see the article by Campos-Outcalt of this issue), venereal disease, air-travel-associated thrombosis, excessive alcohol use, and perhaps other wellness issues. Creating a travel advisory service within most practices will not supplant the benefits of having travelers review the CDC travel Web site or the need to refer some patients to travel medicine experts regarding specific diseases and vaccinations. But it may create the opportunity for interaction, dialogue, and even a blood pressure check with patients who might not otherwise have the time or see the need to schedule a visit with a physician in the absence of an acute medical concern.

Before going abroad to areas that might pose a risk to their health, most people ought to visit their primary care physicians and many should be referred to a specialist in travel medicine.

In this article, we review the key elements of the pretravel consult as it relates to the prevention and self-treatment of the most common diseases that pose health risks for travelers. We also give guidelines for when to refer patients to a specialist.

WHY PRIMARY CARE PHYSICIANS NEED TO KNOW TRAVEL MEDICINE

International travel to exotic locations is becoming more popular. In 2008, one out of five Americans traveled abroad, and 38 million visits were to developing countries where there are significant health risks for travelers.¹

One third to one half of travelers to developing countries experience some kind of illness while abroad, most commonly diarrhea or upper respiratory infections, which typically lead to 3 lost days during a 2-week trip.

These illnesses are often preventable and self-treatable.² Unfortunately, studies suggest that most travelers do not seek adequate medical advice, and that when they do they often fail to complete courses of medication.^3,4

All these factors point to the need for primary care providers to become proficient in the pretravel consult and, if necessary, to refer patients to travel specialists and clinics.

WHY REFER TO A TRAVEL CLINIC?

In one study of travelers to areas of high risk for malaria or hepatitis A, 42% of those who consulted only their family doctor became ill, in contrast to 22% of those who attended a travel medicine clinic.⁴

As a rule of thumb, anyone traveling to an area where malaria is endemic should be referred to a specialist, as should anyone at risk of yellow fever or typhoid fever. As many as 8 per 1,000 travelers may return from areas of risk infected with malaria.⁵

Long-term travelers and people who will spend time in urban slums or rural or remote regions have an even greater need for referral to a travel clinic, as they are at higher risk of exposure to Japanese encephalitis, cholera, epidemic meningitis, dengue fever, and rabies.⁶

THE PRETRAVEL CONSULT: ESSENTIALS

A pretravel consult ought to be scheduled 4 to 6 weeks in advance of the trip, since many vaccines require that much time to induce immunity, and some require a series of shots.

Unfortunately, many patients who think of arranging a travel consult make the appointment at the last minute, and some come with an incomplete knowledge of their travel plans. However, even without enough advance notice, a consult can be beneficial.

Travelers sometimes change their itineraries in-country or engage in unanticipated risky behaviors. A good travel medicine physician tries to anticipate even these unplanned risks and changes in itinerary.

Where is the traveler going? When? For how long?

The pretravel consult starts with a detailed discussion of the patient’s itinerary. It needs to include length, dates, and location of travel, as well as anticipated activities and accommodations.

A remarkable number of travelers come to consults not knowing the names of specific countries they will visit, perhaps saying only that they are going to Africa or South America. An accurate itinerary is indispensible, as appropriate medical advice is highly specific to country and region. The incidence and geographic distribution of many travelers’ diseases change over time, and this requires physicians to consult the most current information available.

Tropical countries, in general, are risky, but each pathogen has a unique distribution that may vary between urban and rural areas or by season. Detailed, up-to-date information is available from the US Centers for Disease Control and Prevention (CDC) (www.cdc.gov) for individual countries and for specific provinces and locations within those countries. Physicians should consult the CDC whenever advising a patient preparing to travel. ⁷

How is the traveler’s current health?

Several immunizations cannot be given to the very young, the elderly, or those who are immunocompromised.

The greatest risk of death to travelers is not from tropical diseases but from cardiovascular disease, which according to one study is responsible for half of deaths abroad.⁸ Patients with heart disease or other known health concerns need to be counseled to avoid activities that will put them at further risk. The advice applies especially in situations such as remote travel or even cruises, where prompt emergency medical care may be difficult or impossible to obtain.

People infected with human immunodeficiency virus (HIV) face discriminatory travel prohibitions in 74 countries.⁹

Foreign-born travelers who are visiting family and friends in developing countries may have lost their immunity to local pathogens and thus can be more at risk because they are not prepared to take necessary health precautions.

Also, a significant number of travelers become infected but develop illnesses only after they return, so a posttravel visit may be necessary.⁶

Prescription and even over-the-the-counter drugs may be difficult or impossible to obtain in foreign countries, and ample supplies should be brought along.

Is the traveler up to date on routine immunizations?

A number of infectious diseases that have been controlled or eradicated in North America through regular childhood immunizations are still endemic in many remote areas and developing countries. All travelers should be up to date on routine immunizations, including those for measles-mumps-rubella, tetanus, polio, meningitis, and hepatitis A and B.

Polio. A one-time polio booster is recommended for adults traveling to certain countries or areas of the world.

Meningitis vaccine is now routinely given to young people, but adult patients may need it before they travel.

Hepatitis A is contracted through fecal contamination of food and water. Common sources are foods prepared in an unhygienic manner, raw fruits and vegetables, shellfish, and contaminated water.

Hepatitis B vaccine is also now routinely given to young people, but it should be offered to travelers planning to stay more than 1 month and to long-term expatriates. This vaccine is also recommended for travelers who may be exposed to blood or body fluids, who are contemplating sexual activity or tattooing in the host country, or who may require medical or dental care while traveling, as well as for adventure travelers or travelers to remote regions.

The vaccination is given in a three-dose schedule at 0, 1, and 6 months. For protection against both hepatitis A and B, the vaccine Twinrix can be used on the same schedule as for hepatitis B. An accelerated schedule of 0, 7, and 21 days with a booster at 12 months allows completion of the entire series in 4 weeks, thus putting completion of vaccination before travel in the same time frame as other vaccines in a series, such as those for rabies and Japanese encephalitis.

PREVENTIVE COUNSELING

In addition, travelers going abroad should be advised on measures to avoid diarrhea, insectvector diseases, accidents, excessive exposure to the sun, altitude sickness, and other risks their itineraries may expose them to.

Avoiding traveler’s diarrhea

Traveler’s diarrhea is by far the most common health problem experienced abroad. It is prevalent in Mexico, where 20 million visits by Americans occur each year. A quarter to half of visitors to developing countries contract traveler’s diarrhea and, on average, lose 2 to 3 days of their business trip or vacation.^3,10 The disease therefore imposes not only discomfort but also financial losses on travelers, especially business travelers.

Though many pathogens may be responsible, the most common one is Escherichia coli, usually transmitted by human fecal contamination of food or drink. Preventive measures against E coli are the same as for other foodborne and waterborne infections, such as hepatitis A, cholera, and typhoid fever.

The rule for avoiding traveler’s diarrhea may be summarized by the CDC-coined phrase, “boil it, cook it, peel it, or forget it.” Simple, written advice is most likely to be followed. ⁶ Thorough boiling or cooking kills bacteria in contaminated food, and food should be served steaming hot. Travelers should only eat foods they know have been well cooked, declining cold dishes like salsa or casseroles. They should avoid tap water for brushing teeth or in the form of ice cubes and should stick to drinking bottled beverages, preferably carbonated ones. No matter how appetizing a salad looks, travelers should avoid eating fresh fruits and vegetables unless they are sure that they were peeled under sanitary conditions. Simply eating at a high-priced restaurant is not a guarantee of uncontaminated food. Before meals or any hand-to-mouth contact, hands should be washed in soap and water or with sanitizers.

Travelers to remote areas may wish to acquire filtering devices, chlorine, or iodine for treating water. A combination of filtering and iodine treatment is most effective.

While this advice is undoubtedly wise, the evidence shows that, in practice, most travelers fail to take all precautions, and the benefits of this counseling have been difficult to demonstrate.¹¹ Therefore, physicians should prescribe drugs for prophylaxis and self-treatment of traveler’s diarrhea during travel.

Bismuth subsalicylate (Pepto-Bismol) taken as two tablets or 2 oz of liquid 4 times a day while traveling may reduce the risk of diarrhea by one half, though it should be avoided by patients with contraindications to aspirin.^3,6

Self-treating traveler’s diarrhea

Proper hydration is crucial, since dehydration can worsen and prolong symptoms.

Ciprofloxacin (Cipro) 500 mg orally two times daily for 3 to 5 days is effective.

Azithromycin (Zithromax) 500 mg daily for 3 to 5 days may be better in some areas of Southeast Asia, where fluoroquinolone-resistant bacteria are prevalent.

Rifaximin (Xifaxan), a nonsystemic antibiotic, is another option. The dosage is 200 mg three times a day for 3 days.

Avoiding insect bites

Malaria, yellow fever, tickborne encephalitis, and dengue fever are all transmitted by insect bites. Often the best protection is to avoid being bitten.

Bites can be avoided by using insect repellants containing diethyltoluamide (DEET) or picardin. If the traveler is going to be out in the sun, he or she should apply sunscreen first, then DEET on top of that. Anopheles, which transmits malaria, is a night-biting mosquito and may be avoided by staying in screened areas at dusk and dawn and by using bed netting. Permethrin, an insecticide, can be applied to clothing and mosquito netting.

Other things to avoid

Accidents are the second most common cause of death in travelers (after cardiovascular disease), accounting for as many as one-third of deaths.⁹ Several studies indicate road accidents are the major cause of accidental death, but also significant are drowning and air crashes. Travelers should be advised that transportation in developing countries is often more dangerous than at home. Seaside vacationers should be aware of the dangers of riptides and other threats to swimmers and should obey warnings posted at beaches.

Sexually transmitted diseases. When appropriate, physicians should warn travelers about the dangers of contracting HIV and other sexually transmitted diseases, especially in sub-Saharan Africa.

Sunburn, dehydration. Travelers should regularly use sunscreen and should remain hydrated.

Crimes against and involving tourists are a serious threat in many places, including some popular destinations. All of the 100,000 young people traveling to Mexico each year for spring break should read the US Department of State warnings against crime and possible arrest in that country.¹² Travelers who are victims of crimes in foreign countries should contact their national consulate as soon as possible. The US Department of State issues advisories on countries where there is danger to travelers because of political turmoil, crime, or other causes.¹³

Motion sickness and jet lag can be ameliorated by proper hydration, avoiding caffeine, and using a scopolamine patch or dimenhydrinate (Dramamine).¹

When traveling to wilderness areas

Wilderness and expedition medicine is a complex subset of travel medicine.¹⁴ All travelers need to understand the risks of whatever activities they undertake.

Mountain climbers and skiers have to contend with altitude sickness and frostbite. Scuba divers have the risks of decompression sickness, barotrauma, and hazardous marine life. Travelers on expeditions may have to deal with predatory animals, exotic parasites, and ethnic or political violence. People who participate in these activities should do so only when they are properly certified and educated in the associated health risks.

Ordinary tourists should enjoy safe adventures with well-established tour agencies and venues and should be cautioned against activities that expose them to dangers they may not be prepared to confront.

Insurance, evacuation, and emergency care

Health insurance often does not pay for preventive travel medicine. Unfortunately, cost can be a factor in immunizations and other health care. The cost of most travelers’ medications and vaccinations is generally comparable to that of other immunizations. The exceptions are two specialized vaccines—ie, for Japanese encephalitis ($1,000 or more for a full course) and for rabies, which can cost considerably more. Pricing by different providers can vary widely.

Travelers, especially those who are pregnant, elderly, disabled, or immunocompromised or who have preexisting diseases, need to review their insurance policies to make certain that care in foreign countries is covered. If not, evacuation insurance can be purchased at a relatively modest cost.

TRAVEL TO AREAS OF MALARIA

While many travelers can confidently consult their primary care provider, those traveling to places where malaria is prevalent should be referred to a physician with a thorough and current knowledge of the incidence of drugresistant strains of the disease and other complex issues in travel medicine. Short-term and long-term travelers are often approached differently, but a travel medicine consult should be obtained for any patient traveling to a region with malaria risk.

Based on data from the US Centers for Disease Control and Prevention.

Malaria kills up to 3 million each year

Malaria, caused by the Plasmodium parasite, transmitted by the night-biting Anopheles mosquito, is responsible worldwide for between 1 and 3 million deaths annually, mostly of children in sub-Saharan Africa.¹⁵ Every year about 1,500 Americans are diagnosed with malaria and, on average, 10 die.⁶

Nearly all cases of malaria and deaths from it are preventable. Prophylaxis is imperative for travelers to affected areas, as is preventive counseling. Based on the patient’s itinerary, the physician needs to thoroughly research potential exposure to drug-resistant strains before choosing which antimalarial regimen to prescribe.

Malaria causes symptoms of anemia, fever, or nausea and, without treatment, can lead to coma and death. Because two of the five strains, P vivax and P ovale, can remain dormant in an infected person’s liver for up to 1 year and, in rare cases, up to 4 years after travel, it is imperative that a returned traveler who experiences flu-like symptoms seek medical attention and inform the treating physician of the need to screen for malarial infection. The primary means of diagnosis is through microscopic examination of the blood.

No malaria vaccine, but prophylactic drugs are available

Unlike many of the illnesses discussed below for which vaccines are available, malaria prophylaxis requires the active participation of the patient in completing a course of medication, so noncompliance becomes a risk.

A number of prophylactic drugs are available. The choice depends on the locally resistant strains.¹⁶

Chloroquine (Aralen), the traditional malarial prophylactic drug, is still effective against many strains, primarily in Central America and some areas of the Middle East. The dosage is 500 mg once a week, started 1 week before travel and continued for 4 weeks after return to the United States.

Mefloquine (Lariam) is dosed at 250 mg weekly. The patient should be carefully screened for depression, anxiety, and other mood disorders. Even the report of bad dreams or nightmares should make a patient be considered a poor candidate for this medication. The patient should start taking this drug 3 weeks before travel to provide time to assess for adverse effects and, if necessary, to change the antimalarial regimen. Mefloquine is taken weekly while traveling and is continued for 4 weeks after return.

Doxycycline (Vibramycin) is an antibiotic. As an antimalarial prophylactic, it is taken as 100 mg daily beginning 2 days prior to travel and continuing while travelling and for 4 weeks after return.

Atovaquone-proguanil (Malarone) prevents infection at the blood stage and in the liver. It is well tolerated and is begun 2 days before travel. It is taken daily while traveling and daily for 1 week after return.

Yellow fever

From the US Centers for Disease Control and Prevention.

Immunization is required for entry to more than 20 African nations and is recommended for those traveling to most of South America. The only physicians who can give this vaccine are those who have approval from their state health department and have been issued an official stamp, used on the World Health Organization (WHO) yellow fever vaccination card. Several countries require the card for entry from places where yellow fever is present. For any multicountry travel involving at least one area where yellow fever is endemic, the entire itinerary needs to be reviewed to make sure all legal entry requirements are met. The WHO maintains a current list of these requirements.¹⁷ If there is any doubt, it is generally best to refer and certify the traveler.

Referral should be timely. The vaccine must be given 10 days prior to entry into a country where yellow fever is endemic; it is valid for 10 years.

The yellow fever vaccine is a live-attenuated vaccine and should not be given to infants younger than 9 months old, adults over age 60 who are not properly screened and informed, or pregnant women. Immunocompromised patients are excluded from receiving this vaccine, as are patients taking immunosuppressant drugs and patients with thymus disorders such as myasthenia gravis. Patients who have had chemotherapy must wait 3 months before being vaccinated. Those on steroids (eg, prednisone 20 mg or more daily) must wait until 2 weeks after cessation of steroids to receive this vaccine. Patients who cannot be vaccinated should be advised not to travel to areas with a high risk of yellow fever.

Women contemplating pregnancy should use contraception for 28 days after yellow fever vaccination. Children younger than 9 months and the elderly are at higher risk of adverse reactions from the vaccine, either neurotropic or viscerotropic disease that mimics yellow fever infection. It is possible for physicians to write a medical waiver of contraindication to vaccination for patients who should not be immunized.

Typhoid fever

Typhoid fever can occur anywhere in the world, but it is endemic in the tropics. Worldwide, an estimated 200,000 deaths occur each year from typhoid fever, and 400 cases are reported annually in the United States, most commonly acquired by travelers to the Indian subcontinent.¹⁸ One study indicates that 95% of infected travelers had not been vaccinated, and a significant number returned with drugresistant strains.¹⁹

Typhoid fever is caused by ingestion of Salmonella typhi bacteria. It causes a febrile illness with infection of the digestive tract and reticuloendothelial system.

Prevention is the same as for traveler’s diarrhea: drink no local water and eat nothing raw. Vaccination can be provided in an intramuscular shot or a series of oral capsules. The shot is well tolerated and is valid for 3 years. The capsule provides 5 years of immunity. Vaccination is recommended for people going to areas with a high prevalence of typhoid fever, such as India, and for people planning to spend more than 2 weeks in an area where typhoid is endemic, as well as for adventurous eaters.

SOME TRAVELERS NEED MORE PROTECTION

Some travelers need more preventive measures than typical tourists or other short-term visitors. Long-term visitors or travelers to remote or other high-risk areas (eg, adventure travelers, relief workers, mission workers) may need, in addition to the measures described above, measures against Japanese encephalitis, rabies, cholera, epidemic meningitis, and dengue fever.

Japanese encephalitis

Japanese encephalitis virus is transmitted by mosquito bite. The major regions where it is endemic are rural India and Southeast Asia, most typically in areas with rice paddies and pig farms. Travelers at risk are expatriates to these areas, those planning a long stay, and remote-adventure travelers.

The vaccine JE-VAX is given as a series of three shots, on days 0, 7, and 28. Another vaccine, Ixiaro, is given in a series of two shots, on days 0 and 28.

Patients who are allergic to bee or wasp stings should not be vaccinated. The patient should remain in the office for 30 minutes after each dose to permit observation for mild anaphylactic reactions such as angioedema and urticaria, and should complete the series 10 days before travel to allow for observation for delayed reactions. Patients must weigh the risk of contracting the disease against the high cost of the vaccine.

Rabies

Rabies is a potential risk anywhere in the world except in Western Europe and Australia. Because the vaccine is costly, it is generally not given for prophylaxis except for travelers certain to have contact with animals, especially the major vectors, ie, dogs, cats, bats, and monkeys.²⁰ Counseling about vigilance in avoiding animal contact and not promoting interaction through feeding wild animals should be part of any pretravel consult. Rabies, once acquired, is fatal.

The patient should be instructed on proper care of a bite from a potential rabies source and told to halt travel and seek medical attention. The wound should be cleaned with soap and water for 15 minutes to remove any saliva and virus from the soft tissue; this has proven to be effective in animal experiments. A virucidal such as benzalkonium chloride (Zephiran) or aqueous iodine should then be put in the wound.

Preexposure vaccination is done in a three-dose series (given on days 0, 7, and 21– 28). The patient should complete the series and adhere to the dosing schedule as closely as possible. It may be necessary to find a source of vaccine for the patient once he or she has arrived in the destination country.

If bitten, travelers without preexposure vaccination must find a source of vaccine and human rabies immune globulin (HRIG) before continuing on their trip. Postexposure treatment is 20 IU/kg of HRIG infiltrated around the wound to wall off the virus inoculation site. If the wound is in a digit or small area and not all of the HRIG can be given, then the remaining HRIG is given intramuscularly at a site distant from the vaccine site. If the patient has multiple bites, the HRIG should be diluted so it can be infiltrated around all wounds. The HRIG should be given immediately or within 7 days of beginning the vaccine series once a source is located. Later treatment than this can interfere with the patient’s ability to mount an immune reaction.

Rabies vaccine is initiated at the same time as HRIG and is given on days 0, 3, 7, 14, and 28. The CDC may soon change the schedule to allow for only four postexposure shots, but this has not yet been done as of this writing.

The patient vaccinated before exposure requires only booster doses of rabies vaccine at days 0 and 3.

Cholera

Cholera is an epidemic gastrointestinal disease historically responsible for millions of deaths. It is endemic in most tropical countries, especially in Africa and southern and southeastern Asia.²¹

High-risk patients, most often those working with refugees and disaster victims in endemic areas, should receive the traveler’s diarrhea and cholera vaccine Dukoral, which immunizes against Vibrio cholera and enterotoxogenic E coli. The vaccine, which is not available in the United States but is available abroad, is given as two oral doses 1 week apart for adults and three oral doses for children ages 2 to 6, and the second dose must be given 7 days before travel; this provides protection for 6 months.

At various times, the above vaccines have been in short supply. Travel medicine consults should be obtained for proper identification of the at-risk traveler for efficient use of any possibly limited vaccine.

Epidemic meningitis

The vaccine against epidemic meningitis is now routinely given in the United States to adolescents at the age of 12 or upon entry to college or the military. The fatality rate from the disease is 10%.

Meningococcal disease transmission peaks in the sub-Saharan “meningitis belt” in the dry season of December through June. Travelers to these areas at these times should be immunized. Travelers planning close contact with the local population (eg, health care workers) should be immunized. Patients traveling to Saudi Arabia for Hajj in Mecca must be immunized for meningitis for entry to the country during this time. The vaccine must be given within 3 years of entering the country and not less than 10 days before.

Dengue fever

Dengue fever is a flavivirus transmitted through the Aedes aegypti mosquito. No vaccine is available for dengue fever, so for now the only advice is to avoid insect vectors.

There are four closely related but serologically different dengue viruses that provide only weak cross-protection. In fact, previous infection with one serotype in a traveler then infected with another poses a risk of dengue hemorrhagic fever.

Because of inattention to public sanitation, this virus and its mosquito vector have reemerged in areas where they were once eliminated. The viral infection is a risk for the traveler to both urban and rural areas in the Americas, Southeast Asia, and Africa. The Pan American Health Organization has seen the number of reported dengue cases increase from 66,000 in 1980 to 700,000 in 2003.²²

Before going abroad to areas that might pose a risk to their health, most people ought to visit their primary care physicians and many should be referred to a specialist in travel medicine.

In this article, we review the key elements of the pretravel consult as it relates to the prevention and self-treatment of the most common diseases that pose health risks for travelers. We also give guidelines for when to refer patients to a specialist.

WHY PRIMARY CARE PHYSICIANS NEED TO KNOW TRAVEL MEDICINE

International travel to exotic locations is becoming more popular. In 2008, one out of five Americans traveled abroad, and 38 million visits were to developing countries where there are significant health risks for travelers.¹

One third to one half of travelers to developing countries experience some kind of illness while abroad, most commonly diarrhea or upper respiratory infections, which typically lead to 3 lost days during a 2-week trip.

These illnesses are often preventable and self-treatable.² Unfortunately, studies suggest that most travelers do not seek adequate medical advice, and that when they do they often fail to complete courses of medication.^3,4

All these factors point to the need for primary care providers to become proficient in the pretravel consult and, if necessary, to refer patients to travel specialists and clinics.

WHY REFER TO A TRAVEL CLINIC?

In one study of travelers to areas of high risk for malaria or hepatitis A, 42% of those who consulted only their family doctor became ill, in contrast to 22% of those who attended a travel medicine clinic.⁴

As a rule of thumb, anyone traveling to an area where malaria is endemic should be referred to a specialist, as should anyone at risk of yellow fever or typhoid fever. As many as 8 per 1,000 travelers may return from areas of risk infected with malaria.⁵

Long-term travelers and people who will spend time in urban slums or rural or remote regions have an even greater need for referral to a travel clinic, as they are at higher risk of exposure to Japanese encephalitis, cholera, epidemic meningitis, dengue fever, and rabies.⁶

THE PRETRAVEL CONSULT: ESSENTIALS

A pretravel consult ought to be scheduled 4 to 6 weeks in advance of the trip, since many vaccines require that much time to induce immunity, and some require a series of shots.

Unfortunately, many patients who think of arranging a travel consult make the appointment at the last minute, and some come with an incomplete knowledge of their travel plans. However, even without enough advance notice, a consult can be beneficial.

Travelers sometimes change their itineraries in-country or engage in unanticipated risky behaviors. A good travel medicine physician tries to anticipate even these unplanned risks and changes in itinerary.

Where is the traveler going? When? For how long?

The pretravel consult starts with a detailed discussion of the patient’s itinerary. It needs to include length, dates, and location of travel, as well as anticipated activities and accommodations.

A remarkable number of travelers come to consults not knowing the names of specific countries they will visit, perhaps saying only that they are going to Africa or South America. An accurate itinerary is indispensible, as appropriate medical advice is highly specific to country and region. The incidence and geographic distribution of many travelers’ diseases change over time, and this requires physicians to consult the most current information available.

Tropical countries, in general, are risky, but each pathogen has a unique distribution that may vary between urban and rural areas or by season. Detailed, up-to-date information is available from the US Centers for Disease Control and Prevention (CDC) (www.cdc.gov) for individual countries and for specific provinces and locations within those countries. Physicians should consult the CDC whenever advising a patient preparing to travel. ⁷

How is the traveler’s current health?

Several immunizations cannot be given to the very young, the elderly, or those who are immunocompromised.

The greatest risk of death to travelers is not from tropical diseases but from cardiovascular disease, which according to one study is responsible for half of deaths abroad.⁸ Patients with heart disease or other known health concerns need to be counseled to avoid activities that will put them at further risk. The advice applies especially in situations such as remote travel or even cruises, where prompt emergency medical care may be difficult or impossible to obtain.

People infected with human immunodeficiency virus (HIV) face discriminatory travel prohibitions in 74 countries.⁹

Foreign-born travelers who are visiting family and friends in developing countries may have lost their immunity to local pathogens and thus can be more at risk because they are not prepared to take necessary health precautions.

Also, a significant number of travelers become infected but develop illnesses only after they return, so a posttravel visit may be necessary.⁶

Prescription and even over-the-the-counter drugs may be difficult or impossible to obtain in foreign countries, and ample supplies should be brought along.

Is the traveler up to date on routine immunizations?

A number of infectious diseases that have been controlled or eradicated in North America through regular childhood immunizations are still endemic in many remote areas and developing countries. All travelers should be up to date on routine immunizations, including those for measles-mumps-rubella, tetanus, polio, meningitis, and hepatitis A and B.

Polio. A one-time polio booster is recommended for adults traveling to certain countries or areas of the world.

Meningitis vaccine is now routinely given to young people, but adult patients may need it before they travel.

Hepatitis A is contracted through fecal contamination of food and water. Common sources are foods prepared in an unhygienic manner, raw fruits and vegetables, shellfish, and contaminated water.

Hepatitis B vaccine is also now routinely given to young people, but it should be offered to travelers planning to stay more than 1 month and to long-term expatriates. This vaccine is also recommended for travelers who may be exposed to blood or body fluids, who are contemplating sexual activity or tattooing in the host country, or who may require medical or dental care while traveling, as well as for adventure travelers or travelers to remote regions.

The vaccination is given in a three-dose schedule at 0, 1, and 6 months. For protection against both hepatitis A and B, the vaccine Twinrix can be used on the same schedule as for hepatitis B. An accelerated schedule of 0, 7, and 21 days with a booster at 12 months allows completion of the entire series in 4 weeks, thus putting completion of vaccination before travel in the same time frame as other vaccines in a series, such as those for rabies and Japanese encephalitis.

PREVENTIVE COUNSELING

In addition, travelers going abroad should be advised on measures to avoid diarrhea, insectvector diseases, accidents, excessive exposure to the sun, altitude sickness, and other risks their itineraries may expose them to.

Avoiding traveler’s diarrhea

Traveler’s diarrhea is by far the most common health problem experienced abroad. It is prevalent in Mexico, where 20 million visits by Americans occur each year. A quarter to half of visitors to developing countries contract traveler’s diarrhea and, on average, lose 2 to 3 days of their business trip or vacation.^3,10 The disease therefore imposes not only discomfort but also financial losses on travelers, especially business travelers.

Though many pathogens may be responsible, the most common one is Escherichia coli, usually transmitted by human fecal contamination of food or drink. Preventive measures against E coli are the same as for other foodborne and waterborne infections, such as hepatitis A, cholera, and typhoid fever.

The rule for avoiding traveler’s diarrhea may be summarized by the CDC-coined phrase, “boil it, cook it, peel it, or forget it.” Simple, written advice is most likely to be followed. ⁶ Thorough boiling or cooking kills bacteria in contaminated food, and food should be served steaming hot. Travelers should only eat foods they know have been well cooked, declining cold dishes like salsa or casseroles. They should avoid tap water for brushing teeth or in the form of ice cubes and should stick to drinking bottled beverages, preferably carbonated ones. No matter how appetizing a salad looks, travelers should avoid eating fresh fruits and vegetables unless they are sure that they were peeled under sanitary conditions. Simply eating at a high-priced restaurant is not a guarantee of uncontaminated food. Before meals or any hand-to-mouth contact, hands should be washed in soap and water or with sanitizers.

Travelers to remote areas may wish to acquire filtering devices, chlorine, or iodine for treating water. A combination of filtering and iodine treatment is most effective.

While this advice is undoubtedly wise, the evidence shows that, in practice, most travelers fail to take all precautions, and the benefits of this counseling have been difficult to demonstrate.¹¹ Therefore, physicians should prescribe drugs for prophylaxis and self-treatment of traveler’s diarrhea during travel.

Bismuth subsalicylate (Pepto-Bismol) taken as two tablets or 2 oz of liquid 4 times a day while traveling may reduce the risk of diarrhea by one half, though it should be avoided by patients with contraindications to aspirin.^3,6

Self-treating traveler’s diarrhea

Proper hydration is crucial, since dehydration can worsen and prolong symptoms.

Ciprofloxacin (Cipro) 500 mg orally two times daily for 3 to 5 days is effective.

Azithromycin (Zithromax) 500 mg daily for 3 to 5 days may be better in some areas of Southeast Asia, where fluoroquinolone-resistant bacteria are prevalent.

Rifaximin (Xifaxan), a nonsystemic antibiotic, is another option. The dosage is 200 mg three times a day for 3 days.

Avoiding insect bites

Malaria, yellow fever, tickborne encephalitis, and dengue fever are all transmitted by insect bites. Often the best protection is to avoid being bitten.

Bites can be avoided by using insect repellants containing diethyltoluamide (DEET) or picardin. If the traveler is going to be out in the sun, he or she should apply sunscreen first, then DEET on top of that. Anopheles, which transmits malaria, is a night-biting mosquito and may be avoided by staying in screened areas at dusk and dawn and by using bed netting. Permethrin, an insecticide, can be applied to clothing and mosquito netting.

Other things to avoid

Accidents are the second most common cause of death in travelers (after cardiovascular disease), accounting for as many as one-third of deaths.⁹ Several studies indicate road accidents are the major cause of accidental death, but also significant are drowning and air crashes. Travelers should be advised that transportation in developing countries is often more dangerous than at home. Seaside vacationers should be aware of the dangers of riptides and other threats to swimmers and should obey warnings posted at beaches.

Sexually transmitted diseases. When appropriate, physicians should warn travelers about the dangers of contracting HIV and other sexually transmitted diseases, especially in sub-Saharan Africa.

Sunburn, dehydration. Travelers should regularly use sunscreen and should remain hydrated.

Crimes against and involving tourists are a serious threat in many places, including some popular destinations. All of the 100,000 young people traveling to Mexico each year for spring break should read the US Department of State warnings against crime and possible arrest in that country.¹² Travelers who are victims of crimes in foreign countries should contact their national consulate as soon as possible. The US Department of State issues advisories on countries where there is danger to travelers because of political turmoil, crime, or other causes.¹³

Motion sickness and jet lag can be ameliorated by proper hydration, avoiding caffeine, and using a scopolamine patch or dimenhydrinate (Dramamine).¹

When traveling to wilderness areas

Wilderness and expedition medicine is a complex subset of travel medicine.¹⁴ All travelers need to understand the risks of whatever activities they undertake.

Mountain climbers and skiers have to contend with altitude sickness and frostbite. Scuba divers have the risks of decompression sickness, barotrauma, and hazardous marine life. Travelers on expeditions may have to deal with predatory animals, exotic parasites, and ethnic or political violence. People who participate in these activities should do so only when they are properly certified and educated in the associated health risks.

Ordinary tourists should enjoy safe adventures with well-established tour agencies and venues and should be cautioned against activities that expose them to dangers they may not be prepared to confront.

Insurance, evacuation, and emergency care

Health insurance often does not pay for preventive travel medicine. Unfortunately, cost can be a factor in immunizations and other health care. The cost of most travelers’ medications and vaccinations is generally comparable to that of other immunizations. The exceptions are two specialized vaccines—ie, for Japanese encephalitis ($1,000 or more for a full course) and for rabies, which can cost considerably more. Pricing by different providers can vary widely.

Travelers, especially those who are pregnant, elderly, disabled, or immunocompromised or who have preexisting diseases, need to review their insurance policies to make certain that care in foreign countries is covered. If not, evacuation insurance can be purchased at a relatively modest cost.

TRAVEL TO AREAS OF MALARIA

While many travelers can confidently consult their primary care provider, those traveling to places where malaria is prevalent should be referred to a physician with a thorough and current knowledge of the incidence of drugresistant strains of the disease and other complex issues in travel medicine. Short-term and long-term travelers are often approached differently, but a travel medicine consult should be obtained for any patient traveling to a region with malaria risk.

Based on data from the US Centers for Disease Control and Prevention.

Malaria kills up to 3 million each year

Malaria, caused by the Plasmodium parasite, transmitted by the night-biting Anopheles mosquito, is responsible worldwide for between 1 and 3 million deaths annually, mostly of children in sub-Saharan Africa.¹⁵ Every year about 1,500 Americans are diagnosed with malaria and, on average, 10 die.⁶

Nearly all cases of malaria and deaths from it are preventable. Prophylaxis is imperative for travelers to affected areas, as is preventive counseling. Based on the patient’s itinerary, the physician needs to thoroughly research potential exposure to drug-resistant strains before choosing which antimalarial regimen to prescribe.

Malaria causes symptoms of anemia, fever, or nausea and, without treatment, can lead to coma and death. Because two of the five strains, P vivax and P ovale, can remain dormant in an infected person’s liver for up to 1 year and, in rare cases, up to 4 years after travel, it is imperative that a returned traveler who experiences flu-like symptoms seek medical attention and inform the treating physician of the need to screen for malarial infection. The primary means of diagnosis is through microscopic examination of the blood.

No malaria vaccine, but prophylactic drugs are available

Unlike many of the illnesses discussed below for which vaccines are available, malaria prophylaxis requires the active participation of the patient in completing a course of medication, so noncompliance becomes a risk.

A number of prophylactic drugs are available. The choice depends on the locally resistant strains.¹⁶

Chloroquine (Aralen), the traditional malarial prophylactic drug, is still effective against many strains, primarily in Central America and some areas of the Middle East. The dosage is 500 mg once a week, started 1 week before travel and continued for 4 weeks after return to the United States.

Mefloquine (Lariam) is dosed at 250 mg weekly. The patient should be carefully screened for depression, anxiety, and other mood disorders. Even the report of bad dreams or nightmares should make a patient be considered a poor candidate for this medication. The patient should start taking this drug 3 weeks before travel to provide time to assess for adverse effects and, if necessary, to change the antimalarial regimen. Mefloquine is taken weekly while traveling and is continued for 4 weeks after return.

Doxycycline (Vibramycin) is an antibiotic. As an antimalarial prophylactic, it is taken as 100 mg daily beginning 2 days prior to travel and continuing while travelling and for 4 weeks after return.

Atovaquone-proguanil (Malarone) prevents infection at the blood stage and in the liver. It is well tolerated and is begun 2 days before travel. It is taken daily while traveling and daily for 1 week after return.

Yellow fever

From the US Centers for Disease Control and Prevention.

Immunization is required for entry to more than 20 African nations and is recommended for those traveling to most of South America. The only physicians who can give this vaccine are those who have approval from their state health department and have been issued an official stamp, used on the World Health Organization (WHO) yellow fever vaccination card. Several countries require the card for entry from places where yellow fever is present. For any multicountry travel involving at least one area where yellow fever is endemic, the entire itinerary needs to be reviewed to make sure all legal entry requirements are met. The WHO maintains a current list of these requirements.¹⁷ If there is any doubt, it is generally best to refer and certify the traveler.

Referral should be timely. The vaccine must be given 10 days prior to entry into a country where yellow fever is endemic; it is valid for 10 years.

The yellow fever vaccine is a live-attenuated vaccine and should not be given to infants younger than 9 months old, adults over age 60 who are not properly screened and informed, or pregnant women. Immunocompromised patients are excluded from receiving this vaccine, as are patients taking immunosuppressant drugs and patients with thymus disorders such as myasthenia gravis. Patients who have had chemotherapy must wait 3 months before being vaccinated. Those on steroids (eg, prednisone 20 mg or more daily) must wait until 2 weeks after cessation of steroids to receive this vaccine. Patients who cannot be vaccinated should be advised not to travel to areas with a high risk of yellow fever.

Women contemplating pregnancy should use contraception for 28 days after yellow fever vaccination. Children younger than 9 months and the elderly are at higher risk of adverse reactions from the vaccine, either neurotropic or viscerotropic disease that mimics yellow fever infection. It is possible for physicians to write a medical waiver of contraindication to vaccination for patients who should not be immunized.

Typhoid fever

Typhoid fever can occur anywhere in the world, but it is endemic in the tropics. Worldwide, an estimated 200,000 deaths occur each year from typhoid fever, and 400 cases are reported annually in the United States, most commonly acquired by travelers to the Indian subcontinent.¹⁸ One study indicates that 95% of infected travelers had not been vaccinated, and a significant number returned with drugresistant strains.¹⁹

Typhoid fever is caused by ingestion of Salmonella typhi bacteria. It causes a febrile illness with infection of the digestive tract and reticuloendothelial system.

Prevention is the same as for traveler’s diarrhea: drink no local water and eat nothing raw. Vaccination can be provided in an intramuscular shot or a series of oral capsules. The shot is well tolerated and is valid for 3 years. The capsule provides 5 years of immunity. Vaccination is recommended for people going to areas with a high prevalence of typhoid fever, such as India, and for people planning to spend more than 2 weeks in an area where typhoid is endemic, as well as for adventurous eaters.

SOME TRAVELERS NEED MORE PROTECTION

Some travelers need more preventive measures than typical tourists or other short-term visitors. Long-term visitors or travelers to remote or other high-risk areas (eg, adventure travelers, relief workers, mission workers) may need, in addition to the measures described above, measures against Japanese encephalitis, rabies, cholera, epidemic meningitis, and dengue fever.

Japanese encephalitis

Japanese encephalitis virus is transmitted by mosquito bite. The major regions where it is endemic are rural India and Southeast Asia, most typically in areas with rice paddies and pig farms. Travelers at risk are expatriates to these areas, those planning a long stay, and remote-adventure travelers.

The vaccine JE-VAX is given as a series of three shots, on days 0, 7, and 28. Another vaccine, Ixiaro, is given in a series of two shots, on days 0 and 28.

Patients who are allergic to bee or wasp stings should not be vaccinated. The patient should remain in the office for 30 minutes after each dose to permit observation for mild anaphylactic reactions such as angioedema and urticaria, and should complete the series 10 days before travel to allow for observation for delayed reactions. Patients must weigh the risk of contracting the disease against the high cost of the vaccine.

Rabies

Rabies is a potential risk anywhere in the world except in Western Europe and Australia. Because the vaccine is costly, it is generally not given for prophylaxis except for travelers certain to have contact with animals, especially the major vectors, ie, dogs, cats, bats, and monkeys.²⁰ Counseling about vigilance in avoiding animal contact and not promoting interaction through feeding wild animals should be part of any pretravel consult. Rabies, once acquired, is fatal.

The patient should be instructed on proper care of a bite from a potential rabies source and told to halt travel and seek medical attention. The wound should be cleaned with soap and water for 15 minutes to remove any saliva and virus from the soft tissue; this has proven to be effective in animal experiments. A virucidal such as benzalkonium chloride (Zephiran) or aqueous iodine should then be put in the wound.

Preexposure vaccination is done in a three-dose series (given on days 0, 7, and 21– 28). The patient should complete the series and adhere to the dosing schedule as closely as possible. It may be necessary to find a source of vaccine for the patient once he or she has arrived in the destination country.

If bitten, travelers without preexposure vaccination must find a source of vaccine and human rabies immune globulin (HRIG) before continuing on their trip. Postexposure treatment is 20 IU/kg of HRIG infiltrated around the wound to wall off the virus inoculation site. If the wound is in a digit or small area and not all of the HRIG can be given, then the remaining HRIG is given intramuscularly at a site distant from the vaccine site. If the patient has multiple bites, the HRIG should be diluted so it can be infiltrated around all wounds. The HRIG should be given immediately or within 7 days of beginning the vaccine series once a source is located. Later treatment than this can interfere with the patient’s ability to mount an immune reaction.

Rabies vaccine is initiated at the same time as HRIG and is given on days 0, 3, 7, 14, and 28. The CDC may soon change the schedule to allow for only four postexposure shots, but this has not yet been done as of this writing.

The patient vaccinated before exposure requires only booster doses of rabies vaccine at days 0 and 3.

Cholera

Cholera is an epidemic gastrointestinal disease historically responsible for millions of deaths. It is endemic in most tropical countries, especially in Africa and southern and southeastern Asia.²¹

High-risk patients, most often those working with refugees and disaster victims in endemic areas, should receive the traveler’s diarrhea and cholera vaccine Dukoral, which immunizes against Vibrio cholera and enterotoxogenic E coli. The vaccine, which is not available in the United States but is available abroad, is given as two oral doses 1 week apart for adults and three oral doses for children ages 2 to 6, and the second dose must be given 7 days before travel; this provides protection for 6 months.

At various times, the above vaccines have been in short supply. Travel medicine consults should be obtained for proper identification of the at-risk traveler for efficient use of any possibly limited vaccine.

Epidemic meningitis

The vaccine against epidemic meningitis is now routinely given in the United States to adolescents at the age of 12 or upon entry to college or the military. The fatality rate from the disease is 10%.

Meningococcal disease transmission peaks in the sub-Saharan “meningitis belt” in the dry season of December through June. Travelers to these areas at these times should be immunized. Travelers planning close contact with the local population (eg, health care workers) should be immunized. Patients traveling to Saudi Arabia for Hajj in Mecca must be immunized for meningitis for entry to the country during this time. The vaccine must be given within 3 years of entering the country and not less than 10 days before.

Dengue fever

Dengue fever is a flavivirus transmitted through the Aedes aegypti mosquito. No vaccine is available for dengue fever, so for now the only advice is to avoid insect vectors.

There are four closely related but serologically different dengue viruses that provide only weak cross-protection. In fact, previous infection with one serotype in a traveler then infected with another poses a risk of dengue hemorrhagic fever.

Because of inattention to public sanitation, this virus and its mosquito vector have reemerged in areas where they were once eliminated. The viral infection is a risk for the traveler to both urban and rural areas in the Americas, Southeast Asia, and Africa. The Pan American Health Organization has seen the number of reported dengue cases increase from 66,000 in 1980 to 700,000 in 2003.²²

Before going abroad to areas that might pose a risk to their health, most people ought to visit their primary care physicians and many should be referred to a specialist in travel medicine.

In this article, we review the key elements of the pretravel consult as it relates to the prevention and self-treatment of the most common diseases that pose health risks for travelers. We also give guidelines for when to refer patients to a specialist.

WHY PRIMARY CARE PHYSICIANS NEED TO KNOW TRAVEL MEDICINE

International travel to exotic locations is becoming more popular. In 2008, one out of five Americans traveled abroad, and 38 million visits were to developing countries where there are significant health risks for travelers.¹

One third to one half of travelers to developing countries experience some kind of illness while abroad, most commonly diarrhea or upper respiratory infections, which typically lead to 3 lost days during a 2-week trip.

These illnesses are often preventable and self-treatable.² Unfortunately, studies suggest that most travelers do not seek adequate medical advice, and that when they do they often fail to complete courses of medication.^3,4

All these factors point to the need for primary care providers to become proficient in the pretravel consult and, if necessary, to refer patients to travel specialists and clinics.

WHY REFER TO A TRAVEL CLINIC?

In one study of travelers to areas of high risk for malaria or hepatitis A, 42% of those who consulted only their family doctor became ill, in contrast to 22% of those who attended a travel medicine clinic.⁴

As a rule of thumb, anyone traveling to an area where malaria is endemic should be referred to a specialist, as should anyone at risk of yellow fever or typhoid fever. As many as 8 per 1,000 travelers may return from areas of risk infected with malaria.⁵

Long-term travelers and people who will spend time in urban slums or rural or remote regions have an even greater need for referral to a travel clinic, as they are at higher risk of exposure to Japanese encephalitis, cholera, epidemic meningitis, dengue fever, and rabies.⁶

THE PRETRAVEL CONSULT: ESSENTIALS

A pretravel consult ought to be scheduled 4 to 6 weeks in advance of the trip, since many vaccines require that much time to induce immunity, and some require a series of shots.

Unfortunately, many patients who think of arranging a travel consult make the appointment at the last minute, and some come with an incomplete knowledge of their travel plans. However, even without enough advance notice, a consult can be beneficial.

Travelers sometimes change their itineraries in-country or engage in unanticipated risky behaviors. A good travel medicine physician tries to anticipate even these unplanned risks and changes in itinerary.

Where is the traveler going? When? For how long?

The pretravel consult starts with a detailed discussion of the patient’s itinerary. It needs to include length, dates, and location of travel, as well as anticipated activities and accommodations.

A remarkable number of travelers come to consults not knowing the names of specific countries they will visit, perhaps saying only that they are going to Africa or South America. An accurate itinerary is indispensible, as appropriate medical advice is highly specific to country and region. The incidence and geographic distribution of many travelers’ diseases change over time, and this requires physicians to consult the most current information available.

Tropical countries, in general, are risky, but each pathogen has a unique distribution that may vary between urban and rural areas or by season. Detailed, up-to-date information is available from the US Centers for Disease Control and Prevention (CDC) (www.cdc.gov) for individual countries and for specific provinces and locations within those countries. Physicians should consult the CDC whenever advising a patient preparing to travel. ⁷

How is the traveler’s current health?

Several immunizations cannot be given to the very young, the elderly, or those who are immunocompromised.

The greatest risk of death to travelers is not from tropical diseases but from cardiovascular disease, which according to one study is responsible for half of deaths abroad.⁸ Patients with heart disease or other known health concerns need to be counseled to avoid activities that will put them at further risk. The advice applies especially in situations such as remote travel or even cruises, where prompt emergency medical care may be difficult or impossible to obtain.

People infected with human immunodeficiency virus (HIV) face discriminatory travel prohibitions in 74 countries.⁹

Foreign-born travelers who are visiting family and friends in developing countries may have lost their immunity to local pathogens and thus can be more at risk because they are not prepared to take necessary health precautions.

Also, a significant number of travelers become infected but develop illnesses only after they return, so a posttravel visit may be necessary.⁶

Prescription and even over-the-the-counter drugs may be difficult or impossible to obtain in foreign countries, and ample supplies should be brought along.

Is the traveler up to date on routine immunizations?

A number of infectious diseases that have been controlled or eradicated in North America through regular childhood immunizations are still endemic in many remote areas and developing countries. All travelers should be up to date on routine immunizations, including those for measles-mumps-rubella, tetanus, polio, meningitis, and hepatitis A and B.

Polio. A one-time polio booster is recommended for adults traveling to certain countries or areas of the world.

Meningitis vaccine is now routinely given to young people, but adult patients may need it before they travel.

Hepatitis A is contracted through fecal contamination of food and water. Common sources are foods prepared in an unhygienic manner, raw fruits and vegetables, shellfish, and contaminated water.

Hepatitis B vaccine is also now routinely given to young people, but it should be offered to travelers planning to stay more than 1 month and to long-term expatriates. This vaccine is also recommended for travelers who may be exposed to blood or body fluids, who are contemplating sexual activity or tattooing in the host country, or who may require medical or dental care while traveling, as well as for adventure travelers or travelers to remote regions.

The vaccination is given in a three-dose schedule at 0, 1, and 6 months. For protection against both hepatitis A and B, the vaccine Twinrix can be used on the same schedule as for hepatitis B. An accelerated schedule of 0, 7, and 21 days with a booster at 12 months allows completion of the entire series in 4 weeks, thus putting completion of vaccination before travel in the same time frame as other vaccines in a series, such as those for rabies and Japanese encephalitis.

PREVENTIVE COUNSELING

In addition, travelers going abroad should be advised on measures to avoid diarrhea, insectvector diseases, accidents, excessive exposure to the sun, altitude sickness, and other risks their itineraries may expose them to.

Avoiding traveler’s diarrhea

Traveler’s diarrhea is by far the most common health problem experienced abroad. It is prevalent in Mexico, where 20 million visits by Americans occur each year. A quarter to half of visitors to developing countries contract traveler’s diarrhea and, on average, lose 2 to 3 days of their business trip or vacation.^3,10 The disease therefore imposes not only discomfort but also financial losses on travelers, especially business travelers.

Though many pathogens may be responsible, the most common one is Escherichia coli, usually transmitted by human fecal contamination of food or drink. Preventive measures against E coli are the same as for other foodborne and waterborne infections, such as hepatitis A, cholera, and typhoid fever.

The rule for avoiding traveler’s diarrhea may be summarized by the CDC-coined phrase, “boil it, cook it, peel it, or forget it.” Simple, written advice is most likely to be followed. ⁶ Thorough boiling or cooking kills bacteria in contaminated food, and food should be served steaming hot. Travelers should only eat foods they know have been well cooked, declining cold dishes like salsa or casseroles. They should avoid tap water for brushing teeth or in the form of ice cubes and should stick to drinking bottled beverages, preferably carbonated ones. No matter how appetizing a salad looks, travelers should avoid eating fresh fruits and vegetables unless they are sure that they were peeled under sanitary conditions. Simply eating at a high-priced restaurant is not a guarantee of uncontaminated food. Before meals or any hand-to-mouth contact, hands should be washed in soap and water or with sanitizers.

Travelers to remote areas may wish to acquire filtering devices, chlorine, or iodine for treating water. A combination of filtering and iodine treatment is most effective.

While this advice is undoubtedly wise, the evidence shows that, in practice, most travelers fail to take all precautions, and the benefits of this counseling have been difficult to demonstrate.¹¹ Therefore, physicians should prescribe drugs for prophylaxis and self-treatment of traveler’s diarrhea during travel.

Bismuth subsalicylate (Pepto-Bismol) taken as two tablets or 2 oz of liquid 4 times a day while traveling may reduce the risk of diarrhea by one half, though it should be avoided by patients with contraindications to aspirin.^3,6

Self-treating traveler’s diarrhea

Proper hydration is crucial, since dehydration can worsen and prolong symptoms.

Ciprofloxacin (Cipro) 500 mg orally two times daily for 3 to 5 days is effective.

Azithromycin (Zithromax) 500 mg daily for 3 to 5 days may be better in some areas of Southeast Asia, where fluoroquinolone-resistant bacteria are prevalent.

Rifaximin (Xifaxan), a nonsystemic antibiotic, is another option. The dosage is 200 mg three times a day for 3 days.

Avoiding insect bites

Malaria, yellow fever, tickborne encephalitis, and dengue fever are all transmitted by insect bites. Often the best protection is to avoid being bitten.

Bites can be avoided by using insect repellants containing diethyltoluamide (DEET) or picardin. If the traveler is going to be out in the sun, he or she should apply sunscreen first, then DEET on top of that. Anopheles, which transmits malaria, is a night-biting mosquito and may be avoided by staying in screened areas at dusk and dawn and by using bed netting. Permethrin, an insecticide, can be applied to clothing and mosquito netting.

Other things to avoid

Accidents are the second most common cause of death in travelers (after cardiovascular disease), accounting for as many as one-third of deaths.⁹ Several studies indicate road accidents are the major cause of accidental death, but also significant are drowning and air crashes. Travelers should be advised that transportation in developing countries is often more dangerous than at home. Seaside vacationers should be aware of the dangers of riptides and other threats to swimmers and should obey warnings posted at beaches.

Sexually transmitted diseases. When appropriate, physicians should warn travelers about the dangers of contracting HIV and other sexually transmitted diseases, especially in sub-Saharan Africa.

Sunburn, dehydration. Travelers should regularly use sunscreen and should remain hydrated.

Crimes against and involving tourists are a serious threat in many places, including some popular destinations. All of the 100,000 young people traveling to Mexico each year for spring break should read the US Department of State warnings against crime and possible arrest in that country.¹² Travelers who are victims of crimes in foreign countries should contact their national consulate as soon as possible. The US Department of State issues advisories on countries where there is danger to travelers because of political turmoil, crime, or other causes.¹³

Motion sickness and jet lag can be ameliorated by proper hydration, avoiding caffeine, and using a scopolamine patch or dimenhydrinate (Dramamine).¹

When traveling to wilderness areas

Wilderness and expedition medicine is a complex subset of travel medicine.¹⁴ All travelers need to understand the risks of whatever activities they undertake.

Mountain climbers and skiers have to contend with altitude sickness and frostbite. Scuba divers have the risks of decompression sickness, barotrauma, and hazardous marine life. Travelers on expeditions may have to deal with predatory animals, exotic parasites, and ethnic or political violence. People who participate in these activities should do so only when they are properly certified and educated in the associated health risks.

Ordinary tourists should enjoy safe adventures with well-established tour agencies and venues and should be cautioned against activities that expose them to dangers they may not be prepared to confront.

Insurance, evacuation, and emergency care

Health insurance often does not pay for preventive travel medicine. Unfortunately, cost can be a factor in immunizations and other health care. The cost of most travelers’ medications and vaccinations is generally comparable to that of other immunizations. The exceptions are two specialized vaccines—ie, for Japanese encephalitis ($1,000 or more for a full course) and for rabies, which can cost considerably more. Pricing by different providers can vary widely.

Travelers, especially those who are pregnant, elderly, disabled, or immunocompromised or who have preexisting diseases, need to review their insurance policies to make certain that care in foreign countries is covered. If not, evacuation insurance can be purchased at a relatively modest cost.

TRAVEL TO AREAS OF MALARIA

While many travelers can confidently consult their primary care provider, those traveling to places where malaria is prevalent should be referred to a physician with a thorough and current knowledge of the incidence of drugresistant strains of the disease and other complex issues in travel medicine. Short-term and long-term travelers are often approached differently, but a travel medicine consult should be obtained for any patient traveling to a region with malaria risk.

Based on data from the US Centers for Disease Control and Prevention.

Malaria kills up to 3 million each year

Malaria, caused by the Plasmodium parasite, transmitted by the night-biting Anopheles mosquito, is responsible worldwide for between 1 and 3 million deaths annually, mostly of children in sub-Saharan Africa.¹⁵ Every year about 1,500 Americans are diagnosed with malaria and, on average, 10 die.⁶

Nearly all cases of malaria and deaths from it are preventable. Prophylaxis is imperative for travelers to affected areas, as is preventive counseling. Based on the patient’s itinerary, the physician needs to thoroughly research potential exposure to drug-resistant strains before choosing which antimalarial regimen to prescribe.

Malaria causes symptoms of anemia, fever, or nausea and, without treatment, can lead to coma and death. Because two of the five strains, P vivax and P ovale, can remain dormant in an infected person’s liver for up to 1 year and, in rare cases, up to 4 years after travel, it is imperative that a returned traveler who experiences flu-like symptoms seek medical attention and inform the treating physician of the need to screen for malarial infection. The primary means of diagnosis is through microscopic examination of the blood.

No malaria vaccine, but prophylactic drugs are available

Unlike many of the illnesses discussed below for which vaccines are available, malaria prophylaxis requires the active participation of the patient in completing a course of medication, so noncompliance becomes a risk.

A number of prophylactic drugs are available. The choice depends on the locally resistant strains.¹⁶

Chloroquine (Aralen), the traditional malarial prophylactic drug, is still effective against many strains, primarily in Central America and some areas of the Middle East. The dosage is 500 mg once a week, started 1 week before travel and continued for 4 weeks after return to the United States.

Mefloquine (Lariam) is dosed at 250 mg weekly. The patient should be carefully screened for depression, anxiety, and other mood disorders. Even the report of bad dreams or nightmares should make a patient be considered a poor candidate for this medication. The patient should start taking this drug 3 weeks before travel to provide time to assess for adverse effects and, if necessary, to change the antimalarial regimen. Mefloquine is taken weekly while traveling and is continued for 4 weeks after return.

Doxycycline (Vibramycin) is an antibiotic. As an antimalarial prophylactic, it is taken as 100 mg daily beginning 2 days prior to travel and continuing while travelling and for 4 weeks after return.

Atovaquone-proguanil (Malarone) prevents infection at the blood stage and in the liver. It is well tolerated and is begun 2 days before travel. It is taken daily while traveling and daily for 1 week after return.

Yellow fever

From the US Centers for Disease Control and Prevention.

Immunization is required for entry to more than 20 African nations and is recommended for those traveling to most of South America. The only physicians who can give this vaccine are those who have approval from their state health department and have been issued an official stamp, used on the World Health Organization (WHO) yellow fever vaccination card. Several countries require the card for entry from places where yellow fever is present. For any multicountry travel involving at least one area where yellow fever is endemic, the entire itinerary needs to be reviewed to make sure all legal entry requirements are met. The WHO maintains a current list of these requirements.¹⁷ If there is any doubt, it is generally best to refer and certify the traveler.

Referral should be timely. The vaccine must be given 10 days prior to entry into a country where yellow fever is endemic; it is valid for 10 years.

The yellow fever vaccine is a live-attenuated vaccine and should not be given to infants younger than 9 months old, adults over age 60 who are not properly screened and informed, or pregnant women. Immunocompromised patients are excluded from receiving this vaccine, as are patients taking immunosuppressant drugs and patients with thymus disorders such as myasthenia gravis. Patients who have had chemotherapy must wait 3 months before being vaccinated. Those on steroids (eg, prednisone 20 mg or more daily) must wait until 2 weeks after cessation of steroids to receive this vaccine. Patients who cannot be vaccinated should be advised not to travel to areas with a high risk of yellow fever.

Women contemplating pregnancy should use contraception for 28 days after yellow fever vaccination. Children younger than 9 months and the elderly are at higher risk of adverse reactions from the vaccine, either neurotropic or viscerotropic disease that mimics yellow fever infection. It is possible for physicians to write a medical waiver of contraindication to vaccination for patients who should not be immunized.

Typhoid fever

Typhoid fever can occur anywhere in the world, but it is endemic in the tropics. Worldwide, an estimated 200,000 deaths occur each year from typhoid fever, and 400 cases are reported annually in the United States, most commonly acquired by travelers to the Indian subcontinent.¹⁸ One study indicates that 95% of infected travelers had not been vaccinated, and a significant number returned with drugresistant strains.¹⁹

Typhoid fever is caused by ingestion of Salmonella typhi bacteria. It causes a febrile illness with infection of the digestive tract and reticuloendothelial system.

Prevention is the same as for traveler’s diarrhea: drink no local water and eat nothing raw. Vaccination can be provided in an intramuscular shot or a series of oral capsules. The shot is well tolerated and is valid for 3 years. The capsule provides 5 years of immunity. Vaccination is recommended for people going to areas with a high prevalence of typhoid fever, such as India, and for people planning to spend more than 2 weeks in an area where typhoid is endemic, as well as for adventurous eaters.

SOME TRAVELERS NEED MORE PROTECTION

Some travelers need more preventive measures than typical tourists or other short-term visitors. Long-term visitors or travelers to remote or other high-risk areas (eg, adventure travelers, relief workers, mission workers) may need, in addition to the measures described above, measures against Japanese encephalitis, rabies, cholera, epidemic meningitis, and dengue fever.

Japanese encephalitis

Japanese encephalitis virus is transmitted by mosquito bite. The major regions where it is endemic are rural India and Southeast Asia, most typically in areas with rice paddies and pig farms. Travelers at risk are expatriates to these areas, those planning a long stay, and remote-adventure travelers.

The vaccine JE-VAX is given as a series of three shots, on days 0, 7, and 28. Another vaccine, Ixiaro, is given in a series of two shots, on days 0 and 28.

Patients who are allergic to bee or wasp stings should not be vaccinated. The patient should remain in the office for 30 minutes after each dose to permit observation for mild anaphylactic reactions such as angioedema and urticaria, and should complete the series 10 days before travel to allow for observation for delayed reactions. Patients must weigh the risk of contracting the disease against the high cost of the vaccine.

Rabies

Rabies is a potential risk anywhere in the world except in Western Europe and Australia. Because the vaccine is costly, it is generally not given for prophylaxis except for travelers certain to have contact with animals, especially the major vectors, ie, dogs, cats, bats, and monkeys.²⁰ Counseling about vigilance in avoiding animal contact and not promoting interaction through feeding wild animals should be part of any pretravel consult. Rabies, once acquired, is fatal.

The patient should be instructed on proper care of a bite from a potential rabies source and told to halt travel and seek medical attention. The wound should be cleaned with soap and water for 15 minutes to remove any saliva and virus from the soft tissue; this has proven to be effective in animal experiments. A virucidal such as benzalkonium chloride (Zephiran) or aqueous iodine should then be put in the wound.

Preexposure vaccination is done in a three-dose series (given on days 0, 7, and 21– 28). The patient should complete the series and adhere to the dosing schedule as closely as possible. It may be necessary to find a source of vaccine for the patient once he or she has arrived in the destination country.

If bitten, travelers without preexposure vaccination must find a source of vaccine and human rabies immune globulin (HRIG) before continuing on their trip. Postexposure treatment is 20 IU/kg of HRIG infiltrated around the wound to wall off the virus inoculation site. If the wound is in a digit or small area and not all of the HRIG can be given, then the remaining HRIG is given intramuscularly at a site distant from the vaccine site. If the patient has multiple bites, the HRIG should be diluted so it can be infiltrated around all wounds. The HRIG should be given immediately or within 7 days of beginning the vaccine series once a source is located. Later treatment than this can interfere with the patient’s ability to mount an immune reaction.

Rabies vaccine is initiated at the same time as HRIG and is given on days 0, 3, 7, 14, and 28. The CDC may soon change the schedule to allow for only four postexposure shots, but this has not yet been done as of this writing.

The patient vaccinated before exposure requires only booster doses of rabies vaccine at days 0 and 3.

Cholera

Cholera is an epidemic gastrointestinal disease historically responsible for millions of deaths. It is endemic in most tropical countries, especially in Africa and southern and southeastern Asia.²¹

High-risk patients, most often those working with refugees and disaster victims in endemic areas, should receive the traveler’s diarrhea and cholera vaccine Dukoral, which immunizes against Vibrio cholera and enterotoxogenic E coli. The vaccine, which is not available in the United States but is available abroad, is given as two oral doses 1 week apart for adults and three oral doses for children ages 2 to 6, and the second dose must be given 7 days before travel; this provides protection for 6 months.

At various times, the above vaccines have been in short supply. Travel medicine consults should be obtained for proper identification of the at-risk traveler for efficient use of any possibly limited vaccine.

Epidemic meningitis

The vaccine against epidemic meningitis is now routinely given in the United States to adolescents at the age of 12 or upon entry to college or the military. The fatality rate from the disease is 10%.

Meningococcal disease transmission peaks in the sub-Saharan “meningitis belt” in the dry season of December through June. Travelers to these areas at these times should be immunized. Travelers planning close contact with the local population (eg, health care workers) should be immunized. Patients traveling to Saudi Arabia for Hajj in Mecca must be immunized for meningitis for entry to the country during this time. The vaccine must be given within 3 years of entering the country and not less than 10 days before.

Dengue fever

Dengue fever is a flavivirus transmitted through the Aedes aegypti mosquito. No vaccine is available for dengue fever, so for now the only advice is to avoid insect vectors.

There are four closely related but serologically different dengue viruses that provide only weak cross-protection. In fact, previous infection with one serotype in a traveler then infected with another poses a risk of dengue hemorrhagic fever.

Because of inattention to public sanitation, this virus and its mosquito vector have reemerged in areas where they were once eliminated. The viral infection is a risk for the traveler to both urban and rural areas in the Americas, Southeast Asia, and Africa. The Pan American Health Organization has seen the number of reported dengue cases increase from 66,000 in 1980 to 700,000 in 2003.²²

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

Major depressive disorder (MDD) and bipolar spectrum disorders are associated with some symptoms of—and fully defined—posttraumatic stress disorder (PTSD). Many traumatic experiences can lead to this comorbidity, the most common being exposure to or witnessing combat for men and rape and sexual molestation for women.1

Trauma has major prognostic and treatment implications for affectively ill patients, including those whose symptoms do not meet PTSD’s full diagnostic criteria. This article aims to help clinicians by:

• presenting evidence characterizing the overlap between affective disorders and PTSD
• reviewing evidence that the bipolar spectrum may be broader than generally thought, an insight that affects PTSD treatment
• making a case for routine PTSD screening for all patients with affective illnesses
• recommending PTSD treatments tailored to the patient’s comorbid affective disorder.

Overlap of trauma and affective illness

PTSD is remarkably comorbid with mood disorders. Americans with MDD and bipolar disorder (BPD) are 7 and 9.4 times, respectively, more likely to meet criteria for PTSD than persons in the general population, according to odds ratios Kessler et al² calculated from the National Comorbidity Survey database.

I have never seen a patient with PTSD who did not also meet criteria for an affective disorder. The concurrence of PTSD and MDD is not the product of overlapping diagnostic criteria. Rather, evidence indicates these are distinct diagnostic entities.³ A review of diagnostic criteria for PTSD and hypomania/mania leads to the same conclusion.

Bipolar spectrum disorders

DSM-IV-TR assumes that mood disorders fall neatly into boxes. Other data (Table 1)^4–8 indicate that these disorders fall along a continuum or—more conservatively—that the scope of bipolarity is much wider than DSM-IV-TR recognizes. This is a controversial topic, and the individual clinician’s position could impact how one manages PTSD patients.

Table 1

Evidence of bipolar spectrum features in major depressive episodes

In this article, I include bipolar I disorder, bipolar II disorder, and mixed depression within the “bipolar spectrum disorders.” If one accepts this—and I do—it follows that 50% to 70% of all major depressive episodes (MDEs) are bipolar in nature.^4–9 Depending on your practice setting, you may see a higher or lower base rate of bipolar spectrum disorders.

Mixed depression is not recognized in DSM-IV-TR, and the purpose of this article is not to defend its inclusion as a bipolar spectrum phenomenon. A proposed definition of mixed depression⁹ requires the presence of an MDE contaminated by ≥3 features of hypomania or mania, without euphoria or inflated self-esteem/grandiosity (Table 2).¹⁰

Some experts believe episodes of hypomania and mania frequently occur in the illness course of persons with mixed depression; indeed, mixed depression is a predictor of a bipolar course. It is observed in outpatient⁹ and inpatient settings.¹¹ Common forms of mixed depression feature combinations of irritability, psychomotor agitation (mild to severe), increased talkativeness (which may fall short of frank pressured speech), racing or “crowded” thoughts (or “mental overactivity”), and distractibility. Other than increased self-esteem/grandiosity, any symptoms within DSM-IV-TR criterion B for a hypomanic or manic episode may be seen in mixed depression. Psychosis is an exclusion criterion for mixed depression.

Mixed depression responds poorly to antidepressant monotherapy. Validation studies suggest that mixed depression is a bipolar variant, as determined by its capacity to predict a bipolar course and its association with a family history of bipolar disorder and age of onset.⁹

Table 2

Diagnostic characteristics of a hypomanic episode, DSM-IV-TR criteria A and B

PTSD risk in affective illness

An adolescent sample. A preliminary cross-sectional study conducted by our group indicates that adolescents with affective disorders may have a much higher risk of developing PTSD than psychiatric comparison subjects.¹² We used modules from the Structured Clinical Interview for DSM-IV (SCID) to screen for intra-episode psychopathology (as opposed to lifetime prevalence of disorders) in 79 adolescents with MDD, 34 with BPD as defined in the DSM-IV-TR, and 26 with neither affective disorder (psychiatric controls). We found:

• 38.2% of subjects with BPD met criteria for PTSD, compared with 13.9% of those with MDD (OR 4.9; P =.001)
• 3.8% of adolescents without a mood disorder met criteria for PTSD.

We also found that comorbid PTSD was associated with a 4.5-fold higher risk of a suicide attempt, even after we controlled for BPD diagnosis. When we controlled for the presence of other concurrent anxiety disorders, the likelihood of an adolescent with PTSD having attempted suicide remained significant (OR 3.4; P=.023). This finding suggests that PTSD is an independent risk factor for a suicide attempt.

An adult sample. We then focused on adults meeting criteria for MDD or BPD. In a study of 187 consecutively presenting affectively ill patients, we used the SCID to screen for multiple anxiety disorders including PTSD.¹³ Lifetime—as opposed to intra-episode—PTSD prevalence was 23.8% among the 118 patients with MDD and 62.3% among the 69 patients with BPD. A patient with BPD was 5 times more likely to have PTSD than a patient with MDD (OR 5.3; P < .0001). The most common cause of trauma leading to PTSD was sexual molestation or rape as a child or adolescent in this predominantly female Latino population.

Populations at risk for PTSD

The prevalence of PTSD in clinical samples varies, depending on the population studied. For instance, women are at much higher risk for developing PTSD than men, even in comparisons where men are exposed to a greater number of traumatic events and analyses control for differences in the prevalence of sexual abuse. The gender difference is greater if the trauma occurs during childhood.¹⁴ Essentially all patients in our adolescent and adult studies developed PTSD in response to childhood or adolescent sexual trauma.^12,13

A population exposed to a high rate of violent crime would be expected to show a higher PTSD prevalence than one exposed to substantially less violence. The base rate of PTSD also is much higher in affectively ill patients than in the general population.

An analysis by Otto et al¹⁵ found a 16% lifetime prevalence of concomitant PTSD in 1,214 persons with BPD (not the manifold forms within the bipolar spectrum). Oquendo et al¹⁶ reported a 25.7% lifetime prevalence of PTSD in 230 patients with a history of MDD. Other epidemiologic² and clinical studies^12,13 suggest a considerably higher base rate of PTSD among persons with bipolar disorders than those with MDD.

The method of ascertaining the presence of this disorder may be another variable affecting the reported PTSD prevalence. Persistent avoidance—including “efforts to avoid thoughts, feelings, or conversations associated with the trauma”—is a diagnostic feature of PTSD.¹⁰ Researchers and clinicians who do not intentionally screen patients for PTSD are not likely to detect it. Determining the true prevalence of PTSD requires empathic inquiry about exposure to traumatic events.

PTSD screening

Humans are remarkably resilient, and most persons exposed to major trauma are thought not to develop PTSD. However, in my experience, because PTSD appears to be common among persons with affective illness, determining whether such patients have been traumatized is important for prognosis and treatment selection.

To get started, you could create a 1-page form to record traumatic events and identify features of PTSD according to DSM-IV-TR criteria (Checklist).¹⁰ PTSD screening without a form can become second nature with practice; an experienced clinician can screen a traumatized patient for the disorder within 3 to 5 minutes.

When screening for a history of trauma, ask patients in a straightforward manner if they have:

• been victims of violent crimes
• witnessed violent crimes
• been exposed to events in which people could have suffered grave injury
• experienced emotional, physical, or sexual abuse.

A person who has experienced emotional abuse but not physical or sexual abuse cannot meet DSM-IV-TR criterion A and therefore does not meet full criteria for PTSD. Many emotionally abused persons meet criteria B through F, however, and they are most reasonably managed similarly to persons who also meet criterion A. When formulating a treatment plan, I recommend using clinical judgment rather than rigid adherence to DSM-IV-TR.

Checklist

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Treating PTSD in depression

Pharmacotherapy and psychotherapeutic interventions are important to PTSD patients’ recovery. Limited resources often prevent these patients from receiving expert psychotherapeutic intervention, however, leaving pharmacotherapy as the mainstay of treatment. This is unfortunate, because psychological interventions may be sufficient and preferred in some instances (Box).^17–20

Pharmacotherapy for comorbid MDD. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are first-line interventions for PTSD in depressed patients who do not meet criteria for a bipolar spectrum disorder. Placebo-controlled studies suggest that sertraline,^21,22 fluoxetine,²³ and paroxetine,²⁴ are effective; doses higher than those used to treat depression may be required. Extended-release venlafaxine²⁵ in dosages similar to those needed for depressive disorders also can be effective. Bupropion does not appear to be beneficial in treating PTSD.

The monoamine oxidase inhibitor phenelzine was long used successfully in treating PTSD but for the most part has been replaced by SSRIs. Because of its associated dietary restrictions, risk of hypertensive crises, and other side effects, phenelzine probably is best reserved for patients who do not respond to treatment with SSRIs or venlafaxine.

Pharmacotherapy for comorbid bipolar spectrum. If one accepts that most patients meeting criteria for MDE have a bipolar spectrum disorder, then most affectively ill patients with PTSD would need to be treated as if they have bipolar disorder. Oddly enough, this creates difficulties for the use of not only antidepressants and benzodiazepines, but also mood stabilizers:

• Patients with BPD and comorbid anxiety disorders, including PTSD, may be resistant to mood stabilizers.^26,27
• Antidepressants can precipitate hypomanic or manic switches or onset of mixed hypomania, a mixed state, or rapid cycling in patients with a bipolar spectrum disorder.^28–30
• Benzodiazepines do not appear to relieve acute or chronic PTSD-related distress, and discontinuation could cause rebound symptoms.³¹

Because no outcome studies have addressed PTSD management in patients with bipolar spectrum disorders, clinicians must rely on their judgment when formulating treatment plans. One strategy is to treat patients with mood stabilizers, then leave well enough alone if both the mood and anxiety symptoms remit (which is possible but unlikely in my experience). I often start treatment for the bipolar spectrum disorder and co-existing PTSD using mood stabilizers (including atypical antipsychotics) and prazosin, an α-1antagonist originally used for treating hypertension.

Prazosin can help diminish nightmares, dreams, and other painful recollections of trauma.^32,33 The drug does not affect time to sleep onset. It also has been reported to reduce avoidance behavior and hyperarousal, such as irritability and anger.³⁴ This has been my experience.

Box

Prazosin to treat PTSD-related symptoms in children or adolescents has not been studied, but it can be useful in adults over a wide range of doses. As little as 1 mg at bedtime may confer benefit, although the mean prazosin dose in an 8-week, placebo-controlled study of 40 combat veterans was 13.3 mg in the evening.³³

I often initiate prazosin treatment as follows:

• 1 mg on the first night of treatment
• 2 mg on the second night
• 3 mg on the third night
• then, if tolerated, 1 mg upon waking, 1 mg 8 hours later, and 3 mg at bedtime. I then slowly adjust the dose schedule based on the patient’s needs, such as minimizing painful re-experiencing of the trauma. Reducing avoidance and hyperarousal also are reasonable targets. For example, when using prazosin to treat extremely angry men with PTSD stemming from exposure to violent crimes, I have observed that even “murderous” rage ceases with prazosin treatment, only to reappear when prazosin is discontinued.

In treating approximately 100 patients with prazosin, I have not exceeded 16 mg/d. Dosages used for treating hypertension usually are 5 to 20 mg/d. When using prazosin, I always:

• warn patients that faintness or fainting is a side effect and record this caveat in their chart
• obtain sitting and standing blood pressure and pulse before starting treatment and subsequently
• ask patients if they feel dizzy when changing posture before and after initiating treatment.

Most of my PTSD patients are suffering so much that they are willing to accept the risk of fainting associated with prazosin use. For PTSD comorbid with severe panic disorder,^12,13 I find that a benzodiazepine with antipanic properties such as alprazolam or clonazepam often works well in conjunction with prazosin.

Some patients with bipolar spectrum disorders might benefit from the addition of an SSRI after mood stabilizer treatment proves effective. However, I have never managed a patient in this manner, and like my own treatment strategy, this has not been subjected to rigorous empiric inquiry. In my view, psychological treatment is much preferred to antidepressant therapy.

Related resource

• Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet. 2007;369:935-945.

Drug brand names

• Alprazolam • Xanax
• Bupropion • Wellbutrin
• Clonazepam • Klonopin
• D-cycloserine • Seromycin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Phenelzine • Nardil
• Prazosin • Minipress
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Dilsaver reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Major depressive disorder (MDD) and bipolar spectrum disorders are associated with some symptoms of—and fully defined—posttraumatic stress disorder (PTSD). Many traumatic experiences can lead to this comorbidity, the most common being exposure to or witnessing combat for men and rape and sexual molestation for women.1

Trauma has major prognostic and treatment implications for affectively ill patients, including those whose symptoms do not meet PTSD’s full diagnostic criteria. This article aims to help clinicians by:

• presenting evidence characterizing the overlap between affective disorders and PTSD
• reviewing evidence that the bipolar spectrum may be broader than generally thought, an insight that affects PTSD treatment
• making a case for routine PTSD screening for all patients with affective illnesses
• recommending PTSD treatments tailored to the patient’s comorbid affective disorder.

Overlap of trauma and affective illness

PTSD is remarkably comorbid with mood disorders. Americans with MDD and bipolar disorder (BPD) are 7 and 9.4 times, respectively, more likely to meet criteria for PTSD than persons in the general population, according to odds ratios Kessler et al² calculated from the National Comorbidity Survey database.

I have never seen a patient with PTSD who did not also meet criteria for an affective disorder. The concurrence of PTSD and MDD is not the product of overlapping diagnostic criteria. Rather, evidence indicates these are distinct diagnostic entities.³ A review of diagnostic criteria for PTSD and hypomania/mania leads to the same conclusion.

Bipolar spectrum disorders

DSM-IV-TR assumes that mood disorders fall neatly into boxes. Other data (Table 1)^4–8 indicate that these disorders fall along a continuum or—more conservatively—that the scope of bipolarity is much wider than DSM-IV-TR recognizes. This is a controversial topic, and the individual clinician’s position could impact how one manages PTSD patients.

Table 1

Evidence of bipolar spectrum features in major depressive episodes

In this article, I include bipolar I disorder, bipolar II disorder, and mixed depression within the “bipolar spectrum disorders.” If one accepts this—and I do—it follows that 50% to 70% of all major depressive episodes (MDEs) are bipolar in nature.^4–9 Depending on your practice setting, you may see a higher or lower base rate of bipolar spectrum disorders.

Mixed depression is not recognized in DSM-IV-TR, and the purpose of this article is not to defend its inclusion as a bipolar spectrum phenomenon. A proposed definition of mixed depression⁹ requires the presence of an MDE contaminated by ≥3 features of hypomania or mania, without euphoria or inflated self-esteem/grandiosity (Table 2).¹⁰

Some experts believe episodes of hypomania and mania frequently occur in the illness course of persons with mixed depression; indeed, mixed depression is a predictor of a bipolar course. It is observed in outpatient⁹ and inpatient settings.¹¹ Common forms of mixed depression feature combinations of irritability, psychomotor agitation (mild to severe), increased talkativeness (which may fall short of frank pressured speech), racing or “crowded” thoughts (or “mental overactivity”), and distractibility. Other than increased self-esteem/grandiosity, any symptoms within DSM-IV-TR criterion B for a hypomanic or manic episode may be seen in mixed depression. Psychosis is an exclusion criterion for mixed depression.

Mixed depression responds poorly to antidepressant monotherapy. Validation studies suggest that mixed depression is a bipolar variant, as determined by its capacity to predict a bipolar course and its association with a family history of bipolar disorder and age of onset.⁹

Table 2

Diagnostic characteristics of a hypomanic episode, DSM-IV-TR criteria A and B

PTSD risk in affective illness

An adolescent sample. A preliminary cross-sectional study conducted by our group indicates that adolescents with affective disorders may have a much higher risk of developing PTSD than psychiatric comparison subjects.¹² We used modules from the Structured Clinical Interview for DSM-IV (SCID) to screen for intra-episode psychopathology (as opposed to lifetime prevalence of disorders) in 79 adolescents with MDD, 34 with BPD as defined in the DSM-IV-TR, and 26 with neither affective disorder (psychiatric controls). We found:

• 38.2% of subjects with BPD met criteria for PTSD, compared with 13.9% of those with MDD (OR 4.9; P =.001)
• 3.8% of adolescents without a mood disorder met criteria for PTSD.

We also found that comorbid PTSD was associated with a 4.5-fold higher risk of a suicide attempt, even after we controlled for BPD diagnosis. When we controlled for the presence of other concurrent anxiety disorders, the likelihood of an adolescent with PTSD having attempted suicide remained significant (OR 3.4; P=.023). This finding suggests that PTSD is an independent risk factor for a suicide attempt.

An adult sample. We then focused on adults meeting criteria for MDD or BPD. In a study of 187 consecutively presenting affectively ill patients, we used the SCID to screen for multiple anxiety disorders including PTSD.¹³ Lifetime—as opposed to intra-episode—PTSD prevalence was 23.8% among the 118 patients with MDD and 62.3% among the 69 patients with BPD. A patient with BPD was 5 times more likely to have PTSD than a patient with MDD (OR 5.3; P < .0001). The most common cause of trauma leading to PTSD was sexual molestation or rape as a child or adolescent in this predominantly female Latino population.

Populations at risk for PTSD

The prevalence of PTSD in clinical samples varies, depending on the population studied. For instance, women are at much higher risk for developing PTSD than men, even in comparisons where men are exposed to a greater number of traumatic events and analyses control for differences in the prevalence of sexual abuse. The gender difference is greater if the trauma occurs during childhood.¹⁴ Essentially all patients in our adolescent and adult studies developed PTSD in response to childhood or adolescent sexual trauma.^12,13

A population exposed to a high rate of violent crime would be expected to show a higher PTSD prevalence than one exposed to substantially less violence. The base rate of PTSD also is much higher in affectively ill patients than in the general population.

An analysis by Otto et al¹⁵ found a 16% lifetime prevalence of concomitant PTSD in 1,214 persons with BPD (not the manifold forms within the bipolar spectrum). Oquendo et al¹⁶ reported a 25.7% lifetime prevalence of PTSD in 230 patients with a history of MDD. Other epidemiologic² and clinical studies^12,13 suggest a considerably higher base rate of PTSD among persons with bipolar disorders than those with MDD.

The method of ascertaining the presence of this disorder may be another variable affecting the reported PTSD prevalence. Persistent avoidance—including “efforts to avoid thoughts, feelings, or conversations associated with the trauma”—is a diagnostic feature of PTSD.¹⁰ Researchers and clinicians who do not intentionally screen patients for PTSD are not likely to detect it. Determining the true prevalence of PTSD requires empathic inquiry about exposure to traumatic events.

PTSD screening

Humans are remarkably resilient, and most persons exposed to major trauma are thought not to develop PTSD. However, in my experience, because PTSD appears to be common among persons with affective illness, determining whether such patients have been traumatized is important for prognosis and treatment selection.

To get started, you could create a 1-page form to record traumatic events and identify features of PTSD according to DSM-IV-TR criteria (Checklist).¹⁰ PTSD screening without a form can become second nature with practice; an experienced clinician can screen a traumatized patient for the disorder within 3 to 5 minutes.

When screening for a history of trauma, ask patients in a straightforward manner if they have:

• been victims of violent crimes
• witnessed violent crimes
• been exposed to events in which people could have suffered grave injury
• experienced emotional, physical, or sexual abuse.

A person who has experienced emotional abuse but not physical or sexual abuse cannot meet DSM-IV-TR criterion A and therefore does not meet full criteria for PTSD. Many emotionally abused persons meet criteria B through F, however, and they are most reasonably managed similarly to persons who also meet criterion A. When formulating a treatment plan, I recommend using clinical judgment rather than rigid adherence to DSM-IV-TR.

Checklist

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Treating PTSD in depression

Pharmacotherapy and psychotherapeutic interventions are important to PTSD patients’ recovery. Limited resources often prevent these patients from receiving expert psychotherapeutic intervention, however, leaving pharmacotherapy as the mainstay of treatment. This is unfortunate, because psychological interventions may be sufficient and preferred in some instances (Box).^17–20

Pharmacotherapy for comorbid MDD. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are first-line interventions for PTSD in depressed patients who do not meet criteria for a bipolar spectrum disorder. Placebo-controlled studies suggest that sertraline,^21,22 fluoxetine,²³ and paroxetine,²⁴ are effective; doses higher than those used to treat depression may be required. Extended-release venlafaxine²⁵ in dosages similar to those needed for depressive disorders also can be effective. Bupropion does not appear to be beneficial in treating PTSD.

The monoamine oxidase inhibitor phenelzine was long used successfully in treating PTSD but for the most part has been replaced by SSRIs. Because of its associated dietary restrictions, risk of hypertensive crises, and other side effects, phenelzine probably is best reserved for patients who do not respond to treatment with SSRIs or venlafaxine.

Pharmacotherapy for comorbid bipolar spectrum. If one accepts that most patients meeting criteria for MDE have a bipolar spectrum disorder, then most affectively ill patients with PTSD would need to be treated as if they have bipolar disorder. Oddly enough, this creates difficulties for the use of not only antidepressants and benzodiazepines, but also mood stabilizers:

• Patients with BPD and comorbid anxiety disorders, including PTSD, may be resistant to mood stabilizers.^26,27
• Antidepressants can precipitate hypomanic or manic switches or onset of mixed hypomania, a mixed state, or rapid cycling in patients with a bipolar spectrum disorder.^28–30
• Benzodiazepines do not appear to relieve acute or chronic PTSD-related distress, and discontinuation could cause rebound symptoms.³¹

Because no outcome studies have addressed PTSD management in patients with bipolar spectrum disorders, clinicians must rely on their judgment when formulating treatment plans. One strategy is to treat patients with mood stabilizers, then leave well enough alone if both the mood and anxiety symptoms remit (which is possible but unlikely in my experience). I often start treatment for the bipolar spectrum disorder and co-existing PTSD using mood stabilizers (including atypical antipsychotics) and prazosin, an α-1antagonist originally used for treating hypertension.

Prazosin can help diminish nightmares, dreams, and other painful recollections of trauma.^32,33 The drug does not affect time to sleep onset. It also has been reported to reduce avoidance behavior and hyperarousal, such as irritability and anger.³⁴ This has been my experience.

Box

Prazosin to treat PTSD-related symptoms in children or adolescents has not been studied, but it can be useful in adults over a wide range of doses. As little as 1 mg at bedtime may confer benefit, although the mean prazosin dose in an 8-week, placebo-controlled study of 40 combat veterans was 13.3 mg in the evening.³³

I often initiate prazosin treatment as follows:

• 1 mg on the first night of treatment
• 2 mg on the second night
• 3 mg on the third night
• then, if tolerated, 1 mg upon waking, 1 mg 8 hours later, and 3 mg at bedtime. I then slowly adjust the dose schedule based on the patient’s needs, such as minimizing painful re-experiencing of the trauma. Reducing avoidance and hyperarousal also are reasonable targets. For example, when using prazosin to treat extremely angry men with PTSD stemming from exposure to violent crimes, I have observed that even “murderous” rage ceases with prazosin treatment, only to reappear when prazosin is discontinued.

In treating approximately 100 patients with prazosin, I have not exceeded 16 mg/d. Dosages used for treating hypertension usually are 5 to 20 mg/d. When using prazosin, I always:

• warn patients that faintness or fainting is a side effect and record this caveat in their chart
• obtain sitting and standing blood pressure and pulse before starting treatment and subsequently
• ask patients if they feel dizzy when changing posture before and after initiating treatment.

Most of my PTSD patients are suffering so much that they are willing to accept the risk of fainting associated with prazosin use. For PTSD comorbid with severe panic disorder,^12,13 I find that a benzodiazepine with antipanic properties such as alprazolam or clonazepam often works well in conjunction with prazosin.

Some patients with bipolar spectrum disorders might benefit from the addition of an SSRI after mood stabilizer treatment proves effective. However, I have never managed a patient in this manner, and like my own treatment strategy, this has not been subjected to rigorous empiric inquiry. In my view, psychological treatment is much preferred to antidepressant therapy.

Related resource

• Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet. 2007;369:935-945.

Drug brand names

• Alprazolam • Xanax
• Bupropion • Wellbutrin
• Clonazepam • Klonopin
• D-cycloserine • Seromycin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Phenelzine • Nardil
• Prazosin • Minipress
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Dilsaver reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Major depressive disorder (MDD) and bipolar spectrum disorders are associated with some symptoms of—and fully defined—posttraumatic stress disorder (PTSD). Many traumatic experiences can lead to this comorbidity, the most common being exposure to or witnessing combat for men and rape and sexual molestation for women.1

Trauma has major prognostic and treatment implications for affectively ill patients, including those whose symptoms do not meet PTSD’s full diagnostic criteria. This article aims to help clinicians by:

• presenting evidence characterizing the overlap between affective disorders and PTSD
• reviewing evidence that the bipolar spectrum may be broader than generally thought, an insight that affects PTSD treatment
• making a case for routine PTSD screening for all patients with affective illnesses
• recommending PTSD treatments tailored to the patient’s comorbid affective disorder.

Overlap of trauma and affective illness

PTSD is remarkably comorbid with mood disorders. Americans with MDD and bipolar disorder (BPD) are 7 and 9.4 times, respectively, more likely to meet criteria for PTSD than persons in the general population, according to odds ratios Kessler et al² calculated from the National Comorbidity Survey database.

I have never seen a patient with PTSD who did not also meet criteria for an affective disorder. The concurrence of PTSD and MDD is not the product of overlapping diagnostic criteria. Rather, evidence indicates these are distinct diagnostic entities.³ A review of diagnostic criteria for PTSD and hypomania/mania leads to the same conclusion.

Bipolar spectrum disorders

DSM-IV-TR assumes that mood disorders fall neatly into boxes. Other data (Table 1)^4–8 indicate that these disorders fall along a continuum or—more conservatively—that the scope of bipolarity is much wider than DSM-IV-TR recognizes. This is a controversial topic, and the individual clinician’s position could impact how one manages PTSD patients.

Table 1

Evidence of bipolar spectrum features in major depressive episodes

In this article, I include bipolar I disorder, bipolar II disorder, and mixed depression within the “bipolar spectrum disorders.” If one accepts this—and I do—it follows that 50% to 70% of all major depressive episodes (MDEs) are bipolar in nature.^4–9 Depending on your practice setting, you may see a higher or lower base rate of bipolar spectrum disorders.

Mixed depression is not recognized in DSM-IV-TR, and the purpose of this article is not to defend its inclusion as a bipolar spectrum phenomenon. A proposed definition of mixed depression⁹ requires the presence of an MDE contaminated by ≥3 features of hypomania or mania, without euphoria or inflated self-esteem/grandiosity (Table 2).¹⁰

Some experts believe episodes of hypomania and mania frequently occur in the illness course of persons with mixed depression; indeed, mixed depression is a predictor of a bipolar course. It is observed in outpatient⁹ and inpatient settings.¹¹ Common forms of mixed depression feature combinations of irritability, psychomotor agitation (mild to severe), increased talkativeness (which may fall short of frank pressured speech), racing or “crowded” thoughts (or “mental overactivity”), and distractibility. Other than increased self-esteem/grandiosity, any symptoms within DSM-IV-TR criterion B for a hypomanic or manic episode may be seen in mixed depression. Psychosis is an exclusion criterion for mixed depression.

Mixed depression responds poorly to antidepressant monotherapy. Validation studies suggest that mixed depression is a bipolar variant, as determined by its capacity to predict a bipolar course and its association with a family history of bipolar disorder and age of onset.⁹

Table 2

Diagnostic characteristics of a hypomanic episode, DSM-IV-TR criteria A and B

PTSD risk in affective illness

An adolescent sample. A preliminary cross-sectional study conducted by our group indicates that adolescents with affective disorders may have a much higher risk of developing PTSD than psychiatric comparison subjects.¹² We used modules from the Structured Clinical Interview for DSM-IV (SCID) to screen for intra-episode psychopathology (as opposed to lifetime prevalence of disorders) in 79 adolescents with MDD, 34 with BPD as defined in the DSM-IV-TR, and 26 with neither affective disorder (psychiatric controls). We found:

• 38.2% of subjects with BPD met criteria for PTSD, compared with 13.9% of those with MDD (OR 4.9; P =.001)
• 3.8% of adolescents without a mood disorder met criteria for PTSD.

We also found that comorbid PTSD was associated with a 4.5-fold higher risk of a suicide attempt, even after we controlled for BPD diagnosis. When we controlled for the presence of other concurrent anxiety disorders, the likelihood of an adolescent with PTSD having attempted suicide remained significant (OR 3.4; P=.023). This finding suggests that PTSD is an independent risk factor for a suicide attempt.

An adult sample. We then focused on adults meeting criteria for MDD or BPD. In a study of 187 consecutively presenting affectively ill patients, we used the SCID to screen for multiple anxiety disorders including PTSD.¹³ Lifetime—as opposed to intra-episode—PTSD prevalence was 23.8% among the 118 patients with MDD and 62.3% among the 69 patients with BPD. A patient with BPD was 5 times more likely to have PTSD than a patient with MDD (OR 5.3; P < .0001). The most common cause of trauma leading to PTSD was sexual molestation or rape as a child or adolescent in this predominantly female Latino population.

Populations at risk for PTSD

The prevalence of PTSD in clinical samples varies, depending on the population studied. For instance, women are at much higher risk for developing PTSD than men, even in comparisons where men are exposed to a greater number of traumatic events and analyses control for differences in the prevalence of sexual abuse. The gender difference is greater if the trauma occurs during childhood.¹⁴ Essentially all patients in our adolescent and adult studies developed PTSD in response to childhood or adolescent sexual trauma.^12,13

A population exposed to a high rate of violent crime would be expected to show a higher PTSD prevalence than one exposed to substantially less violence. The base rate of PTSD also is much higher in affectively ill patients than in the general population.

An analysis by Otto et al¹⁵ found a 16% lifetime prevalence of concomitant PTSD in 1,214 persons with BPD (not the manifold forms within the bipolar spectrum). Oquendo et al¹⁶ reported a 25.7% lifetime prevalence of PTSD in 230 patients with a history of MDD. Other epidemiologic² and clinical studies^12,13 suggest a considerably higher base rate of PTSD among persons with bipolar disorders than those with MDD.

The method of ascertaining the presence of this disorder may be another variable affecting the reported PTSD prevalence. Persistent avoidance—including “efforts to avoid thoughts, feelings, or conversations associated with the trauma”—is a diagnostic feature of PTSD.¹⁰ Researchers and clinicians who do not intentionally screen patients for PTSD are not likely to detect it. Determining the true prevalence of PTSD requires empathic inquiry about exposure to traumatic events.

PTSD screening

Humans are remarkably resilient, and most persons exposed to major trauma are thought not to develop PTSD. However, in my experience, because PTSD appears to be common among persons with affective illness, determining whether such patients have been traumatized is important for prognosis and treatment selection.

To get started, you could create a 1-page form to record traumatic events and identify features of PTSD according to DSM-IV-TR criteria (Checklist).¹⁰ PTSD screening without a form can become second nature with practice; an experienced clinician can screen a traumatized patient for the disorder within 3 to 5 minutes.

When screening for a history of trauma, ask patients in a straightforward manner if they have:

• been victims of violent crimes
• witnessed violent crimes
• been exposed to events in which people could have suffered grave injury
• experienced emotional, physical, or sexual abuse.

A person who has experienced emotional abuse but not physical or sexual abuse cannot meet DSM-IV-TR criterion A and therefore does not meet full criteria for PTSD. Many emotionally abused persons meet criteria B through F, however, and they are most reasonably managed similarly to persons who also meet criterion A. When formulating a treatment plan, I recommend using clinical judgment rather than rigid adherence to DSM-IV-TR.

Checklist

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Treating PTSD in depression

Pharmacotherapy and psychotherapeutic interventions are important to PTSD patients’ recovery. Limited resources often prevent these patients from receiving expert psychotherapeutic intervention, however, leaving pharmacotherapy as the mainstay of treatment. This is unfortunate, because psychological interventions may be sufficient and preferred in some instances (Box).^17–20

Pharmacotherapy for comorbid MDD. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are first-line interventions for PTSD in depressed patients who do not meet criteria for a bipolar spectrum disorder. Placebo-controlled studies suggest that sertraline,^21,22 fluoxetine,²³ and paroxetine,²⁴ are effective; doses higher than those used to treat depression may be required. Extended-release venlafaxine²⁵ in dosages similar to those needed for depressive disorders also can be effective. Bupropion does not appear to be beneficial in treating PTSD.

The monoamine oxidase inhibitor phenelzine was long used successfully in treating PTSD but for the most part has been replaced by SSRIs. Because of its associated dietary restrictions, risk of hypertensive crises, and other side effects, phenelzine probably is best reserved for patients who do not respond to treatment with SSRIs or venlafaxine.

Pharmacotherapy for comorbid bipolar spectrum. If one accepts that most patients meeting criteria for MDE have a bipolar spectrum disorder, then most affectively ill patients with PTSD would need to be treated as if they have bipolar disorder. Oddly enough, this creates difficulties for the use of not only antidepressants and benzodiazepines, but also mood stabilizers:

• Patients with BPD and comorbid anxiety disorders, including PTSD, may be resistant to mood stabilizers.^26,27
• Antidepressants can precipitate hypomanic or manic switches or onset of mixed hypomania, a mixed state, or rapid cycling in patients with a bipolar spectrum disorder.^28–30
• Benzodiazepines do not appear to relieve acute or chronic PTSD-related distress, and discontinuation could cause rebound symptoms.³¹

Because no outcome studies have addressed PTSD management in patients with bipolar spectrum disorders, clinicians must rely on their judgment when formulating treatment plans. One strategy is to treat patients with mood stabilizers, then leave well enough alone if both the mood and anxiety symptoms remit (which is possible but unlikely in my experience). I often start treatment for the bipolar spectrum disorder and co-existing PTSD using mood stabilizers (including atypical antipsychotics) and prazosin, an α-1antagonist originally used for treating hypertension.

Prazosin can help diminish nightmares, dreams, and other painful recollections of trauma.^32,33 The drug does not affect time to sleep onset. It also has been reported to reduce avoidance behavior and hyperarousal, such as irritability and anger.³⁴ This has been my experience.

Box

Prazosin to treat PTSD-related symptoms in children or adolescents has not been studied, but it can be useful in adults over a wide range of doses. As little as 1 mg at bedtime may confer benefit, although the mean prazosin dose in an 8-week, placebo-controlled study of 40 combat veterans was 13.3 mg in the evening.³³

I often initiate prazosin treatment as follows:

• 1 mg on the first night of treatment
• 2 mg on the second night
• 3 mg on the third night
• then, if tolerated, 1 mg upon waking, 1 mg 8 hours later, and 3 mg at bedtime. I then slowly adjust the dose schedule based on the patient’s needs, such as minimizing painful re-experiencing of the trauma. Reducing avoidance and hyperarousal also are reasonable targets. For example, when using prazosin to treat extremely angry men with PTSD stemming from exposure to violent crimes, I have observed that even “murderous” rage ceases with prazosin treatment, only to reappear when prazosin is discontinued.

In treating approximately 100 patients with prazosin, I have not exceeded 16 mg/d. Dosages used for treating hypertension usually are 5 to 20 mg/d. When using prazosin, I always:

• warn patients that faintness or fainting is a side effect and record this caveat in their chart
• obtain sitting and standing blood pressure and pulse before starting treatment and subsequently
• ask patients if they feel dizzy when changing posture before and after initiating treatment.

Most of my PTSD patients are suffering so much that they are willing to accept the risk of fainting associated with prazosin use. For PTSD comorbid with severe panic disorder,^12,13 I find that a benzodiazepine with antipanic properties such as alprazolam or clonazepam often works well in conjunction with prazosin.

Some patients with bipolar spectrum disorders might benefit from the addition of an SSRI after mood stabilizer treatment proves effective. However, I have never managed a patient in this manner, and like my own treatment strategy, this has not been subjected to rigorous empiric inquiry. In my view, psychological treatment is much preferred to antidepressant therapy.

Related resource

• Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet. 2007;369:935-945.

Drug brand names

• Alprazolam • Xanax
• Bupropion • Wellbutrin
• Clonazepam • Klonopin
• D-cycloserine • Seromycin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Phenelzine • Nardil
• Prazosin • Minipress
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Dilsaver reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Stubborn pneumonia turns out to be cancer

AFTER RECEIVING ANTIBIOTICS FOR PNEUMONIA, a 37-year-old man improved but didn’t fully recover; his radiographs didn’t return to normal. He’d never smoked cigarettes.

During the several months after the pneumonia, the patient’s doctor ordered repeat radiographs and prescribed antibiotics and pain medication. When the patient’s spine collapsed, the doctor diagnosed metastatic lung cancer. The patient received palliative treatment and ultimately died.

PLAINTIFF’S CLAIM The doctor was negligent in failing to change the patient’s treatment after 2 or 3 months and failing to order a computed tomography (CT) scan or refer the patient to a pulmonologist.

THE DEFENSE No information about the doctor’s defense is available.

VERDICT $1.25 million Washington settlement.

COMMENT I’d like a nickel for every case of delayed diagnosis of lung cancer based on clearly abnormal chest radiographs. We can argue about whether diagnosis would make a difference, but we need to follow up assiduously on abnormal radiographs and document our actions.

Rapidly raised serum sodium leads to osmotic demyelination

A 60-YEAR-OLD WOMAN went to her local medical center complaining of a cough for the previous 2 weeks, decreased appetite and oral intake, and generalized body aches. She first went to urgent care, where laboratory studies showed critically low levels of sodium and potassium. Based on these results, the woman was told to go to the facility’s emergency department (ED).

In the ED, she reported feeling very weak and tired and having body aches and pain. When laboratory tests showed that her sodium and potassium levels had fallen further, she was admitted to the intensive care unit (ICU).

The doctor who saw the patient in the ICU ordered intravenous fluids with normal saline and potassium supplements. He then had the patient admitted to the ICU at another hospital. The physician at that hospital continued to prescribe IV sodium and potassium until the patient was discharged with diagnoses that included hyponatremia and hypokalemia.

Ten days later, the patient returned to the ED complaining of slurred speech for the previous 2 days. A CT scan of her head showed a possible basilar tip aneurysm. Subsequent magnetic resonance imaging with and without contrast and intracranial magnetic resonance angiography confirmed a basilar tip aneurysm and showed findings suggestive of osmotic demyelination. Neurologic examination revealed dysarthria, right upper extremity weakness without spasticity, and periods of confusion interspersed with lucid intervals.

A subsequent neurologic consultation confirmed osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Neurologic examination at that time found continued mild dysarthria, problems standing, inability to walk unsupported, mild oral and pharyngeal dysphagia, and language and writing deficits.

PLAINTIFF’S CLAIM The patient’s sodium level was increased at an inappropriately rapid rate, which caused neurologically devastating osmotic demyelination. Serum sodium should have been monitored every 4 hours during the first 24 hours of treatment. The plaintiff also alleged negligence in continuing normal saline after the patient’s serum sodium was measured at 112 mEq/L.

THE DEFENSE The treatment provided was appropriate.

VERDICT $550,000 California settlement.

COMMENT Avoiding osmotic demyelination syndrome requires careful treatment and monitoring. I have independently reviewed several allegations of malpractice involving this uncommon, but devastating condition. Two recent articles summarize the treatment of this disorder: Sterns RH, Silver S, Klein-schmidt-DeMasters BK, et al. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother. 2007;7:1791-1797; and Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658.

Iodine contrast media kills man with known shellfish allergy

A 41-YEAR-OLD MAN WITH CHEST PAIN was admitted to his local hospital, where he received a diagnosis of acute coronary syndrome. After treatment in the emergency department, the patient was admitted to the telemetry unit by an internist, the partner of the patient’s primary care physician. The patient’s admission records noted that he had an allergy to shellfish.

The next morning, a cardiologist was called in. The cardiologist then called in an interventional cardiologist, who scheduled a cardiac catheterization. The interventional cardiologist ordered 1 dose of steroids, followed a few minutes later by contrast iodine. The patient immediately suffered a severe allergic reaction and died.

PLAINTIFF’S CLAIM The internist who admitted the patient to the telemetry unit took an incomplete history regarding the patient’s allergies (although the admission records contained that information). No information about the claims against the 2 cardiologists is available.

THE DEFENSE No information about the defense is available.

VERDICT $4.7 million gross verdict in Florida.

COMMENT In addition to considering the risk of dye loads and carefully checking renal function, remember to assess for allergy when administering contrast agents. Failure to do so in this case led to the death of the patient and a multimillion-dollar verdict.

Stubborn pneumonia turns out to be cancer

AFTER RECEIVING ANTIBIOTICS FOR PNEUMONIA, a 37-year-old man improved but didn’t fully recover; his radiographs didn’t return to normal. He’d never smoked cigarettes.

During the several months after the pneumonia, the patient’s doctor ordered repeat radiographs and prescribed antibiotics and pain medication. When the patient’s spine collapsed, the doctor diagnosed metastatic lung cancer. The patient received palliative treatment and ultimately died.

PLAINTIFF’S CLAIM The doctor was negligent in failing to change the patient’s treatment after 2 or 3 months and failing to order a computed tomography (CT) scan or refer the patient to a pulmonologist.

THE DEFENSE No information about the doctor’s defense is available.

VERDICT $1.25 million Washington settlement.

COMMENT I’d like a nickel for every case of delayed diagnosis of lung cancer based on clearly abnormal chest radiographs. We can argue about whether diagnosis would make a difference, but we need to follow up assiduously on abnormal radiographs and document our actions.

Rapidly raised serum sodium leads to osmotic demyelination

A 60-YEAR-OLD WOMAN went to her local medical center complaining of a cough for the previous 2 weeks, decreased appetite and oral intake, and generalized body aches. She first went to urgent care, where laboratory studies showed critically low levels of sodium and potassium. Based on these results, the woman was told to go to the facility’s emergency department (ED).

In the ED, she reported feeling very weak and tired and having body aches and pain. When laboratory tests showed that her sodium and potassium levels had fallen further, she was admitted to the intensive care unit (ICU).

The doctor who saw the patient in the ICU ordered intravenous fluids with normal saline and potassium supplements. He then had the patient admitted to the ICU at another hospital. The physician at that hospital continued to prescribe IV sodium and potassium until the patient was discharged with diagnoses that included hyponatremia and hypokalemia.

Ten days later, the patient returned to the ED complaining of slurred speech for the previous 2 days. A CT scan of her head showed a possible basilar tip aneurysm. Subsequent magnetic resonance imaging with and without contrast and intracranial magnetic resonance angiography confirmed a basilar tip aneurysm and showed findings suggestive of osmotic demyelination. Neurologic examination revealed dysarthria, right upper extremity weakness without spasticity, and periods of confusion interspersed with lucid intervals.

A subsequent neurologic consultation confirmed osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Neurologic examination at that time found continued mild dysarthria, problems standing, inability to walk unsupported, mild oral and pharyngeal dysphagia, and language and writing deficits.

PLAINTIFF’S CLAIM The patient’s sodium level was increased at an inappropriately rapid rate, which caused neurologically devastating osmotic demyelination. Serum sodium should have been monitored every 4 hours during the first 24 hours of treatment. The plaintiff also alleged negligence in continuing normal saline after the patient’s serum sodium was measured at 112 mEq/L.

THE DEFENSE The treatment provided was appropriate.

VERDICT $550,000 California settlement.

COMMENT Avoiding osmotic demyelination syndrome requires careful treatment and monitoring. I have independently reviewed several allegations of malpractice involving this uncommon, but devastating condition. Two recent articles summarize the treatment of this disorder: Sterns RH, Silver S, Klein-schmidt-DeMasters BK, et al. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother. 2007;7:1791-1797; and Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658.

Iodine contrast media kills man with known shellfish allergy

A 41-YEAR-OLD MAN WITH CHEST PAIN was admitted to his local hospital, where he received a diagnosis of acute coronary syndrome. After treatment in the emergency department, the patient was admitted to the telemetry unit by an internist, the partner of the patient’s primary care physician. The patient’s admission records noted that he had an allergy to shellfish.

The next morning, a cardiologist was called in. The cardiologist then called in an interventional cardiologist, who scheduled a cardiac catheterization. The interventional cardiologist ordered 1 dose of steroids, followed a few minutes later by contrast iodine. The patient immediately suffered a severe allergic reaction and died.

PLAINTIFF’S CLAIM The internist who admitted the patient to the telemetry unit took an incomplete history regarding the patient’s allergies (although the admission records contained that information). No information about the claims against the 2 cardiologists is available.

THE DEFENSE No information about the defense is available.

VERDICT $4.7 million gross verdict in Florida.

COMMENT In addition to considering the risk of dye loads and carefully checking renal function, remember to assess for allergy when administering contrast agents. Failure to do so in this case led to the death of the patient and a multimillion-dollar verdict.

Stubborn pneumonia turns out to be cancer

AFTER RECEIVING ANTIBIOTICS FOR PNEUMONIA, a 37-year-old man improved but didn’t fully recover; his radiographs didn’t return to normal. He’d never smoked cigarettes.

During the several months after the pneumonia, the patient’s doctor ordered repeat radiographs and prescribed antibiotics and pain medication. When the patient’s spine collapsed, the doctor diagnosed metastatic lung cancer. The patient received palliative treatment and ultimately died.

PLAINTIFF’S CLAIM The doctor was negligent in failing to change the patient’s treatment after 2 or 3 months and failing to order a computed tomography (CT) scan or refer the patient to a pulmonologist.

THE DEFENSE No information about the doctor’s defense is available.

VERDICT $1.25 million Washington settlement.

COMMENT I’d like a nickel for every case of delayed diagnosis of lung cancer based on clearly abnormal chest radiographs. We can argue about whether diagnosis would make a difference, but we need to follow up assiduously on abnormal radiographs and document our actions.

Rapidly raised serum sodium leads to osmotic demyelination

A 60-YEAR-OLD WOMAN went to her local medical center complaining of a cough for the previous 2 weeks, decreased appetite and oral intake, and generalized body aches. She first went to urgent care, where laboratory studies showed critically low levels of sodium and potassium. Based on these results, the woman was told to go to the facility’s emergency department (ED).

In the ED, she reported feeling very weak and tired and having body aches and pain. When laboratory tests showed that her sodium and potassium levels had fallen further, she was admitted to the intensive care unit (ICU).

The doctor who saw the patient in the ICU ordered intravenous fluids with normal saline and potassium supplements. He then had the patient admitted to the ICU at another hospital. The physician at that hospital continued to prescribe IV sodium and potassium until the patient was discharged with diagnoses that included hyponatremia and hypokalemia.

Ten days later, the patient returned to the ED complaining of slurred speech for the previous 2 days. A CT scan of her head showed a possible basilar tip aneurysm. Subsequent magnetic resonance imaging with and without contrast and intracranial magnetic resonance angiography confirmed a basilar tip aneurysm and showed findings suggestive of osmotic demyelination. Neurologic examination revealed dysarthria, right upper extremity weakness without spasticity, and periods of confusion interspersed with lucid intervals.

A subsequent neurologic consultation confirmed osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Neurologic examination at that time found continued mild dysarthria, problems standing, inability to walk unsupported, mild oral and pharyngeal dysphagia, and language and writing deficits.

PLAINTIFF’S CLAIM The patient’s sodium level was increased at an inappropriately rapid rate, which caused neurologically devastating osmotic demyelination. Serum sodium should have been monitored every 4 hours during the first 24 hours of treatment. The plaintiff also alleged negligence in continuing normal saline after the patient’s serum sodium was measured at 112 mEq/L.

THE DEFENSE The treatment provided was appropriate.

VERDICT $550,000 California settlement.

COMMENT Avoiding osmotic demyelination syndrome requires careful treatment and monitoring. I have independently reviewed several allegations of malpractice involving this uncommon, but devastating condition. Two recent articles summarize the treatment of this disorder: Sterns RH, Silver S, Klein-schmidt-DeMasters BK, et al. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother. 2007;7:1791-1797; and Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658.

Iodine contrast media kills man with known shellfish allergy

A 41-YEAR-OLD MAN WITH CHEST PAIN was admitted to his local hospital, where he received a diagnosis of acute coronary syndrome. After treatment in the emergency department, the patient was admitted to the telemetry unit by an internist, the partner of the patient’s primary care physician. The patient’s admission records noted that he had an allergy to shellfish.

The next morning, a cardiologist was called in. The cardiologist then called in an interventional cardiologist, who scheduled a cardiac catheterization. The interventional cardiologist ordered 1 dose of steroids, followed a few minutes later by contrast iodine. The patient immediately suffered a severe allergic reaction and died.

PLAINTIFF’S CLAIM The internist who admitted the patient to the telemetry unit took an incomplete history regarding the patient’s allergies (although the admission records contained that information). No information about the claims against the 2 cardiologists is available.

THE DEFENSE No information about the defense is available.

VERDICT $4.7 million gross verdict in Florida.

COMMENT In addition to considering the risk of dye loads and carefully checking renal function, remember to assess for allergy when administering contrast agents. Failure to do so in this case led to the death of the patient and a multimillion-dollar verdict.

Over the last decade, the prevalence of chronic kidney disease (CKD) has grown approximately 20% to 25%, and current estimates are that the disease affects about 15% of the general population.¹ All-cause hospitalization rates are almost 3 times higher among CKD patients than in those without the disease, and costs associated with CKD account for as much as 28% of the Medicare budget.¹ Most disturbingly, the incidence at which patients diagnosed with CKD progress to end-stage renal disease (ESRD) continues to increase annually, reaching 354 cases per million population in 2007.¹ By 2020, estimates are that more than 750,000 people in the United States will need dialysis for kidney failure.¹

Guidelines exist, but awareness falls short
Several initiatives to increase awareness of CKD have been publicized. They include the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), which issued clinical practice guidelines for treating chronic kidney disease in 2002, and Healthy People 2010, which includes specific measures to reduce the number of new cases and the complications, disability, economic costs, and mortality associated with the disease.^2,3 Despite these efforts, studies show that many primary care providers are still unaware of these guidelines.^4,5

Patients go undiagnosed until they reach the later stages of the disease, and many receive suboptimal care—even when they are identified—including lack of timely referral to a nephrologist and inadequate management of CKD comorbidities.^6-13 (More on comorbidities, in a bit.)

Plus, there’s a lack of support … Care for these conditions is complex and difficult, and consultation or referral to a nephrologist may not be readily available, as the current pool of specialists is barely adequate to meet the needs of a growing population of CKD patients and the number of physicians-in-training entering the specialty is not adequate to meet the need.¹⁴ In this situation, primary care providers will have to assume an ever-enlarging share of the responsibility for care of CKD patients, including some clinical activities that are currently performed by specialists.

The first step: Screen all patients for CKD

Incorporating CKD screening into routine blood work for all patients facilitates earlier detection, evaluation, and treatment of the disease. Screening tests include the estimated glomerular filtration rate (GFR) based on serum creatinine as well as measurements of urine albumin and proteinuria. The persistence of proteinuria must be confirmed by 2 of 3 abnormal readings over a minimum of 3 months, because factors such as fever or exercise may affect test results. Measurement of albumin or total protein concentration in a spot sample avoids the need for timed collections. Factoring the concentration of total protein or albumin by urine creatinine concentration and using age/sex-specific thresholds eliminates most variations in measurement.¹⁵

Keep these comorbidities on your radar screen

Diabetes and hypertension are 2 of the most common causes of CKD in the United States, and the number of kidney failure cases due to these problems is increasing. The most important adverse outcomes of CKD are not only progression to ESRD, but also increased risk for cardiovascular disease (CVD). Studies show that the presence of albuminuria and a decreased estimated GFR consistently and incrementally increase the risk for CVD.¹⁶ Decreased GFR is an independent risk factor for CVD outcomes and for all-cause mortality, including sudden death in patients with existing coronary artery disease. Moreover, patients with CKD are 100 times more likely to die from CVD than to develop kidney failure.¹⁶

Depression is another prevalent, yet commonly overlooked, comorbid condition. Patients with any chronic disease are at risk for depression, with the incidence rising with the severity of the medical condition.¹⁷ CKD is no exception. Rates of depression as high as 29%, as well as rates of anxiety disorders as high as 46%, have been documented in patients on dialysis.¹⁸ Patients with depression are impaired in overall functioning and less able to follow medical regimens.¹⁷ In addition, low quality of life and depression predict higher morbidity and mortality rates in patients with ESRD.¹⁹ Because the diagnosis of depression is frequently missed in primary care settings, screening for depression should be a basic element in CKD management.²⁰

Clinical management of kidney disease

The treatment goal for early-stage kidney disease is to address the risk factors that contribute to the progression of kidney disease: hypertension, heart disease, stroke, diabetes, and dyslipidemia. The TABLE reviews clinical management areas by disease stage.

Prescribe angiotensin antagonists. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors antagonize the toxic effects of increases in circulating angiotensin II and are therefore a key component of a therapeutic strategy to halt progressive kidney disease.^2,21

Review medications, promote a healthier lifestyle. In addition to prescribing ARBs or ACE inhibitors, the family physician should review the CKD patient’s current medications to eliminate nephrotoxic drugs and adjust other medications on the basis of the patient’s creatinine clearance. Other measures include making sure vaccinations for influenza, pneumococcal pneumonia, and hepatitis B are up to date and emphasizing the importance of smoking cessation and exercise.

Treat comorbid conditions. Hypertension and diabetes must be treated aggressively. Patients with dyslipidemia should be managed with statins.² Certain complications of progressive kidney disease, such as anemia, bone/mineral metabolic disease, and metabolic disorders, are typically treated by a nephrologist. Nevertheless, primary care providers need to understand these conditions in order to work together with the nephrologist in managing the CKD patient.

Check thyroid hormone and vitamin D levels. Understanding which factors predict disease progression or poor outcome is particularly useful. Most patients with CKD have low T3 syndrome, that is, low serum triiodothyronine levels in the absence of a thyroidal illness. In a recent paper, Song and colleagues showed that low T3 syndrome was common in early CKD and that estimated GFR was positively related with T3, independent of age and serum albumin.²²

In another recent study, Ravani et al showed that plasma 25-hydroxyvitamin D is an independent, inverse predictor of disease progression and death in patients with stage 2 to 5 CKD.²³ Vitamin D deficiency has been linked to CVD and early mortality in patients on hemodialysis.²³ Checking for these 2 markers—low T3 syndrome and vitamin D deficiency—should therefore be part of your screening process for early stage CKD.

Refer to a dietitian. Dietary modification is another important component of the treatment plan. Dietary modifications are often needed to protect against CVD, help control blood pressure, reduce proteinuria, and improve metabolic control in patients with diabetes.^2,24 Dietary modifications for CKD patients may go well beyond standard recommendations for a heart-healthy diet.^2,24 Calcium, sodium, phosphorus, and potassium may need to be restricted according to laboratory values and stage of the disease.²⁵ The KDOQI guidelines recommend referring CKD patients to a registered dietitian with experience in CKD for a complete nutritional assessment, comprehensive education on dietary restrictions and guidelines, and detailed dietary instruction.²

Manage CKD-associated anemia. Current guidelines do not propose normalizing hemoglobin in patients with renal disease, because lower levels of hemoglobin probably represent an adaptive response and correction to a “normal” level may disturb that response and lead to worse outcomes.²⁶ For a discussion of management of anemia associated with CKD, see “Anemia and chronic kidney disease: What’s the connection?” in the January 2010 issue of this journal.²⁷

Refer to a nephrologist early. A recent study by Chan et al demonstrates the beneficial effects of early referral to a nephrologist.²⁸ There is no clear definition of early vs late referral and, at times, the only criterion is how much time elapsed before the patient was put on dialysis. Referral is considered “late” when management could have been improved by earlier contact with a specialist. It is probably prudent to refer stage 3 and 4 patients, at least for initial consultation. Chan’s meta-analysis found that patients referred late had nearly a 2-fold risk of death compared with those with early referrals. This risk persists at least up to 1 year after the initiation of renal replacement therapy.

Prepare patients for dialysis. It is very important that new hemodialysis patients present for initial treatment with an arteriovenous fistula in place, as first access for hemodialysis. Fistula placement is one of the most important reasons for timely referral to a nephrologist. Later referral is associated with a significantly prolonged hospital stay for initial renal replacement therapy. Late-referred patients are sicker, and many of the complications discussed here have not been optimally treated.

The optimal time to start preparing your patient for dialysis is when GFR measures between 15 and 29 mL/min/1.73 m². Preparation includes counseling on nutrition and exercise, hepatitis B vaccination if needed, and scheduling for fistula placement.²⁹

The hardest part: Changing habits
Effective CKD treatment must emphasize lifestyle management. You need to persuade smokers to quit and “couch potatoes” to start exercising regularly. Eating habits need to change, as well: This means fewer calories and restrictions on intake of salt and certain minerals. Medications for high blood pressure, diabetes, and kidney disease need to be taken consistently, as prescribed. The TABLE reviews the lifestyle issues that are particularly salient at each stage of CKD.

TABLE
Keying interventions to CKD stages

Lifestyle modifications like these are very difficult, and helping patients make them involves much more than simple patient education. In 1 study, Durose et al found that patients on hemodialysis failed to stay on their diets even when they knew which dietary restrictions they should follow and what the consequences of going off their diets would be.³⁰

Update your persuasive techniques: take on the role of coach

Newer theories of behavior change no longer rely on simply providing information and advice, but rather address the complex interaction of motivations involved in attempts to change. These include cues to action, perception of benefits and consequences, environmental and cultural influences, sense of self-efficacy, ambivalence, and the intention to change.³¹

Unfortunately, health care providers are rarely trained in motivational techniques. Often, their approach to inducing change is authoritarian, confrontational, overly forceful, or guilt inducing. Such attitudes not only limit progress, but are actually correlated with negative behavioral and clinical outcomes.^32,33 Recent research has verified the power of the patient–provider interaction in influencing treatment adherence and lifestyle change.³³

To be successful in getting patients to adopt new behaviors, physicians need to move away from authoritarian modes and take on some of the attributes of a coach urging on the team.

How this coaching technique works
Motivational Interviewing is a health coaching technique that has been shown to be causally and independently associated with positive behavioral outcomes.³⁴ The techniques used in the motivational interviewing approach are summarized in “The motivational interviewing tool kit”. Motivational interviewing is a goal-oriented, patient-centered counseling style for helping patients explore and resolve their ambivalence about behavior change.³⁵ The approach has been used in diverse populations, settings, and medical conditions. Its efficacy was first demonstrated in the treatment of addictions to illegal drugs and alcohol.³⁶ Continued research and 2 recent meta-analyses using rigorous methodology have validated the usefulness of this approach.^37,38

Motivational interviewing has been shown to be effective in improving general health status and sense of well-being, promoting physical activity, improving nutritional habits, encouraging medication adherence, and managing chronic conditions such as hypertension, hypercholesterolemia, obesity, and diabetes.³⁵ A review of the literature on health behavior change demonstrates that motivational interviewing outperforms traditional advice-giving in the treatment of a broad range of behavioral problems and diseases.³⁸

Motivational interviewing is focused on helping patients explore their ambivalence and identify individual barriers that are preventing change. The skill set that motivational interviewing provides can be modified for use in the brief patient encounters typically found in the primary care setting. For an example of how you might use motivational interviewing techniques with your CKD patients, see “Talking about change: A motivational interviewing conversation”.

Your crucial role
CKD is well on its way to becoming a full-blown epidemic in the United States. Primary care providers carry the brunt of responsibility for the care of these patients, and with an increasing shortage of nephrologists, the scope of those activities will likely grow. Physicians in solo or small group practice must be prepared to deliver both the clinical and behavioral/lifestyle components of care themselves. While this is a challenging endeavor, we believe the framework outlined here will improve your ability to meet the complex needs of CKD patients.

CORRESPONDENCE Ariel Linden, DrPH, MS, Linden Consulting Group, 6208 NE Chestnut Street, Hillsboro, OR 97124; [email protected]

Over the last decade, the prevalence of chronic kidney disease (CKD) has grown approximately 20% to 25%, and current estimates are that the disease affects about 15% of the general population.¹ All-cause hospitalization rates are almost 3 times higher among CKD patients than in those without the disease, and costs associated with CKD account for as much as 28% of the Medicare budget.¹ Most disturbingly, the incidence at which patients diagnosed with CKD progress to end-stage renal disease (ESRD) continues to increase annually, reaching 354 cases per million population in 2007.¹ By 2020, estimates are that more than 750,000 people in the United States will need dialysis for kidney failure.¹

Guidelines exist, but awareness falls short
Several initiatives to increase awareness of CKD have been publicized. They include the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), which issued clinical practice guidelines for treating chronic kidney disease in 2002, and Healthy People 2010, which includes specific measures to reduce the number of new cases and the complications, disability, economic costs, and mortality associated with the disease.^2,3 Despite these efforts, studies show that many primary care providers are still unaware of these guidelines.^4,5

Patients go undiagnosed until they reach the later stages of the disease, and many receive suboptimal care—even when they are identified—including lack of timely referral to a nephrologist and inadequate management of CKD comorbidities.^6-13 (More on comorbidities, in a bit.)

Plus, there’s a lack of support … Care for these conditions is complex and difficult, and consultation or referral to a nephrologist may not be readily available, as the current pool of specialists is barely adequate to meet the needs of a growing population of CKD patients and the number of physicians-in-training entering the specialty is not adequate to meet the need.¹⁴ In this situation, primary care providers will have to assume an ever-enlarging share of the responsibility for care of CKD patients, including some clinical activities that are currently performed by specialists.

The first step: Screen all patients for CKD

Incorporating CKD screening into routine blood work for all patients facilitates earlier detection, evaluation, and treatment of the disease. Screening tests include the estimated glomerular filtration rate (GFR) based on serum creatinine as well as measurements of urine albumin and proteinuria. The persistence of proteinuria must be confirmed by 2 of 3 abnormal readings over a minimum of 3 months, because factors such as fever or exercise may affect test results. Measurement of albumin or total protein concentration in a spot sample avoids the need for timed collections. Factoring the concentration of total protein or albumin by urine creatinine concentration and using age/sex-specific thresholds eliminates most variations in measurement.¹⁵

Keep these comorbidities on your radar screen

Diabetes and hypertension are 2 of the most common causes of CKD in the United States, and the number of kidney failure cases due to these problems is increasing. The most important adverse outcomes of CKD are not only progression to ESRD, but also increased risk for cardiovascular disease (CVD). Studies show that the presence of albuminuria and a decreased estimated GFR consistently and incrementally increase the risk for CVD.¹⁶ Decreased GFR is an independent risk factor for CVD outcomes and for all-cause mortality, including sudden death in patients with existing coronary artery disease. Moreover, patients with CKD are 100 times more likely to die from CVD than to develop kidney failure.¹⁶

Depression is another prevalent, yet commonly overlooked, comorbid condition. Patients with any chronic disease are at risk for depression, with the incidence rising with the severity of the medical condition.¹⁷ CKD is no exception. Rates of depression as high as 29%, as well as rates of anxiety disorders as high as 46%, have been documented in patients on dialysis.¹⁸ Patients with depression are impaired in overall functioning and less able to follow medical regimens.¹⁷ In addition, low quality of life and depression predict higher morbidity and mortality rates in patients with ESRD.¹⁹ Because the diagnosis of depression is frequently missed in primary care settings, screening for depression should be a basic element in CKD management.²⁰

Clinical management of kidney disease

The treatment goal for early-stage kidney disease is to address the risk factors that contribute to the progression of kidney disease: hypertension, heart disease, stroke, diabetes, and dyslipidemia. The TABLE reviews clinical management areas by disease stage.

Prescribe angiotensin antagonists. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors antagonize the toxic effects of increases in circulating angiotensin II and are therefore a key component of a therapeutic strategy to halt progressive kidney disease.^2,21

Review medications, promote a healthier lifestyle. In addition to prescribing ARBs or ACE inhibitors, the family physician should review the CKD patient’s current medications to eliminate nephrotoxic drugs and adjust other medications on the basis of the patient’s creatinine clearance. Other measures include making sure vaccinations for influenza, pneumococcal pneumonia, and hepatitis B are up to date and emphasizing the importance of smoking cessation and exercise.

Treat comorbid conditions. Hypertension and diabetes must be treated aggressively. Patients with dyslipidemia should be managed with statins.² Certain complications of progressive kidney disease, such as anemia, bone/mineral metabolic disease, and metabolic disorders, are typically treated by a nephrologist. Nevertheless, primary care providers need to understand these conditions in order to work together with the nephrologist in managing the CKD patient.

Check thyroid hormone and vitamin D levels. Understanding which factors predict disease progression or poor outcome is particularly useful. Most patients with CKD have low T3 syndrome, that is, low serum triiodothyronine levels in the absence of a thyroidal illness. In a recent paper, Song and colleagues showed that low T3 syndrome was common in early CKD and that estimated GFR was positively related with T3, independent of age and serum albumin.²²

In another recent study, Ravani et al showed that plasma 25-hydroxyvitamin D is an independent, inverse predictor of disease progression and death in patients with stage 2 to 5 CKD.²³ Vitamin D deficiency has been linked to CVD and early mortality in patients on hemodialysis.²³ Checking for these 2 markers—low T3 syndrome and vitamin D deficiency—should therefore be part of your screening process for early stage CKD.

Refer to a dietitian. Dietary modification is another important component of the treatment plan. Dietary modifications are often needed to protect against CVD, help control blood pressure, reduce proteinuria, and improve metabolic control in patients with diabetes.^2,24 Dietary modifications for CKD patients may go well beyond standard recommendations for a heart-healthy diet.^2,24 Calcium, sodium, phosphorus, and potassium may need to be restricted according to laboratory values and stage of the disease.²⁵ The KDOQI guidelines recommend referring CKD patients to a registered dietitian with experience in CKD for a complete nutritional assessment, comprehensive education on dietary restrictions and guidelines, and detailed dietary instruction.²

Manage CKD-associated anemia. Current guidelines do not propose normalizing hemoglobin in patients with renal disease, because lower levels of hemoglobin probably represent an adaptive response and correction to a “normal” level may disturb that response and lead to worse outcomes.²⁶ For a discussion of management of anemia associated with CKD, see “Anemia and chronic kidney disease: What’s the connection?” in the January 2010 issue of this journal.²⁷

Refer to a nephrologist early. A recent study by Chan et al demonstrates the beneficial effects of early referral to a nephrologist.²⁸ There is no clear definition of early vs late referral and, at times, the only criterion is how much time elapsed before the patient was put on dialysis. Referral is considered “late” when management could have been improved by earlier contact with a specialist. It is probably prudent to refer stage 3 and 4 patients, at least for initial consultation. Chan’s meta-analysis found that patients referred late had nearly a 2-fold risk of death compared with those with early referrals. This risk persists at least up to 1 year after the initiation of renal replacement therapy.

Prepare patients for dialysis. It is very important that new hemodialysis patients present for initial treatment with an arteriovenous fistula in place, as first access for hemodialysis. Fistula placement is one of the most important reasons for timely referral to a nephrologist. Later referral is associated with a significantly prolonged hospital stay for initial renal replacement therapy. Late-referred patients are sicker, and many of the complications discussed here have not been optimally treated.

The optimal time to start preparing your patient for dialysis is when GFR measures between 15 and 29 mL/min/1.73 m². Preparation includes counseling on nutrition and exercise, hepatitis B vaccination if needed, and scheduling for fistula placement.²⁹

The hardest part: Changing habits
Effective CKD treatment must emphasize lifestyle management. You need to persuade smokers to quit and “couch potatoes” to start exercising regularly. Eating habits need to change, as well: This means fewer calories and restrictions on intake of salt and certain minerals. Medications for high blood pressure, diabetes, and kidney disease need to be taken consistently, as prescribed. The TABLE reviews the lifestyle issues that are particularly salient at each stage of CKD.

TABLE
Keying interventions to CKD stages

Lifestyle modifications like these are very difficult, and helping patients make them involves much more than simple patient education. In 1 study, Durose et al found that patients on hemodialysis failed to stay on their diets even when they knew which dietary restrictions they should follow and what the consequences of going off their diets would be.³⁰

Update your persuasive techniques: take on the role of coach

Newer theories of behavior change no longer rely on simply providing information and advice, but rather address the complex interaction of motivations involved in attempts to change. These include cues to action, perception of benefits and consequences, environmental and cultural influences, sense of self-efficacy, ambivalence, and the intention to change.³¹

Unfortunately, health care providers are rarely trained in motivational techniques. Often, their approach to inducing change is authoritarian, confrontational, overly forceful, or guilt inducing. Such attitudes not only limit progress, but are actually correlated with negative behavioral and clinical outcomes.^32,33 Recent research has verified the power of the patient–provider interaction in influencing treatment adherence and lifestyle change.³³

To be successful in getting patients to adopt new behaviors, physicians need to move away from authoritarian modes and take on some of the attributes of a coach urging on the team.

How this coaching technique works
Motivational Interviewing is a health coaching technique that has been shown to be causally and independently associated with positive behavioral outcomes.³⁴ The techniques used in the motivational interviewing approach are summarized in “The motivational interviewing tool kit”. Motivational interviewing is a goal-oriented, patient-centered counseling style for helping patients explore and resolve their ambivalence about behavior change.³⁵ The approach has been used in diverse populations, settings, and medical conditions. Its efficacy was first demonstrated in the treatment of addictions to illegal drugs and alcohol.³⁶ Continued research and 2 recent meta-analyses using rigorous methodology have validated the usefulness of this approach.^37,38

Motivational interviewing has been shown to be effective in improving general health status and sense of well-being, promoting physical activity, improving nutritional habits, encouraging medication adherence, and managing chronic conditions such as hypertension, hypercholesterolemia, obesity, and diabetes.³⁵ A review of the literature on health behavior change demonstrates that motivational interviewing outperforms traditional advice-giving in the treatment of a broad range of behavioral problems and diseases.³⁸

Motivational interviewing is focused on helping patients explore their ambivalence and identify individual barriers that are preventing change. The skill set that motivational interviewing provides can be modified for use in the brief patient encounters typically found in the primary care setting. For an example of how you might use motivational interviewing techniques with your CKD patients, see “Talking about change: A motivational interviewing conversation”.

Your crucial role
CKD is well on its way to becoming a full-blown epidemic in the United States. Primary care providers carry the brunt of responsibility for the care of these patients, and with an increasing shortage of nephrologists, the scope of those activities will likely grow. Physicians in solo or small group practice must be prepared to deliver both the clinical and behavioral/lifestyle components of care themselves. While this is a challenging endeavor, we believe the framework outlined here will improve your ability to meet the complex needs of CKD patients.

CORRESPONDENCE Ariel Linden, DrPH, MS, Linden Consulting Group, 6208 NE Chestnut Street, Hillsboro, OR 97124; [email protected]

Over the last decade, the prevalence of chronic kidney disease (CKD) has grown approximately 20% to 25%, and current estimates are that the disease affects about 15% of the general population.¹ All-cause hospitalization rates are almost 3 times higher among CKD patients than in those without the disease, and costs associated with CKD account for as much as 28% of the Medicare budget.¹ Most disturbingly, the incidence at which patients diagnosed with CKD progress to end-stage renal disease (ESRD) continues to increase annually, reaching 354 cases per million population in 2007.¹ By 2020, estimates are that more than 750,000 people in the United States will need dialysis for kidney failure.¹

Guidelines exist, but awareness falls short
Several initiatives to increase awareness of CKD have been publicized. They include the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), which issued clinical practice guidelines for treating chronic kidney disease in 2002, and Healthy People 2010, which includes specific measures to reduce the number of new cases and the complications, disability, economic costs, and mortality associated with the disease.^2,3 Despite these efforts, studies show that many primary care providers are still unaware of these guidelines.^4,5

Patients go undiagnosed until they reach the later stages of the disease, and many receive suboptimal care—even when they are identified—including lack of timely referral to a nephrologist and inadequate management of CKD comorbidities.^6-13 (More on comorbidities, in a bit.)

Plus, there’s a lack of support … Care for these conditions is complex and difficult, and consultation or referral to a nephrologist may not be readily available, as the current pool of specialists is barely adequate to meet the needs of a growing population of CKD patients and the number of physicians-in-training entering the specialty is not adequate to meet the need.¹⁴ In this situation, primary care providers will have to assume an ever-enlarging share of the responsibility for care of CKD patients, including some clinical activities that are currently performed by specialists.

The first step: Screen all patients for CKD

Incorporating CKD screening into routine blood work for all patients facilitates earlier detection, evaluation, and treatment of the disease. Screening tests include the estimated glomerular filtration rate (GFR) based on serum creatinine as well as measurements of urine albumin and proteinuria. The persistence of proteinuria must be confirmed by 2 of 3 abnormal readings over a minimum of 3 months, because factors such as fever or exercise may affect test results. Measurement of albumin or total protein concentration in a spot sample avoids the need for timed collections. Factoring the concentration of total protein or albumin by urine creatinine concentration and using age/sex-specific thresholds eliminates most variations in measurement.¹⁵

Keep these comorbidities on your radar screen

Diabetes and hypertension are 2 of the most common causes of CKD in the United States, and the number of kidney failure cases due to these problems is increasing. The most important adverse outcomes of CKD are not only progression to ESRD, but also increased risk for cardiovascular disease (CVD). Studies show that the presence of albuminuria and a decreased estimated GFR consistently and incrementally increase the risk for CVD.¹⁶ Decreased GFR is an independent risk factor for CVD outcomes and for all-cause mortality, including sudden death in patients with existing coronary artery disease. Moreover, patients with CKD are 100 times more likely to die from CVD than to develop kidney failure.¹⁶

Depression is another prevalent, yet commonly overlooked, comorbid condition. Patients with any chronic disease are at risk for depression, with the incidence rising with the severity of the medical condition.¹⁷ CKD is no exception. Rates of depression as high as 29%, as well as rates of anxiety disorders as high as 46%, have been documented in patients on dialysis.¹⁸ Patients with depression are impaired in overall functioning and less able to follow medical regimens.¹⁷ In addition, low quality of life and depression predict higher morbidity and mortality rates in patients with ESRD.¹⁹ Because the diagnosis of depression is frequently missed in primary care settings, screening for depression should be a basic element in CKD management.²⁰

Clinical management of kidney disease

The treatment goal for early-stage kidney disease is to address the risk factors that contribute to the progression of kidney disease: hypertension, heart disease, stroke, diabetes, and dyslipidemia. The TABLE reviews clinical management areas by disease stage.

Prescribe angiotensin antagonists. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors antagonize the toxic effects of increases in circulating angiotensin II and are therefore a key component of a therapeutic strategy to halt progressive kidney disease.^2,21

Review medications, promote a healthier lifestyle. In addition to prescribing ARBs or ACE inhibitors, the family physician should review the CKD patient’s current medications to eliminate nephrotoxic drugs and adjust other medications on the basis of the patient’s creatinine clearance. Other measures include making sure vaccinations for influenza, pneumococcal pneumonia, and hepatitis B are up to date and emphasizing the importance of smoking cessation and exercise.

Treat comorbid conditions. Hypertension and diabetes must be treated aggressively. Patients with dyslipidemia should be managed with statins.² Certain complications of progressive kidney disease, such as anemia, bone/mineral metabolic disease, and metabolic disorders, are typically treated by a nephrologist. Nevertheless, primary care providers need to understand these conditions in order to work together with the nephrologist in managing the CKD patient.

Check thyroid hormone and vitamin D levels. Understanding which factors predict disease progression or poor outcome is particularly useful. Most patients with CKD have low T3 syndrome, that is, low serum triiodothyronine levels in the absence of a thyroidal illness. In a recent paper, Song and colleagues showed that low T3 syndrome was common in early CKD and that estimated GFR was positively related with T3, independent of age and serum albumin.²²

In another recent study, Ravani et al showed that plasma 25-hydroxyvitamin D is an independent, inverse predictor of disease progression and death in patients with stage 2 to 5 CKD.²³ Vitamin D deficiency has been linked to CVD and early mortality in patients on hemodialysis.²³ Checking for these 2 markers—low T3 syndrome and vitamin D deficiency—should therefore be part of your screening process for early stage CKD.

Refer to a dietitian. Dietary modification is another important component of the treatment plan. Dietary modifications are often needed to protect against CVD, help control blood pressure, reduce proteinuria, and improve metabolic control in patients with diabetes.^2,24 Dietary modifications for CKD patients may go well beyond standard recommendations for a heart-healthy diet.^2,24 Calcium, sodium, phosphorus, and potassium may need to be restricted according to laboratory values and stage of the disease.²⁵ The KDOQI guidelines recommend referring CKD patients to a registered dietitian with experience in CKD for a complete nutritional assessment, comprehensive education on dietary restrictions and guidelines, and detailed dietary instruction.²

Manage CKD-associated anemia. Current guidelines do not propose normalizing hemoglobin in patients with renal disease, because lower levels of hemoglobin probably represent an adaptive response and correction to a “normal” level may disturb that response and lead to worse outcomes.²⁶ For a discussion of management of anemia associated with CKD, see “Anemia and chronic kidney disease: What’s the connection?” in the January 2010 issue of this journal.²⁷

Refer to a nephrologist early. A recent study by Chan et al demonstrates the beneficial effects of early referral to a nephrologist.²⁸ There is no clear definition of early vs late referral and, at times, the only criterion is how much time elapsed before the patient was put on dialysis. Referral is considered “late” when management could have been improved by earlier contact with a specialist. It is probably prudent to refer stage 3 and 4 patients, at least for initial consultation. Chan’s meta-analysis found that patients referred late had nearly a 2-fold risk of death compared with those with early referrals. This risk persists at least up to 1 year after the initiation of renal replacement therapy.

Prepare patients for dialysis. It is very important that new hemodialysis patients present for initial treatment with an arteriovenous fistula in place, as first access for hemodialysis. Fistula placement is one of the most important reasons for timely referral to a nephrologist. Later referral is associated with a significantly prolonged hospital stay for initial renal replacement therapy. Late-referred patients are sicker, and many of the complications discussed here have not been optimally treated.

The optimal time to start preparing your patient for dialysis is when GFR measures between 15 and 29 mL/min/1.73 m². Preparation includes counseling on nutrition and exercise, hepatitis B vaccination if needed, and scheduling for fistula placement.²⁹

The hardest part: Changing habits
Effective CKD treatment must emphasize lifestyle management. You need to persuade smokers to quit and “couch potatoes” to start exercising regularly. Eating habits need to change, as well: This means fewer calories and restrictions on intake of salt and certain minerals. Medications for high blood pressure, diabetes, and kidney disease need to be taken consistently, as prescribed. The TABLE reviews the lifestyle issues that are particularly salient at each stage of CKD.

TABLE
Keying interventions to CKD stages

Lifestyle modifications like these are very difficult, and helping patients make them involves much more than simple patient education. In 1 study, Durose et al found that patients on hemodialysis failed to stay on their diets even when they knew which dietary restrictions they should follow and what the consequences of going off their diets would be.³⁰

Update your persuasive techniques: take on the role of coach

Newer theories of behavior change no longer rely on simply providing information and advice, but rather address the complex interaction of motivations involved in attempts to change. These include cues to action, perception of benefits and consequences, environmental and cultural influences, sense of self-efficacy, ambivalence, and the intention to change.³¹

Unfortunately, health care providers are rarely trained in motivational techniques. Often, their approach to inducing change is authoritarian, confrontational, overly forceful, or guilt inducing. Such attitudes not only limit progress, but are actually correlated with negative behavioral and clinical outcomes.^32,33 Recent research has verified the power of the patient–provider interaction in influencing treatment adherence and lifestyle change.³³

To be successful in getting patients to adopt new behaviors, physicians need to move away from authoritarian modes and take on some of the attributes of a coach urging on the team.

How this coaching technique works
Motivational Interviewing is a health coaching technique that has been shown to be causally and independently associated with positive behavioral outcomes.³⁴ The techniques used in the motivational interviewing approach are summarized in “The motivational interviewing tool kit”. Motivational interviewing is a goal-oriented, patient-centered counseling style for helping patients explore and resolve their ambivalence about behavior change.³⁵ The approach has been used in diverse populations, settings, and medical conditions. Its efficacy was first demonstrated in the treatment of addictions to illegal drugs and alcohol.³⁶ Continued research and 2 recent meta-analyses using rigorous methodology have validated the usefulness of this approach.^37,38

Motivational interviewing has been shown to be effective in improving general health status and sense of well-being, promoting physical activity, improving nutritional habits, encouraging medication adherence, and managing chronic conditions such as hypertension, hypercholesterolemia, obesity, and diabetes.³⁵ A review of the literature on health behavior change demonstrates that motivational interviewing outperforms traditional advice-giving in the treatment of a broad range of behavioral problems and diseases.³⁸

Motivational interviewing is focused on helping patients explore their ambivalence and identify individual barriers that are preventing change. The skill set that motivational interviewing provides can be modified for use in the brief patient encounters typically found in the primary care setting. For an example of how you might use motivational interviewing techniques with your CKD patients, see “Talking about change: A motivational interviewing conversation”.

Your crucial role
CKD is well on its way to becoming a full-blown epidemic in the United States. Primary care providers carry the brunt of responsibility for the care of these patients, and with an increasing shortage of nephrologists, the scope of those activities will likely grow. Physicians in solo or small group practice must be prepared to deliver both the clinical and behavioral/lifestyle components of care themselves. While this is a challenging endeavor, we believe the framework outlined here will improve your ability to meet the complex needs of CKD patients.

CORRESPONDENCE Ariel Linden, DrPH, MS, Linden Consulting Group, 6208 NE Chestnut Street, Hillsboro, OR 97124; [email protected]

[email protected]

Acanthosis nigricans is one of the most common skin signs of obesity and hyperinsulinism and is a valuable predictor of insulin resistance in obese children. Patients with both obesity and acanthosis nigricans, compared with those with obesity alone, tend to have higher body mass indexes and increased fasting and evening insulin levels.

Early recognition and intervention are crucial to avoid complications of insulin resistance. The general pediatrician is in the best position to perform the initial assessment. Begin with measuring body mass index (BMI). Then evaluate the patient for the associated risk factors. If you diagnose acanthosis nigricans, screen the patient for associated conditions such as Cushing's syndrome; hypothyroidism; coexisting syndromes (including Prader-Willi, Bardet-Biedl, and leprechaunism); lipodystrophy; or psychiatric disorders including depression or eating disorders.

Children with a BMI under the 85th percentile and no complications can be managed well by their pediatrician. Early intervention is key. Focus on healthful living, increased physical activity, and education of the family regarding associated conditions and the adverse effects that obesity can have on the child's health and quality of life.

The best strategy is to treat the underlying cause of acanthosis nigricans. Address obesity and any secondary insulin resistance because obesity is the No. 1 cause of acanthosis nigricans. Although topical keratolytic lotions or other topical therapies may be of some benefit, results are often disappointing.

It is also important to involve the entire family in the treatment plan. If everyone is not ready for change, success will be limited. Because much embarrassment and stigma are often associated with obesity, discuss treatment, diet, and weight loss in an objective, nonjudgmental, and nonaccusatory fashion. Consider the family's schedule, financial situation, and lifestyle.

Educate patients and family members about appropriate weight for age and height, self-management skills, and a healthy, balanced diet with lower levels of carbohydrates and fats. It is easy for patients and parents to become discouraged, so institute changes gradually.

If a patient presents with obesity and acanthosis nigricans, evaluate the child for other insulin risk factors. These include a BMI above the 85th percentile for age and sex, polycystic ovarian syndrome, hypertension, dyslipidemia, a history of small size for gestational age at birth, premature pubarche, allergic diathesis, and/or a family history of these conditions. Also note that children of certain ethnicities are at higher risk as well, including African, Indian subcontinent, American Indian, and Hispanic populations.

Children with obesity and insulin resistance are at increased future risk for associated complications including orthopedic problems, fatty liver or gallbladder disease, infertility, hyperandrogenism, coronary artery disease and stroke, type 2 diabetes, predisposition to certain cancers, and Alzheimer's disease.

In addition to measurements of blood pressure, height, weight, and BMI, helpful laboratory studies include nonfasting lipid, hemoglobin A_1c, and insulin and glucose levels. Fasting glucose, insulin, and lipid tests are especially recommended for a child whose BMI is at the 85th percentile or greater.

Conditions that can mimic acanthosis nigricans include postinflammatory hyperpigmentation; chronic eczema (especially in children with darker skin and secondary hyperpigmentation or lichenification); and confluent and reticulated papillomatosis of Gougerot and Carteaud (the plaques in this condition are very similar to acanthosis nigricans, but are more reticulated and located on the chest and back). Other conditions to consider in your differential diagnosis include linear epidermal nevi and retained keratin (which presents as brownish patches on the neck or postauricular areas that are easily removed with alcohol, but not with water).

If the diagnosis of acanthosis nigricans is uncertain, referral to a pediatric dermatologist is recommended. Also refer a girl with suspected PCOS or hyperandrogenism and associated acne, which can be difficult to manage, as well as a girl with male-pattern hair loss.

The following criteria can warrant referral of the patient to a specialist other than a pediatric dermatologist:

▸ A child with a BMI at the 85th percentile or greater and any associated complications or any child with a BMI greater than the 95th percentile should be referred to a pediatric obesity treatment specialist, if available.

▸ Referral to a pediatric cardiologist may be needed if hypertension or dyslipidemia is present.

▸ Referral for a sleep study or for evaluation by a pediatric otolaryngologist may be indicated if signs of sleep disturbance suggest sleep apnea or obesity hypoventilation syndrome.

▸ Persistent headaches could indicate pseudotumor cerebri requiring neurologic evaluation.

▸ Referral to an endocrinologist would be indicated if Cushing's syndrome, type 2 diabetes, or hypothyroidism is suspected, or for girls with signs of PCOS or hyperandrogenism. The guidance of a pediatric endocrinologist may be required with certain medications, such as metformin, to decrease insulin resistance and hyperglycemia.

▸ Children with knee or hip pain and x-ray findings suggestive of slipped capital femoral epiphysis or Blount's disease (tibia vara) may need orthopedic evaluation.

▸ Children with abdominal pain may require referral to a pediatric gastroenterologist for evaluation of obesity-associated liver or gallbladder disease.

Regular monitoring of the overweight child with acanthosis nigricans is recommended. If initial screening is negative for type 2 diabetes or insulin resistance, the American Diabetes Association recommends repeating the screening every 2 years for at-risk children. Follow-up screening can also include thyroid studies to evaluate for hypothyroidism and dehydroepiandrosterone sulfate, free testosterone, and a luteinizing hormone to follicle-stimulating hormone (LH:FSH) ratio to screen for hyperandrogenism.

[email protected]

Acanthosis nigricans is one of the most common skin signs of obesity and hyperinsulinism and is a valuable predictor of insulin resistance in obese children. Patients with both obesity and acanthosis nigricans, compared with those with obesity alone, tend to have higher body mass indexes and increased fasting and evening insulin levels.

Early recognition and intervention are crucial to avoid complications of insulin resistance. The general pediatrician is in the best position to perform the initial assessment. Begin with measuring body mass index (BMI). Then evaluate the patient for the associated risk factors. If you diagnose acanthosis nigricans, screen the patient for associated conditions such as Cushing's syndrome; hypothyroidism; coexisting syndromes (including Prader-Willi, Bardet-Biedl, and leprechaunism); lipodystrophy; or psychiatric disorders including depression or eating disorders.

Children with a BMI under the 85th percentile and no complications can be managed well by their pediatrician. Early intervention is key. Focus on healthful living, increased physical activity, and education of the family regarding associated conditions and the adverse effects that obesity can have on the child's health and quality of life.

The best strategy is to treat the underlying cause of acanthosis nigricans. Address obesity and any secondary insulin resistance because obesity is the No. 1 cause of acanthosis nigricans. Although topical keratolytic lotions or other topical therapies may be of some benefit, results are often disappointing.

It is also important to involve the entire family in the treatment plan. If everyone is not ready for change, success will be limited. Because much embarrassment and stigma are often associated with obesity, discuss treatment, diet, and weight loss in an objective, nonjudgmental, and nonaccusatory fashion. Consider the family's schedule, financial situation, and lifestyle.

Educate patients and family members about appropriate weight for age and height, self-management skills, and a healthy, balanced diet with lower levels of carbohydrates and fats. It is easy for patients and parents to become discouraged, so institute changes gradually.

If a patient presents with obesity and acanthosis nigricans, evaluate the child for other insulin risk factors. These include a BMI above the 85th percentile for age and sex, polycystic ovarian syndrome, hypertension, dyslipidemia, a history of small size for gestational age at birth, premature pubarche, allergic diathesis, and/or a family history of these conditions. Also note that children of certain ethnicities are at higher risk as well, including African, Indian subcontinent, American Indian, and Hispanic populations.

Children with obesity and insulin resistance are at increased future risk for associated complications including orthopedic problems, fatty liver or gallbladder disease, infertility, hyperandrogenism, coronary artery disease and stroke, type 2 diabetes, predisposition to certain cancers, and Alzheimer's disease.

In addition to measurements of blood pressure, height, weight, and BMI, helpful laboratory studies include nonfasting lipid, hemoglobin A_1c, and insulin and glucose levels. Fasting glucose, insulin, and lipid tests are especially recommended for a child whose BMI is at the 85th percentile or greater.

Conditions that can mimic acanthosis nigricans include postinflammatory hyperpigmentation; chronic eczema (especially in children with darker skin and secondary hyperpigmentation or lichenification); and confluent and reticulated papillomatosis of Gougerot and Carteaud (the plaques in this condition are very similar to acanthosis nigricans, but are more reticulated and located on the chest and back). Other conditions to consider in your differential diagnosis include linear epidermal nevi and retained keratin (which presents as brownish patches on the neck or postauricular areas that are easily removed with alcohol, but not with water).

If the diagnosis of acanthosis nigricans is uncertain, referral to a pediatric dermatologist is recommended. Also refer a girl with suspected PCOS or hyperandrogenism and associated acne, which can be difficult to manage, as well as a girl with male-pattern hair loss.

The following criteria can warrant referral of the patient to a specialist other than a pediatric dermatologist:

▸ A child with a BMI at the 85th percentile or greater and any associated complications or any child with a BMI greater than the 95th percentile should be referred to a pediatric obesity treatment specialist, if available.

▸ Referral to a pediatric cardiologist may be needed if hypertension or dyslipidemia is present.

▸ Referral for a sleep study or for evaluation by a pediatric otolaryngologist may be indicated if signs of sleep disturbance suggest sleep apnea or obesity hypoventilation syndrome.

▸ Persistent headaches could indicate pseudotumor cerebri requiring neurologic evaluation.

▸ Referral to an endocrinologist would be indicated if Cushing's syndrome, type 2 diabetes, or hypothyroidism is suspected, or for girls with signs of PCOS or hyperandrogenism. The guidance of a pediatric endocrinologist may be required with certain medications, such as metformin, to decrease insulin resistance and hyperglycemia.

▸ Children with knee or hip pain and x-ray findings suggestive of slipped capital femoral epiphysis or Blount's disease (tibia vara) may need orthopedic evaluation.

▸ Children with abdominal pain may require referral to a pediatric gastroenterologist for evaluation of obesity-associated liver or gallbladder disease.

Regular monitoring of the overweight child with acanthosis nigricans is recommended. If initial screening is negative for type 2 diabetes or insulin resistance, the American Diabetes Association recommends repeating the screening every 2 years for at-risk children. Follow-up screening can also include thyroid studies to evaluate for hypothyroidism and dehydroepiandrosterone sulfate, free testosterone, and a luteinizing hormone to follicle-stimulating hormone (LH:FSH) ratio to screen for hyperandrogenism.

[email protected]

Acanthosis nigricans is one of the most common skin signs of obesity and hyperinsulinism and is a valuable predictor of insulin resistance in obese children. Patients with both obesity and acanthosis nigricans, compared with those with obesity alone, tend to have higher body mass indexes and increased fasting and evening insulin levels.

Early recognition and intervention are crucial to avoid complications of insulin resistance. The general pediatrician is in the best position to perform the initial assessment. Begin with measuring body mass index (BMI). Then evaluate the patient for the associated risk factors. If you diagnose acanthosis nigricans, screen the patient for associated conditions such as Cushing's syndrome; hypothyroidism; coexisting syndromes (including Prader-Willi, Bardet-Biedl, and leprechaunism); lipodystrophy; or psychiatric disorders including depression or eating disorders.

Children with a BMI under the 85th percentile and no complications can be managed well by their pediatrician. Early intervention is key. Focus on healthful living, increased physical activity, and education of the family regarding associated conditions and the adverse effects that obesity can have on the child's health and quality of life.

The best strategy is to treat the underlying cause of acanthosis nigricans. Address obesity and any secondary insulin resistance because obesity is the No. 1 cause of acanthosis nigricans. Although topical keratolytic lotions or other topical therapies may be of some benefit, results are often disappointing.

It is also important to involve the entire family in the treatment plan. If everyone is not ready for change, success will be limited. Because much embarrassment and stigma are often associated with obesity, discuss treatment, diet, and weight loss in an objective, nonjudgmental, and nonaccusatory fashion. Consider the family's schedule, financial situation, and lifestyle.

Educate patients and family members about appropriate weight for age and height, self-management skills, and a healthy, balanced diet with lower levels of carbohydrates and fats. It is easy for patients and parents to become discouraged, so institute changes gradually.

If a patient presents with obesity and acanthosis nigricans, evaluate the child for other insulin risk factors. These include a BMI above the 85th percentile for age and sex, polycystic ovarian syndrome, hypertension, dyslipidemia, a history of small size for gestational age at birth, premature pubarche, allergic diathesis, and/or a family history of these conditions. Also note that children of certain ethnicities are at higher risk as well, including African, Indian subcontinent, American Indian, and Hispanic populations.

Children with obesity and insulin resistance are at increased future risk for associated complications including orthopedic problems, fatty liver or gallbladder disease, infertility, hyperandrogenism, coronary artery disease and stroke, type 2 diabetes, predisposition to certain cancers, and Alzheimer's disease.

In addition to measurements of blood pressure, height, weight, and BMI, helpful laboratory studies include nonfasting lipid, hemoglobin A_1c, and insulin and glucose levels. Fasting glucose, insulin, and lipid tests are especially recommended for a child whose BMI is at the 85th percentile or greater.

Conditions that can mimic acanthosis nigricans include postinflammatory hyperpigmentation; chronic eczema (especially in children with darker skin and secondary hyperpigmentation or lichenification); and confluent and reticulated papillomatosis of Gougerot and Carteaud (the plaques in this condition are very similar to acanthosis nigricans, but are more reticulated and located on the chest and back). Other conditions to consider in your differential diagnosis include linear epidermal nevi and retained keratin (which presents as brownish patches on the neck or postauricular areas that are easily removed with alcohol, but not with water).

If the diagnosis of acanthosis nigricans is uncertain, referral to a pediatric dermatologist is recommended. Also refer a girl with suspected PCOS or hyperandrogenism and associated acne, which can be difficult to manage, as well as a girl with male-pattern hair loss.

The following criteria can warrant referral of the patient to a specialist other than a pediatric dermatologist:

▸ A child with a BMI at the 85th percentile or greater and any associated complications or any child with a BMI greater than the 95th percentile should be referred to a pediatric obesity treatment specialist, if available.

▸ Referral to a pediatric cardiologist may be needed if hypertension or dyslipidemia is present.

▸ Referral for a sleep study or for evaluation by a pediatric otolaryngologist may be indicated if signs of sleep disturbance suggest sleep apnea or obesity hypoventilation syndrome.

▸ Persistent headaches could indicate pseudotumor cerebri requiring neurologic evaluation.

▸ Referral to an endocrinologist would be indicated if Cushing's syndrome, type 2 diabetes, or hypothyroidism is suspected, or for girls with signs of PCOS or hyperandrogenism. The guidance of a pediatric endocrinologist may be required with certain medications, such as metformin, to decrease insulin resistance and hyperglycemia.

▸ Children with knee or hip pain and x-ray findings suggestive of slipped capital femoral epiphysis or Blount's disease (tibia vara) may need orthopedic evaluation.

▸ Children with abdominal pain may require referral to a pediatric gastroenterologist for evaluation of obesity-associated liver or gallbladder disease.

Regular monitoring of the overweight child with acanthosis nigricans is recommended. If initial screening is negative for type 2 diabetes or insulin resistance, the American Diabetes Association recommends repeating the screening every 2 years for at-risk children. Follow-up screening can also include thyroid studies to evaluate for hypothyroidism and dehydroepiandrosterone sulfate, free testosterone, and a luteinizing hormone to follicle-stimulating hormone (LH:FSH) ratio to screen for hyperandrogenism.

As for many solid tumors, major advances in the treatment of ovarian cancer are more likely to be made through the introduction of novel targeted approaches rather than by manipulating cytotoxic chemotherapy regimens. Farletuzumab is a monoclonal antibody that binds to and blocks the function of folate receptor alpha, which is expressed in at least 90% of ovarian cancer patients. In platinum-sensitive patients experiencing the first relapse of their disease, farletuzumab enhances CA-125 responses as well as tumor response, as determined by RECIST criteria, compared with historic controls. Farletuzumab therefore represents a promising candidate for evaluation in phase III trials. The FAR-131 study is a multicenter, double-blind, randomized, placebo-controlled trial examining the safety and efficacy of two dose levels of farletuzumab in combination with carboplatin and a taxane in patients with platinum-sensitive ovarian cancer in first relapse. The primary endpoint is progression-free survival; the effects of this combination on overall survival, CA-125 response, duration of second remission, and quality of life are among the secondary objectives of this study.

As for many solid tumors, major advances in the treatment of ovarian cancer are more likely to be made through the introduction of novel targeted approaches rather than by manipulating cytotoxic chemotherapy regimens. Farletuzumab is a monoclonal antibody that binds to and blocks the function of folate receptor alpha, which is expressed in at least 90% of ovarian cancer patients. In platinum-sensitive patients experiencing the first relapse of their disease, farletuzumab enhances CA-125 responses as well as tumor response, as determined by RECIST criteria, compared with historic controls. Farletuzumab therefore represents a promising candidate for evaluation in phase III trials. The FAR-131 study is a multicenter, double-blind, randomized, placebo-controlled trial examining the safety and efficacy of two dose levels of farletuzumab in combination with carboplatin and a taxane in patients with platinum-sensitive ovarian cancer in first relapse. The primary endpoint is progression-free survival; the effects of this combination on overall survival, CA-125 response, duration of second remission, and quality of life are among the secondary objectives of this study.

As for many solid tumors, major advances in the treatment of ovarian cancer are more likely to be made through the introduction of novel targeted approaches rather than by manipulating cytotoxic chemotherapy regimens. Farletuzumab is a monoclonal antibody that binds to and blocks the function of folate receptor alpha, which is expressed in at least 90% of ovarian cancer patients. In platinum-sensitive patients experiencing the first relapse of their disease, farletuzumab enhances CA-125 responses as well as tumor response, as determined by RECIST criteria, compared with historic controls. Farletuzumab therefore represents a promising candidate for evaluation in phase III trials. The FAR-131 study is a multicenter, double-blind, randomized, placebo-controlled trial examining the safety and efficacy of two dose levels of farletuzumab in combination with carboplatin and a taxane in patients with platinum-sensitive ovarian cancer in first relapse. The primary endpoint is progression-free survival; the effects of this combination on overall survival, CA-125 response, duration of second remission, and quality of life are among the secondary objectives of this study.