As the world gets more accessible and we travel for business, pleasure, eleemosynary or political reasons we are exposed to more than divergent cultural mores. Our global travel allows us to become hosts to viruses, parasites, bacteria and heretofore (at least in LA), unknown microbes that cause difficult to diagnose diseases. 


As many of you know, I am a trustee of Save the Children. Next month, several active members and myself will travel to Ethiopia to visit some of our projects in that part of Africa…I’m very excited. Like other travelers to distant lands, I did my due diligence and went on the CDC website to check on the immunizations I would need and then proceeded to the office of an infectious disease specialist to acquire said immunizations and prophylactic medications. It turns out that I was up-to-date on my Yellow Fever, hepatitis A, and tetanus shots, so all I needed was another typhoid immunization. (I had received all the other shots when I went to India a few years ago.) Subsequent to the shot, the specialist wanted to discuss malaria prophylaxis. The easiest she said, was Malarone, a single pill which should be taken 2 days before arriving in an endemic area and 5 days after leaving. Pretty simple…only when I took Malarone during a trip to India, I developed terrible hives. “Oh,” she said, “you’re the only one I have ever heard of who had an allergic reaction” (Actually, I met a documentary film maker who frequently travels to Africa who has experienced this same reaction.) The other anti-malarial prophylactic medication that is effective for Ethiopian travel is doxycycline. Unfortunately this antibiotic needs to be continued 4 weeks after the trip; can cause severe photosensitivity as well as (at least for me) GI symptoms. So I though I might simply pass on these meds and use oodles of DDT on my skin and clothes.
 
Sorry abut this long intro, but now I’ll get to the crux of this week’s newsletter; When I opened JAMA this week, there was an article under “Clinician’s Corner” titled Does This Patient Have Malaria? It obviously caught my eye. And here are some of the facts that were presented:

  • Malaria imperils more than 3 billion (that is a “b”) people and clinically infects 250 million people every year. It kills nearly 1 million people annually, mostly children in sub-Saharan Africa. Although malaria was irradiated in the US in the mid-20th century, clinicians continue to see “imported” malaria from travelers and it accounts for almost 30% of travel-related fevers.
  • In 2008, 1300 cases of malaria were reported in the US (it’s felt however that the true incidence may be higher). In that year, imported malaria (sounds like something expensive!) was due to 2 species of the malarial parasite called Plasmodium falciparum and Plasmodium vivax, mostly acquired in Africa and Asia.

 

Now, just so you understand what happens: Malaria involves the life cycle of mosquitoes and humans. The Anopheline mosquito transmits the malaria parasite (the plasmodia) from an infected person to an uninfected person. After this very unwelcome inoculation, the parasites pass from the skin to the liver cells (hepatocytes) where it multiplies; the liver cells then rupture and “liberate” scores of parasites that re-infect red blood cells. Since the parasites need to get to and divide in the liver to create the disease, the clinical (or blood) stage and symptoms are delayed 7 to 14 days after the bite of the mosquito. That’s when the parasites multiply within the blood cells cause them to rupture and are released. This massive rupture of the blood cells is clinically manifested as fever, shaking, anemia, pallor and jaundice. The damaged red blood cells then engorge the spleen and liver causing enlargement of these organs. This can all result in nausea, vomiting, headache, renal failure, low blood sugar and low platelets and bleeding. Malaria in children can cause cerebral malaria and coma. (OK by now I am truly concerned!)
 
The article dealt with the prevalence of malaria in returning travelers from endemic areas. One sentence stood out… “Compared to travelers returning from nonmalarious (great word) or very low risk areas in a database of more than 30,000 patients, the relative risk (RR) of malaria was most elevated by travel to sub-Saharan Africa (it was 208 or 208% higher), Oceana (77) and less elevated by travel to South Asia (RR, 54), Central America (RR, 38) and Southeast Asia (RR, 12). The most likely symptom for malaria in returning travelers was fever, headache, and chills. And for doctors, the diagnostic tests that were most useful for diagnosis were elevation of bilirubin (showing liver function damage and correlated with jaundice) and low platelet count as well as the clinical finding of an enlarged spleen.”  Oi!


Bottom line: The prevalence of malaria in travelers who develop fevers after they return from malaria-endemic areas is approximates 30%. This may not be information that most of you will need. But as the world contracts (travel wise), you might want to put this fact in the recesses of your list of “may need to know”.  Right now, I am debating between long term doxycycline with all its side effects, and long sleeved clothes, impenetrable slacks, high socks, long pajamas as well as an embedded net to sleep under (I already purchased it). I will certrainly use huge amounts of DDT. I’ll let you know how I feel after the trip. 

 

What’s your bone density? This query is almost as frequent as: What’s your cholesterol level? (Or it should be if you are postmenopausal.)

I know that I have written about the need to consider risk factors for fractures due to osteoporosis. A quick reminder, these include being female, older age, lack of estrogen in menopause, certain medications, previous fractures, smoking, family history of osteoporosis, and low bone density. All these are put together in the FRAX score which should be calculated before considering treatment with bisphosphonates (such as Fosomax, Actonel, Boniva, Reclast) or other osteoporosis medications. And I’ve also addressed the rare complications that can occur as a result of bisphosphonate therapy; more specifically, jaw bone necrosis and atypical fractures of the femur. (If you want a full description, go to the website and you can look it up in the archived articles.)

But before you read about the potential bad stuff that can occur with bisphosphonate therapy (hey, I can use “stuff” to describe things and events, President Obama does!), I want to report on a study that recently came out in The Journal of Clinical Endocrinologic Metabolism. The authors of the article rightly point out that there is substantial morbidity (illness) and mortality associated with osteoporotic fractures. Between 10% and 20 % of individuals who suffer hip fractures die within 1 year. They analyzed all the placebo-controlled randomized trials of osteoporosis treatment in the literature. They eliminated trials that included women who were on estrogen or SERMS such as Evista (which help maintain bone density) and focused only on those trials that were conducted for more than a year with “approved doses of medication”. Based on these criteria, 8 studies were eligible for analysis.


And here is what they found: There was a greater than 10% reduction in mortality for those individuals who were treated with osteoporosis medications when compared to those on placebo. Surprisingly, the reduction in deaths was neither related to age nor to incidence of hip or other non-vertebral fracture.  Now, even if we consider that treatment for osteoporosis reduces fractures by 5%, and hence an approximate reduction in hip fracture mortality of 2% to 3%, this does not explain the total mortality reduction that was found for osteoporosis therapy in these studies.

Bottom line: There may be more to “just” decreasing fracture rates with osteoporosis treatment. Osteoporosis medications can reduce mortality by over 10%, especially when used to treat older, frailer individuals. So before we shy away from their use because of rare (albeit, scary) side effects, we have to remember that osteoporosis therapy can do more than stave off debilitating fractures… it may help save lives.

It’s nice to occasionally report on a positive finding.

Over the past few months, a number of my patients have been diagnosed with breast cancer. They have gone through the requisite biopsies, additional MRI’s, lumpectomies, sentinel node excision and even mastectomy with reconstruction. Every time I am involved in their diagnosis (and have to make that phone call to come in and discuss their options), I realize how difficult it is for them to first be told they have breast cancer and then become “expert” enough to select a team and actively participate in the decisions regarding therapy. The cancer cells that were removed will go through pathologic diagnosis, grading of differentiation, hormone receptor testing, HER2/neu testing, and in some cases oncogene testing. We then discuss therapeutic options and how they affect recurrence, spread and survival. Some women will need radiation and/or chemotherapy in addition to their surgical treatment. Most will need what we call “adjuvant therapy” and in this week’s newsletter I want to give a brief 101 on what this is…

Even if you never have to face the decision about breast cancer therapy yourself, you will probably have friends and/or family members who do. Currently, there are 2.5 million women in the United States who have had breast cancer. About two thirds of them have (or had) breast cancer that is hormone-receptor positive. That means that the cancer cells have the ability to attach to and be “encouraged to grow” by estrogen, progesterone or both. The current recommendation of the American Society of Clinical Oncology (ASCO) is that all post menopausal women who have hormone-positive breast cancer take adjuvant therapy (Adjuvant therapy basically means medication that is continued for years to prevent recurrence or progression of the cancer). The adjuvant therapy they now recommend for postmenopausal women is an aromatase inhibitor (AI). The three AI’s that are currently approved are Arimidex, Femora and Aromasin.

First, a brief explanation of how the AI’s work…Postmenopausal women who, as the name implies, no longer produce estrogen from their ovaries, but they do continue to have some estrogen in their system… Post menopausal estrogen is produced from male hormone (androgen) and steroids secreted by the adrenals as well as the non-egg producing portions of their ovaries. These hormones are converted to estrogens via an aromatase enzyme which is present in fat and other tissues. By blocking this enzyme, AI’s reduce estrogen levels in postmenopausal women by 95%.  At least 2 trials of over 5,000 women with hormone-receptor-positive breast cancers have shown that after more than 4 years the treated women had a more favorable disease-free survival by 85%, a more favorable time-to-recurrence, as well as a lower incidence of breast cancer developing in the other breast compared to women who did not use this therapy.

These AI’s are, however, only used in women who are truly menopausal. For women who develop breast cancer before menopause, the adjuvant therapy currently prescribed is tamoxifen. This is a selective estrogen receptor modulator (SERM) and works by “sitting” on the receptors of the cells of the breast tissue and thus prevents estrogens from attaching to these cells.  But this affect is selective and only breast tissue cells are blocked….tamoxifen has estrogen like effects on the uterus, bone, liver and coagulation system.

Aromatase inhibitor therapy now appears to be superior to tamoxifen for postmenopausal women. But it should only be used after complete and total menopause. Women who still produce estrogen in their ovaries do so via a different pathway: not through conversion by the aromatase enzyme. Indeed if AI therapy is given to a premenopausal woman, her estrogen levels may increase. Hence after chemotherapy (which often causes a temporary cessation of periods), we check to make sure that there are no residual  ovarian follicles that could be stimulated and produce estrogen in the future. This is done with blood tests for FSH (the pituitary hormone that drives ovulation) and estrogen. (This is probably way more than you want or need to know, but hey, I thought it was interesting!)

There is no “free lunch” and, of course, there will be no “free” (of side effects) adjuvant therapy. The AI’s can cause joint pain (arthralgias), hot flashes and a decrease in bone mineral density.  (Estrogen helps maintain bone mass…so when it is totally depleted the bones are more likely to become porous.) Usually the joint pain will diminish after 2 months. If it doesn’t, switching from one AI to another may help. In general, these side effects are less than those commonly seen with tamoxifen which can cause hot flashes, vaginal bleeding, and less frequent but worrisome over-stimulation of the uterine lining resulting in endometrial cancer, as well as abnormal venous clots and even cataracts). One more fact…we now know that the efficacy of tamoxifen decreases in women who take SSRI’s such as Prozac.

Because of the loss of bone mass seen with AI’s before starting therapy, a baseline bone density should be done, then repeated every two years. If a woman with low bone density is at high risk for a fracture or if she already has or develops osteoporosis, she probably should be started on an oral bisphosphonate (examples are Fosomax, Actonel and Boniva) or one that is given intravenously.

Here are the current guidelines from ASCO for women who have hormone-receptor-positive-breast cancer:

  • Consider taking an AI to lengthen disease-free survival and lower risk of recurrence
  • Take the AI for 5 years (this may become longer as trials continue)
  • Women who have been on tamoxifen for 5 years stand to benefit from switching to AI for an additional 5 years
  • A woman who cannot tolerate a particular AI should consider switching to a different AI

Bottom line: There is more to breast cancer therapy than “getting it out” or radiating it. Adjuvant therapy can help prevent it from coming back or spreading.

Links

-->