Editorial Commentary: The Sound of Hoof Beats Does Not Always Mean That It Is a Zebra

The article by Causer et al. [1] is very timely in this age of increasing international travel, drug-resistant malaria, and concerns about the safety of antimalarial drugs. The phenomenon of “chemoprophylaxis failure” described by Causer et al. [1] is by no means new, because it has been known to exist anecdotally by tropical disease practitioners for many years, but it is likely to be unrecognized by a majority of infectious diseases consultants. This article highlights the problem of misdiagnosis of malaria among travelers to developing countries and raises a number of very important issues. The dictum concerning a febrile patient in many, if not all, developing countries where malaria is endemic is that “fever is malaria until proven otherwise.” This, of course, is the same approach that should be taken by North American practitioners in the evaluation of a febrile traveler newly returned from a malarious area. However, the problem highlighted here is that, in the developing world, malaria is frequently overdiagnosed among persons who are taking appropriate and effective antimalarial drugs for chemoprophylaxis. Although sub-Saharan Africa appears to be the most frequent location where this phenomenon has been reported, this is not surprising, because countries in sub-Saharan Africa have some of the highest rates of malaria in the world. Intuitively, one might expect laboratories in the developing world to be particularly expert in the diagnosis of malaria. Unfortunately, often laboratory facilities are substandard, technicians are poorly trained, and the volume of work is excessive in time-dependent situations. Both published and unpublished studies have shown that the rate of false-positive results for malaria films is extraordinarily high in some developing countries. In 1989, Lobel and colleagues at the Centers for Disease Control and Prevention showed that the results for 75% of blood films for State Department personnel diagnosed with malaria in Kenya were found to be falsely positive. In Kenya, Ohrt et al. [2] showed that the initial specificity of slide reading results for 24 experienced microscopists ranged from 0% to 100%, with a mean of 78% [3]. Tests performed by microscopists with >5 years of experience had an average specificity of 15%. In Benin, Holtz et al. [3] reviewed blood films at 8 secondary health care facilities where the rates of false-positive and false-negative results were 48% and 8%, respectively [4]. These findings support the conclusions made by Causer et al. [1] that false-positive blood film results and inaccurate clinical diagnosis, rather than failure of malaria chemoprophylaxis, were responsible for the misdiagnosis of malaria in the university students and staff working in Ghana. However, lest one loses all confidence in malaria diagnoses made in developing countries, other studies have shown that direct microscopy compared well with PCR, the current “gold standard” for malaria diagnosis, with sensitivities and specificities of well over 90%. Causer et al. [1] pointed out, quite correctly, the potential impact of a false diagnosis of malaria in travelers in malarious areas. In the first place, the patient may receive inappropriate or dangerous medications. By way of example, a patient receiving mefloquine prophylaxis recently called me from Nigeria after developing fever and diarrhea on the second day after her arrival in an urban center. The physicians at a hospital recommended by a local foreign embassy (that shall remain nameless) treated her with halofantrine for malaria diagnosed by blood film. In view of the well-described cardiac toxicity of this combination of antimalarials, this case prompted me, during the pretravel interview, to advise travelers who are receiving mefloquine prophylaxis against taking halofantrine (Halfan; GlaxoSmithKline) in the event that they have a diagnosis of malaria made overseas [5]. The problem of finding a health care facility that has well-developed diagnostic services is a difficult one. As noted above, even foreign embassy personnel and expatriates may not be able to ascertain the best location to obtain high-quality health care in their communities. However, there are now a number of travel insurance companies that provide their clients with the names of reliable practitioners and, in some cases, company-run facilities staffed with well-trained personnel [6]. The International Association for Medical Assistance to Travellers (http://www.iamat.org) is a nonprofit membership organization that, for a small donation, provides the names of English-speaking physicians in many countries. Of course, this system of referral physicians does not guarantee an accurate diagnosis of malaria. The second problem is that travelers who receive a diagnosis of malaria may lose confidence in their chemoprophylactic agent and elect to discontinue use of their drug. In fact, the traveler to Nigeria mentioned above called (not collect) to ask whether she should discontinue chemoprophylaxis because “it wasn't working anyway.” Not only does the traveler who has malaria diagnosed lose confidence in his or her antimalarial drug, but so do fellow travelers and other members of the expatriate community in areas of endemicity who hear about a “prophylaxis failure.” Unfortunately, there is no easy answer to this problem. At least part of the solution may rest with the travel medicine advisor or individual giving pretravel health advice. Travelers taking antimalarials—especially those traveling to sub-Saharan Africa—should be advised to seek medical attention immediately at the first sign of fever (a no-brainer), even if they are adherent to their drug regimen. If the diagnosis of malaria is made, the traveler should be told not dispute the diagnosis, but rather to take the recommended treatment (unless one is receiving mefloquine and is being given halofantrine), because there is a remote but definite possibility that the diagnosis is correct. However, it should be emphasized to the traveler that the prophylactic medication should be continued irrespective of the diagnosis of malaria. Also, it might be prudent to recommend that this message be passed along to fellow travelers. As a tangential issue, one of the problems that may be associated with antimalarial prophylaxis failure is the problem of counterfeit antimalarial drugs. At a time when the costs of travel immunizations and antimalarial drugs have become extremely costly—often more than the air ticket itself—there is an increasing tendency for travelers to ask whether they should purchase their malaria chemoprophylaxis medications abroad because of cost considerations. The answer, in a word, should be NO! Recent studies have shown that counterfeit or substandard antimalarial drugs is an increasing and serious problem. In Cameroon, a recent study showed that “38% of 133 chloroquine, 74% of 70 quinine, and 12% of 81 antifolates had either no active ingredient, an insufficient active ingredient, the wrong ingredient, or unknown ingredient(s)” [7, p. 245]. Newton et al. [8] showed that 38% of 104 store-bought samples of “artesunate” in southeast Asia did not contain the drug (a new potential cause of murder!). The suspected malaria chemoprophylaxis failures in the study by Causer et al. [1] have highlighted an important issue for the travel medicine advisor and health care provider who care for the patient at the time of return from a malarious area. Travel medicine practitioners should, when it is appropriate, apprise travelers of the potential problem of malaria overdiagnosis. On the other hand, infectious diseases consultants who evaluate returned travelers who have received a diagnosis of “malaria” abroad need to be aware that the diagnosis should be viewed with healthy skepticism in the context of this case study—or, as we say in the tropical diseases world, “just because you hear hoof beats doesn't mean that it's a zebra.” Potential conflicts of interest. J.S.K.: no conflicts.

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