topnaman

The NY Times reports on the mosquito repelling activity of eucalyptol, a natural oil found in eucalyptus trees. Don’t get your hopes up - the concentration is too low to be effective. Commercial preparations for actual use are now available and they sure beat the smell of DEET.

My friend Atanu Dey at Deeshaa.org often speaks of the fallacy of implementing technological solutions to overcome fundamentally non-technological problems. While Atanu usually invokes this paradigm in reference to India’s primary education challenge, I believe the same concept is relevant to public health efforts. Many public health problems today are non-technological, i.e. we have effective tools for the prevention and treatment of many diseases. This is not to say improved tools won’t help - the smart use of technology helps us solve problems, but rather the fundamental problem is not the lack of effective interventions. In fact, it is usually the deficit of financial/technical resources and good governance. Without these ingredients sustainable public health gains, including malaria control, will remain elusive.

Bate et al. tested antimalarial quality for several drugs in 6 countries across sub-Saharan Africa and found an alarming 35% were substandard as gauged by thin layer chromatography or dissolution tests. The authors did not attempt to assess whether counterfeit or not as the outcome would remain the same - i.e. the drugs are substandard and will fail to cure many cases.

In addition to the widespread availability of artemisinin monotherapies, near 80% were manufactured after WHO’s intense efforts to convince manufacturers to end production, is particularly worrisome. In many of these areas the bulk of medicines are obtained through private sector channels. Thus, widespread substandard drugs (whether counterfeit or legitimate) will promote clinical failures. These treatment failures have grave implications for increased health burden and increased drug pressure selecting for parasite resistance.

This is cool. Often much research feels far removed from everyday applications and practical concerns. So it is terribly rewarding to see a skunk works type creation that has great potential for how we deliver care. The CellScope is a microscope attachment for cellular phones which is designed to allow field workers to take images of specimens and send them to an expert for diagnosis. Developed by engineers at the University of California at Berkeley, the CellScope was designed to handle a range of magnifications including the optical power neccessary to diagnose malaria (malaria slide image from the CellScope).

There are a number of obstacles for the designers to overcome before such a device could become field usable - though I believe all of them should be surmountable. For example, in many malaria infections only a small portion of red blood cells are infected (often <0.5%) which means an accurate diagnosis requires the examination of many different microscope fields. The device therefore needs to image multiple fields automatically and deciding which fields to send is important. Sending too few might result in misdiagnoses and sending all fields places a large workload for technicians at the receiving end. A screening software, in the phone or the receiving workstation, capable of rapidly screening fields and selecting for example 10 out of 100 imaged fields for expert verification could overcome this challenge.

In early April of this year a Vietnamese news source carried an article about the challenges of malaria control and the possibility of future malaria epidemics. A substantial portion of the piece focused on antimalarial resistance, including high failure rates of chloroquine and sulphadoxine-pyrimethamine. What was surprising was a passing mention of artesunate failures “… while treatment using artesunat failed for 7-18 per cent of cases in Dak Lak and south-central Binh Thuan and Ninh Thuan provinces.”

While this is likely just bad reporting, the reported information should be verified. Was it an ACT failure or artesunate monotherapy (which will often fail when given alone)? In case of the latter, why were artesunate monotherapy trials still being conducted, or are they just reporting older data? There are many unanswered questions, including the source of the data though the National Institute of Malariology, Parasitology and Entomology was cited earlier in the article. Protecting artemisinin combination therapies is crucial (previous post here) and to my knowledge no widespread ACT failures outside of the Thai-Cambodia border have yet been reported. Let us hope it remains that way, but history has taught us otherwise.

While most scientists agree that climate change will alter infectious disease ecology, the extent of that influence is unknown - except that less developed countries will bear the brunt of the burden. In Papua New Guinea, one of the world’s most malarious countries, malaria is now occurring in highland areas once thought to be too cold for mosquito survival. In Hawaii, the introduction of avian malaria has decimated local bird populations. What’s next?

Artemisinin combination therapies (ACTs) have become the global standard for the treatment of Plasmodium falciparum malaria in areas with existing or emerging drug resistance. ACTs have several advantages: combination therapy diminishes the probability of de novo mutation, artemisinin is the most schizonticidal drug and reduces parasite biomass very rapidly resulting in faster clearance rates, and artemisinin kills immature gametocytes reducing subsequent transmission. Unfortunately, mismatch in the half-lives of the partner drugs (artemisinin derivatives have very short half lives of ~1-2 hours) leaves windows of monotherapy during which parasites can gain resistance, or those with pre-existing resistance to the partner drug, rebound and cause treatment failure.

In the latest issue of Emerging Infectious Diseases (CDC - open access), Wrongsrichanalai and Meshnick report the declining efficacy of artesunate-mefloquine along the Thai-Cambodian border. (A full disclaimer: Dr Steven Meshnick is my mentor). This border is the traditional birthplace of most drug resistant strains, and it is no surprise that the first widespread reports of ACT failures arrived from here. The failures are probably due to endemic mefloquine resistance generated by years of prior use rather than resistance to artesunate itself though we cannot exclude that possibility. There’s an important lesson for policy makers here: ACTs with partner drugs which have pre-existing resistance in that area will fail rapidly. Early last year SEARO, the Southeast Asia regional office for the WHO, held a meeting on the “Containment of Malaria Multi-Drug Resistance on the Cambodia-Thailand Border” to discuss this challenge. Unfortunately, for people living along the Thai-Cambodia border few therapeutic options remain.

The world’s most potent antimalarial, artemisinin, is not available to physicians in the United States but a CDC investigational new drug (IND) project is trying to change that. Over 1,000 cases of malaria are imported into the United States every year and many cases present with severe complications as most travelers lack any natural immunity. CDC is making artesunate available for free through its Atlanta headquarters and CDC quarantine stations across the country for the treatment of severe malaria.

Artesunate is a water-soluble derivative of artemisinin which can be delivered orally or intravenously, though the later is the preferred route for severe cases. The standard treatment in the United States for severe malaria is IV quinidine (a quinine derivative) which has more side effects including hypoglycemia, necessitates cardiac monitoring, and is not carried by many hospital formularies. Jones et al. in a recent Cochrane review summarized the benefits of artesunate over quinine for the treatment of severe malaria (an additional ~40% reduction in mortality).

Dr. Phillip Rosenthal describes a case in the NEJM which would benefit from the IND and also provides a broader review of clinical aspects of artemisinin use. He notes artemether, a lipid soluble derivative of artemisinin, can suffer from varied absorption but its important to point out that artemether is invaluable in peripheral health facilities in developing countries where it can be delivered intramuscularly by minimally trained staff.

An estimated 250 million nets at $10 a piece are needed to achieve the current UN goal of 80% coverage in high risk groups - pregnant women and children under five. UN secretary general Ban Ki Moon has raised the bar calling for universal coverage with nets by 2010 as part of his plan to end malaria deaths in Africa by the same target date.

Designing grand plans and setting specific target dates are contentious actions. On one hand it’s a desire to create measurable benchmarks, mobilize the malaria community, and capitalize on the current political interest. On the other side such efforts represent an unachievable, unsustainable push which will provide temporary benefit but no long term control progress as donors and countries fatigue and funding disappears.

Insecticide treated nets (ITNs) are an effective intervention for controlling malaria and its laudable to advocate their widespread use. ITNs though are not a magic bullet and in the absence of local capacity, surveillance systems, long-term funding, and adequate health infrastructure, their distribution will be for naught. Thus, it seems the challenge is to not develop tunnel vision as we speed ahead at 200 miles an hour.

As large scale distributions of insecticide treated bed-nets continue, the selection pressure for insecticide resistance increases. Insecticide resistance, particularly to DDT, helped destroy the malaria control efforts of many countries in the 1960s-70s. Monitoring insecticide resistance is part and parcel of any indoor residual spraying (IRS) program, and is arguably even more important for bed-nets. Currently, bed-nets are made with only one type of insecticide - pyrethroids. Pyrethroids are the only widely used insecticides which are both effective and safe for human contact. Since pyrethroid resistant mosquitoes are known to emerge, large scale resistance is likely inevitable.

The only way to detect insecticide resistance and be able to respond with adequate public health measures is by maintaining strong surveillance programs. In Lancet Infectious Diseases, Kelly-Hope et al. draw upon lessons provided by past campaigns and propose sound recommendations for the future. The authors call for insecticide resistance monitoring systems and outline actual specifics for such plans. In addition to country teams, regional centers are important. By conducting advanced biochemical and molecular assays they can detect emerging resistance and provide crucial lead time to plan for policy change. Many groups pay lip service to the importance of such work but few programs possess a concrete strategy. The costs for a quality surveillance program are minimal but the costs due to widespread insecticide resistant mosquitoes would be catastrophic. We cannot afford to continue flying blind.