topnaman | Malaria blog

Rapid diagnostic tests for malaria (and other diseases) can extend diagnosis to remote areas. This is sorely needed. Beyond benefits against the disease at hand, the introduction of diagnostics along with associated systems of quality assurance can strengthen the overall health system (previously discussed here). A major barrier for expanding the use of rapid tests is a short-shelf life under field conditions. Tropical temperature and humidity degrade such diagnostics, which use delicate reagents like antibodies, in a matter of months. The short shelf life can necessitate restocking at a frequency which may not be logistically feasible. Thus, routine operation in many countries leads to the use of compromised, or a complete wastage of, tests.

Cambodia has a solution. The National Malaria Program designed ‘cooler boxes’ using the simple technology of evaporative cooling.They tested the boxes and their ability to maintain temperature, humidity, and extend the usability of malaria tests. RDTs in ambient conditions tested negative on control blood at 210 days while RDTs kept in the cooler box provided positive results up to 360 days. I love this story. First, it tackles a small but immediate need in current operations. Second, the cooler boxes were developed by Cambodia for use in their own programs. Third, they rigorously tested it – with the help of some WHO support (David Bell has been relentlessly working to advance all things rapid diagnosis). It is a judicious use of aid reminiscent of a past WHO where more funds were spent on research, small victories, and demonstration projects.

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From James | Parasitesinhumans.org:

A new study published in the Journal of the American Medical Association suggests that the famous pharaoh Tutankhamun was killed by malaria. According to their analysis, Tutankhamun was weakened by malaria and Köhler disease II. Tutankhamun ruled Egypt in 1334-1325 BC and he died at the early age of 19. His famous tomb, full of treasures, was found in 1922. Tutankhamun’s remains were studied from 2007-09 as part of the King Tutankhamun Family Project. In this study Tutankhamun was examined along with ten other royal mummies from 1410-1324 BC and five royal mummies from 1550-1479 BC.

The goal of the project was to introduce a new approach to medical and molecular Egyptology in order to determine familial relationships of eleven royal mummies and discover pathological features attributable to possible murder, inherited disorders, consanguinity, and infectious diseases. Radiological, anthropological, and genetic studies enabled the unraveling of the mystery behind Tutankhamon’s early death and his relationship with other royal mummies found in the same area. They found that Tutankhamun’s parents were siblings which is thought to have been common practice in the pharaoh family. This poor gene pool led Tutankhamun to have malformations, and he likely had severe impairments from birth.

Köhler disease II severely weakened Tutankhamun. Bone necrosis of the foot caused by Köhler forced him to use a walking stick. He had 130 of these canes in his tomb all showing signs of use and there was a fracture in his leg which was propably caused by a fall. Drawings of him sitting in various running activities such as hunting and of medicine for him to take to the afterlife further reference his medical condition. The scientists found a widening of the metatarsal-phalangeal joint space as well as secondary changes to the second and third metatarsal heads. This suggests that the Köhler disease II was still advancing when Tutankhamun died.

The investigators examined the mummies for various diseases such as tuberculosis, pandemic plague, leprosy and leishmaniasis but none were found. They did however identify DNA of Plasmodium falciparum using PCR primers that amplified small subtelomeric variable open reading frame (STEVOR), merozoite surface protein 1 (MSP1), and the apical membrane antigen 1 (AMA1) gene. The evidence of P. falciparum that was present in four of the royal mummies is the oldest proof of malaria parasites in humans. This study is also a rare piece of evidence that malaria was present in ancient Egypt. Ancient texts do mention people used mosquito nets over their beds. It is not clear however how immune Tutankhamun and other people at that time were against malaria but it’s interesting that a modern scourge might have contributed to the death of the greatest pharaoh of all time.

And I’ve made it another year… Finding the time to update the site certainly has not gotten any easier but writing is still just as fun. This is also a great excuse to look at some numbers.

Comparing some stats between last year and this one:

The top twenty countries in terms of visitors:

While the list generally reflects internet availability/users, I am happy to see that nearly half are malaria endemic nations.

Millions of people owe their lives to Fred Soper. Why isn’t he a hero?

Asks Malcolm Gladwell in his essay The Mosquito Killer. The article is an excellent look at the role played by an American physician in initiating the global malaria eradication efforts of the 50s and 60s.  Gladwell has a very accessible writing style, but sometimes his narrative seems too straightforward… His writing is generally suggestive of a purposeful, yet perhaps artificial, reduction of complexity. In this case the contributions of political climate, national priority, agricultural economics, Soviet and other scientists, and especially George MacDonald’s transmission models are made to pale in comparison to the force of a single, admittedly tenacious, personality.

I had heard of Soper from his role in leading the eradication of the deadly Anopheles gambiae from Brazil (through zealous anti-larval operations across 18,000 sq miles) in the 1930s. It appears, among other achievements, Soper also started PAHO – the Pan American Health Organization which is now the regional arm of WHO. Inspired to learn more, I’ve picked up Soper’s memoirs, Ventures in World Health, from our library and it’s proving to be a fun read.

The world-wide antimalarial resistance network (WWARN) is a great idea. The concept is simple: drug-resistant strains spread and a bigger picture is needed – consolidate data from existing monitoring efforts and standardize protocols to ensure comparability. A series of articles in 2009, published in Malaria Journal, outlined the rationale and a plan for creating a global network. The supplement further details each of the four technical components which comprise drug resistance monitoring: clinical efficacy, in vitro testing, clinical pharmacology, and molecular markers. Results deposited into WWARN, about 28,000 patients thus far, are promised to be open and transparent (hopefully the data will be liberated in the coming months).

A few questions and comments:

The Tropika team reports on the recent WWARN presentation at the MIM conference.

Why is WWARN based at Oxford? A lot of expenses could be saved if the group was hosted, in say New Delhi, where the cost of living is lower and expertise in both malaria and information technology is abundant.

WWARN seems to involve mostly academic researchers. One concern about the viability of any common database is the hesitance of many researchers to share data. Also, much of drug resistance monitoring is conducted directly by national control programs. Will a network of international researchers be able to build credibility with and engage program managers?

Traditionally, the World Health Organization has served to coordinate activities at the supranational level (such as WWARN). WHO is better placed to present itself as a neutral body to promote standardization as well as to request and collate national data. They also have a better relationship with control programs, which would help translate the data into action. Yet, here we seem to have another deliberate effort to bypass them. This is a disturbing trend for the world’s foremost health agency.

Below is a comment, on the PMI clarification, from one of the authors of the WHO Bulletin article.

In regard to the Director’s response to criticisms about the PMI program in Angola, I would like to make a few comments, having written the article in English, with the approval of my two colleagues, especially Martinho Somandjinga, the first author and an experienced and highly competent malaria control official.

The primary fault in the whole story was the use of administrative reports on malaria, based on clinical diagnoses of malaria, which in fact were simply diagnoses of fever and headache.  No blood slides were taken to confirm these administrative reports.  Therein lies the problem.

The secondary problem we pointed out is that WHO, in their global planning and analysis, uses the same faulty administrative reports of fevers, instead of making lab diagnoses for the malaria parasite.

Thirdly, although Mr. Somandjinga and I worked out and recommended to PMI a monitoring plan complete with labs, blood slide collections, and microscopic diagnoses, PMI has continued to ignore the need for this more precise process for monitoring and evaluating their effort in Angola and in the rest of Africa.

The First Law for attacking malaria in Africa is that it is like building a huge cathedral or mosque, it will take generations.  So evaluation and monitoring is essential if we are to make progress over the next several decades.  You cannot control malaria in Africa with public relations, it is a tough disease.

A really good sign however, is the increased role of epidemiologists from CDC in PMI and in Geneva.  These folks know the score.  Some have run studies showing that the false positivity rate of these clinical diagnoses is erratic and can be very high, like 50%!  And a recent study in Khartoum showed a false positive rate of 90%.  So the administrative data is useless, and I trust Robert Newman and Larry Slutsker will work towards establishment of microscopic diagnoses on appropriate sentinel populations.  Then we will know what the problem really is, and where to put our efforts.

It will take a while, but we can do it.  And now is a wonderful time to capture the popular enthusiasm for malaria control in Africa.

Bill Jobin
Cortez, Colorado

The title of this post is a bit sensational for my tastes but honest in regards to the charges levied by Somandjinga et al in the Bulletin of the WHO. The history of malaria control is replete with stories of gaffes small and large. However, the “policy and practice” article contains frank and detailed criticism, which rarely ever appear in print, about USAID/PMI (previously introduced here) operations in Angola. Before summarizing the alleged mistakes, it should be stressed that all human efforts will be imperfect. Seems obvious but we often fail to recognize the difficulties faced in executing programs. This does not excuse lapses in critical thinking – rather it is to stress the importance of process. That the ability to acknowledge errors, learn from them, and iterate efforts may be more important than our propensity to commit mistakes.

Here are the USAID/PMI mistakes as stated, sometimes directly and at other times in between the lines, by the authors:

- Failure to gain demonstrated national commitment (in the form of increased malaria staff or local funds) prior to beginning the program

- Rush to implement the program

- Poor understanding and use of routine data

- Selection of a single control measure

- No pretreatment evaluation

- Disregard for objections from the authors (one of whom is the regional public health manager)

- False assurances regarding CDC support and data collection

- Communication barriers from a lack of language proficiency (Portuguese)

- All of which culminated in the spraying of the homes of 500,000 people in an area without adult mosquitoes or breeding sites, i.e. likely no to minimal malaria transmission

- Overall, inexperience of PMI-Angola leadership in malaria control

Does PMI accept these critiques? Have they learned from their mistakes? I emailed PMI asking if there was a public response to the article or if they wished to provide another perspective on this post. I was pleased to receive a kind and prompt reply which is posted below in its entirety. Readers can draw their own conclusions.

PMI Clarification:

Dear Mr. Naman Shah,

Thank you for your query sent to “Ask the Malaria Coordinator” regarding the recent World Health Organization Bulletin article authored by Somandjinga et al., which critiques some aspects of the President’s Malaria Initiative’s (PMI) work in Angola in 2005/2006.  The indoor residual spraying (IRS) program referred to in the article was the very first round of IRS supported by the PMI in any country.  Although important lessons were undoubtedly learned during implementation of this first spray round in Angola, the implementation of this campaign was considered a success with a 90% acceptance rate among householders in the communities targeted for spraying, more than 590,000 people residing in houses sprayed were protected from malaria, and with no outbreaks of malaria detected in these areas following the spraying campaign.

There are several statements found within the article that are factually incorrect.  It is inaccurate to state that PMI failed to secure national commitment prior to beginning the spray program.  Angola was selected as one of the first three PMI countries.  The process for country selection for the President’s Malaria Initiative has always included high level consultation between US Ambassadors and the host country leadership including Ministries of Health, and Angola was no exception.  The first annual operational plan for PMI support in Angola including support for the aforementioned IRS campaign, as with subsequent annual plans, was prepared in consultation and collaboration with the Angola National Malaria Control Program (NMCP).

Although the article points out that the target areas for the first spray round were areas later found to have low levels of malaria transmission, PMI selected the areas targeted for spraying with the support of the Ministry of Health of Angola and with direct guidance from the Angola National Malaria Control Program Director.  It is important to note that this first spray round was part of a multi-donor effort in the southern provinces of Angola, with PMI support complementing the IRS program supported by WHO in an adjacent province.   Furthermore, the spraying of these malaria-epidemic prone areas was consistent with current WHO guidance for selecting areas appropriate for IRS and the success of the first IRS campaign in Angola carried out in these low transmission areas provided the experience and confidence to enable successful targeting of IRS in higher transmission areas in future spray rounds.

Finally, PMI, working in direct collaboration with NMCPs in the 15 PMI countries and together with other donors and partners, has demonstrated significant progress in scaling-up malaria prevention and control interventions, with clear evidence of reductions in malaria burden in many of the PMI countries.  Specifically related to IRS, since 2005/2006 PMI has been leading efforts to incorporate IRS as a major component of malaria control programs in Africa.  PMI-supported IRS programs work in close collaboration with national and district government counterparts and have expanded emphasis on building local capacity to implement quality IRS activities, including placing significant attention to environmental issues and best practices surrounding the intervention.  Prior to the launch of PMI, IRS was only being implemented by NMCPs in a few southern African countries and in Ethiopia and Eritrea, in addition to limited private sector investments in a handful of African countries.  PMI has played a key role in re-introducing IRS as an effective malaria control tool in Africa.  Currently many African countries that are not among the 15 PMI countries, have begun or are planning implementation of IRS programs after having learned from the successful experience demonstrated by their neighboring NMCPs in collaboration with PMI.

It is important to note that two of the three authors of this article were former contract employees of the PMI IRS implementing partner.

Two events prompted this post. First, several people have asked me if the malaria vaccine they heard about in the news will eliminate malaria. Second, the GSK CEO Andrew Witty discussed pricing strategies (5% profit above the yet unknown production costs) for this vaccine, called RTS,S, at a recent talk. Wait – pricing? We don’t even know how well the vaccine works! The press touts RTS,S as the world’s most advanced malaria vaccine. This is true in someways, it is in phase III trials which is the stage immediately preceding licensure and market sales. In and of itself this is a terrific achievement. However, advanced does not equal effective, and effective does not equal useful. Concerns about vaccine storage, dosing, delivery, and cost still remain.

The available RTS,S phase II results (previously discussed here) were far from spectacular, but efficacy was not the main endpoint of these trials. At that stage the investigators were focused on other aspects of a vaccine such as safety, dose finding, and immune response. The larger phase III study should answer the question of efficacy, but which efficacy are we talking about? Is it the efficacy in reducing all clinical malaria vs severe manifestations vs parasitemia or in children vs adults or for the first vs the fifth year after the receipt of the vaccine? Likely several different endpoints will be presented, and there will be disagreements about which one is meaningful for a particular country. If I were a betting man my guess is poor efficacy and low utility for public health, but I hope I’m wrong.

On a related note – will GSK receive a priority review voucher if RTS,S is licensed? The priority review voucher program was created in 2007 as an market-based incentive for companies to develop drugs and vaccines for neglected diseases. It allows a company to decrease the standard FDA review time, by 6-12 months, for another treatment of their choice. The economic value from the accelerated approval of a blockbuster drug is estimated at $100-500 million. Could the prospect of a voucher influence GSK’s decision to seek FDA approval? There is also the issue of the GSK-owned novel adjuvant (an immune response booster) used with RTS,S. What is the licensing process for adjuvants? I suspect that if an adjuvant has been used in a licensed vaccine, it can then be sold for use in any existing or new vaccine. Or at the least other companies would be more likely to risk using that adjuvant during vaccine development. If so, GSK may have another incentive to license RTS,S. From the talk of their CEO they already seem certain that a vaccine of any form will be pushed through the FDA.

PS GSK’s contribution and committment to the malaria vaccine began in 1987 and is commendable. Other contributors should also be noted. The Walter Reed Research Institute (run by the US Army) conducted much of the key early research. The Gates Foundation, through their Malaria Vaccine Initiative, has funded much of the vaccine’s development costs since 2001.

PPS The first voucher granted under the priority review program was for malaria. Novartis received one for its antimalarial drug Co-artem (artemether+lumefantrine). In this case the drug was not novel, available for almost a decade now, but was only recently licensed in the US making it eligible.

As a follow-up to the previous post on the Calcutta School of Tropical Medicine is a remarkable piece of history on its origins written by Helen Power. The subtitle “institutionalizing medical research in the periphery” summarizes the article and the insights one can expect from reviewing such a process. How are institutions forged? Who decides and why? A recurring theme (in the stories of institutions) I find amusing is the extent to which matters of whim and expediency, as opposed to deliberate intent, influenced history. Amidst our everyday work it is a rare oppurtunity to step back and reflect upon the broader forces (foreign strategy, national politics, financial competition) or petty conflicts (disciplinary divides, ego clashes) which shaped our present, regardless of where we may be.

Need to stay up to date on malaria research? MalariaWorld is a site which consolidates and summarizes recent papers. They also have a blog and a useful list of malaria related job openings and graduate research positions.