WHO Attacks Credibility of Suspected Drug-Resistant Malaria Case from Angola

[Note: See the latest developments here.]

The World Health Organization (WHO) rejects the findings of a paper describing suspected drug-resistant malaria in a Vietnamese migrant worker returning from Angola. (See previous post.) According to WHO's Pascal Ringwald, "It took 4 months for WHO to discover the truth and we will make sure that there will be retraction from the authors." But Patrick Kachur, chief of the Malaria Branch at the Centers for Disease Control (CDC), said "I doubt there will be a retraction," and that the CDC is going ahead with plans in Angola to search for similar cases and conduct tests on parasite clearance times.

Nearly all aspects of the case have been questioned. WHO has contended that the first line of treatment, artesunate, came from a batch recalled because of quality issues. The second line drugs, dihydroartemisinin and piperaquine, were delivered by nasogastric tube, a departure from preferred practice.  Also, the dose given, 1 mg/ kg given twice a day, achieves lower blood concentrations, according to mathematical models, than the recommended single dose of 2.4 mg/ kg once a day. The third line of treatment, quinine and doxycycline, were also delivered by nasogastric tube instead of intravenously as recommended. (Intravenous quinine was not available.) Still, nasogastric quinine worked, saving the patient's life. 

The apparent failure of the artemesinin-based drugs to clear the patient's malaria parasites has been attributed to hyperparasitemia which can impair clearance of parasites from the blood after they have been killed by the drug. Finally, genetic sequencing of the malaria parasites found them negative for K13, the biomarker associated with drug resistant malaria in Southeast Asia. 

The paper's authors have stood behind their research, refuting, for example, the claim that the artesunate used was of poor quality. But the battle continues. "Maybe," said WHO's Ringwald concerning the refutation. "But," when it comes to retraction, "CDC will," he continued.

All current containment efforts focus on Southeast Asia. The possible case from Angola threatens to expand an already fast-growing front, perhaps accounting for the heated debate.

Bin Laden Vaccine Ruse not Behind Spike of Polio in Pakistan

The fake vaccination campaign to ensnare Osama Bin Laden unquestionably harmed polio vaccination efforts in Pakistan. But cases began rising beforehand, in 2008, and actually declined in 2012—after Bin Laden's assassination and the swift disclosure of the fake vaccination plot in mid-2011. 

The Taliban's announcement opposing polio immunization came a year after the vaccine imbroglio and fingered drone attacks. A month after the anouncement, vaccinator shootings began. Nonetheless, the polio situation in 2013 was better than in 2008.

Polio is a political game piece. Religio-political beliefs once halted polio vaccination in Nigeria. The Bin Laden ruse harmed Pakistan's polio effort but by focusing already existing anti-Western, anti-polio sentiments. Kristofer Harrison's article in Foreign Policy, which blames Pakistan's polio regress on the leaking of the vaccine ruse, oversimplifies too dramatically the chain of causality.

Timeline

May 2011 Bin Laden killed

July 2011 Vaccination ruse revealed

June 2012 Taliban announces anti-polio stance because of drones

July 2012 First vaccinators shot

Caseless Polio Outbreak in Israel Extinguished; what about Brazil?

Wild poliovirus began circulating in Israel in early 2013 but, more than a year later, appears to have been halted with no cases of polio reported. Cotemporaneously, however, a sewage sample in Brazil from March tested positive for polio, a strain related to an outbreak in Equatorial Guinea. No further samples in Brazil have tested positive nor have any cases been reported. Risks are likely lower at the World Cup than the annual pilgrimage to Mecca where stringent vaccination requirements have squelched transmission since a large outbreak in 2005.

The caseless transmission seen in Israel is possible in any population immunized only with inactivated polio vaccine (IPV). IPV protects against the potentially debilitating effects of poliovirus but does not prevent infection. Infected vaccinees can remain healthy but still transmit the virus.

The virus in Israel is related to strains originating in Pakistan. Perhaps coming by way of Egypt, the virus found its way into southern Israel, in Be'er Sheva, and spread northward. Those affected were "[m]ainly Arab Israelis but we believe there was some circulation among Jewish populations," according to Itamar Grotto, Director, Public Health Services at the Israeli Ministry of Health. 

In the developing world, polio mostly circulates where a lack of sanitation systems and clean water lead to ingestion of feces-contaminated water harboring the virus. The virus can survive four to six weeks in sewage. However, in Israel, instead of unclean water, "person-to-person transmission [was] through 'dirty' hands," according to Apoorva Mollya, program manager at the Bill & Melinda Gates Foundation. 

Bruce Aylward, assistant director general at the World Health Organization (WHO), explained: "Polio is one of those viruses where you only need an incredibly small infectious dose to get infected. If the virus is circulating in an area, there’s a high probability that you could get exposed."

Research on an outbreak in 1992-93 in a partially-immunized primary school in the Netherlands found evidence of infection in one third of the students. In New York City in the 1950s, a school outbreak quickly spread to an apartment building then to two more schools. 

According to Donda Hansen at the Centers for Disease Control (CDC), person-to-person spread of poliovirus within households can be as rapid and efficient as the adenoviruses that cause colds.

Israel experienced no cases of polio because of very high population coverage with IPV, roughly 95%, and perhaps a bit of luck that the virus either did not reach or didn't cause disease among those without polio antibodies. To stamp out circulation, Israel employed oral polio vaccine (OPV). OPV not only protects against disease but produces a local, mucosal immune response that limits replication of the poliovirus in the intestine, breaking the oral-fecal chain of transmission. After two waves of vaccination aimed at children under ten, first in Israel and then the West Bank and Gaza Strip, sewage samples positive for polio stopped.

WHO waits half a year before judging a type-1 outbreak like Israel's to be extinguished. "[F]ingers crossed that they make it over the 6-month mark," said WHO spokesperson Sona Bari. But in the eyes of Itamar Grotto, "It really seems that the 'event' is over." 

Israel has added the oral vaccine back to its routine immunization schedule, although it is not without risks. OPV uses a live version of the virus which very rarely mutates and causes polio. There were no vaccine-derived cases in Israel even though millions of children were immunized, perhaps because they were already protected by IPV. The science is not conclusive, but according to the Gates Foundation's Mallya, "Generally, it is thought that IPV would protect/prevent against cVDPV (vaccine-derived poliorvirus)."

Brazil uses both. And with over 90% population coverage and polio-specific immunization campaigns every year, the population of Brazil is thought to be well-protected. Owing to the health emergency recently declared by WHO, travelers from polio-infected nations should be vaccinated at least four weeks before traveling. The annual pilgrimage to Mecca has similar requirements although no chances are being taken: "Irrespective of previous immunization history, all visitors under 15 years arriving in Saudi Arabia will also receive 1 dose of OPV at border points," according to Saudi health regulations. In 2005, Nigerian polio strains were suspected of leading to an outbreak of over 300 cases in Indonesia with pilgrims transporting the virus far across the globe, resulting in heightened vaccination requirements in 2006. 

World Cup polio risks in 2010 were far worse than in 2014, based on number of cases and countries. In 2010, 20 countries combined for over one thousand cases versus (so far) 2014's slightly more than one hundred cases in nine countries. Accordingly, the CDC emphasized flu risks more than polio for the World Cup. Hand washing, however, is also mentioned.

Drug Resistant Malaria in Africa: A Suspected Case from Angola

[Note: See the latest developments here.]

A new paper suggests drug-resistant malaria might be present in Angola, perhaps brought there by an annual flow of some 40,000 Vietnamese migrant workers. Pockets of drug-resistant malaria, first found in Cambodia, now spot much of Southeast Asia, including Thailand, Vietnam, Myanmar and Laos. The expanding front comes despite containment efforts, begun in late 2008, aimed at preventing spread to Africa which already has the world’s highest malaria mortality.

A 58-year old Vietnamese construction worker returned from Angola after three years to his malaria-free village in Nam Dinh Province. Four days later, malaria symptoms appeared which went undiagnosed and eventually resulted in hospitalization. But artesunate, the frontline, fast-acting anti-malarial given to the patient, scarcely dented the number of teeming parasites. Even in severe malaria cases like this, patients usually begin to get better in just one day because artemisinin-based drugs act so quickly. (The patient also received the slower acting clindamycin to eliminate any parasites surviving the artemisinin onslaught, a combination approach meant to prevent drug resistance.)

Switching to a different combination of dihydroartemisinin and piperaquine also failed to knock down parasite levels. Only when subjected to quinine and doxycycline did malaria subside, allowing the once-endangered patient to return home about one month after admission.

The strength of resistance to the frontline artemisinin-based drugs seems considerably greater than that seen in Southeast Asia. As a rule of thumb, researchers suspect resistance if artemisinin doesn’t fully eliminate parasites after three days in cases of “uncomplicated” malaria. The Vietnamese patient’s severe malaria makes comparisons problematic. Still, Nick White, of Mahidol Oxford Tropical Medicine Research Unit, has "never seen such resistance, even in Cambodia." White, other researchers and the World Health Organization (WHO) are withholding final judgment as to whether this single case means artemisinin-resistant Plasmodium falciparum malaria is now present in Angola. According to White, “No, this doesn’t mean there is resistance in Africa—there may be but you need more than this.”

White raises the possibility that parasites actually killed by artemisinin might have remained in the patient’s blood, giving an appearance of resistance. Pascal Ringwald, WHO lead for the drug-resistant malaria containment effort, further explained: “the hyperparasitemia (10%) associated with insufficient drug blood levels could explain the extremely slow clearance after artesunate treatment...” Christopher Plowe, Howard Hughes Medical Institute investigator and professor at the University of Maryland, notes that “many factors other than intrinsic parasite resistance affect the treatment outcome, including immunity, fluid dynamics, pharmacokinetics and so forth.” But Plowe concludes: “This did look more like bona fide high-level resistance.” Continued Plowe:

“This is deeply worrying. It is just one case but the evidence of resistance is pretty good. It seems plausible that artemisinin-resistant parasites were carried to Angola from Vietnam and then locally transmitted among these migrant workers.”

How has it been missed, particularly if resistance is so strong? “Bit odd no one has noticed this before if this is a focus of the most artemisinin resistant parasites in the world,” observed White. Reports from Angola to WHO in 2013 found no evidence of resistance. There was “No sign of delayed clearance and 100% dihydroartemsinin-piperaquine efficacy,” according to Ringwald, who added that “Data were validated by CDC Atlanta.” However, Ringwald acknowledged that “the studies were not performed in the same province,” Luanda Sul, suspected as the origin of the drug-resistant malaria. The WorldWide Antimalarial Resistance Network (WWARN) has no data on Angola. WWARN is working on a study of three-day parasite clearance rates in Africa based on data from 15,000 patients, but fewer than one hundred are from Angola and come from a 2003 study in Kuito, well outside Luanda Sul province.*

A missing piece of the puzzle is whether malaria parasites in this case exhibit mutations in the K13 gene, a biomarker associated with artemisinin resistance in Southeast Asia. The status of such a test is far from clear. According to Ringwald, “It is not a WHO study and it not under our control,” who notes that the case occurred over a year ago. Conceivably, there are no samples to test. The corresponding author of the study did not reply to an email inquiry.

Ringwald downplays the importance of the case and asserts that “Artemisinin resistance is already reported in Africa.” But while mutations in K13 have been reported, clinical resistance in Africa has not. Also, the mutations reported there so far might merely be polymorphisms that are not part of a genetic network that confers resistance to artemisinin.

While Ringwald expressed skepticism about the Vietnamese case, “Nevertheless, we are investigating with CDC Atlanta in Angola if K13+ is also present like many other countries.” Further, in order “to reassure everybody we will specifically conduct [a study of parasite clearance rates] with dihydroartemisinin-piperaquine in the same province,” Luanda Sul .

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Related: Drug resistant malaria takes new ground, raising fears of global spread

*This post has been updated. WWARN's study of three-day clearance in 15,000 people previously was said to have no data from Angola. The study includes 93 patients from Kuito, Angola in 2003.


Why is WHO crying wolf on polio?

The World Health Organization (WHO) recently declared polio to be a public health emergency, prompting fears and headlines about possible spread even to the United States. But the eradication goal actually sits closer than ever. The “emergency” comes not from health risk but schedule risk to the 2018 eradication deadline. Because polio is the number one priority of Bill Gates, WHO now invokes the specter of polio outbreaks, a ploy to galvanize the public reminiscent of weapons of mass destruction.

Polio is 99% wiped out, crushed over decades from hundreds of thousands of cases to fewer than 2,000 a year so far in the 21st century. Risk of spread has only gone down together with the fall in cases and countries with transmission. Today, in two of the three remaining polio endemic countries, Nigeria and Afghanistan, cases hover tantalizingly close to zero, unprecedented historic lows. Pakistan, the third endemic country, has wrecked eradication progress for years. But the ongoing shooting of vaccinators by extremists in Pakistan, for example, did not prompt the polio “emergency.” Instead, WHO cited an outbreak of 36 cases in Syria and the subsequent export of a single case to Iraq. But the Syrian outbreak has been snuffed and amounts to nearly a non-event in the annals of polio conflagrations. The year before, Somalia saw a much larger, 194-case detonation, large enough to reach Kenya and Ethiopia and paralyze two dozen more. Today, WHO reports the other cause for alarm is cross border polio transmission from Cameroon to Equatorial Guinea. However, the six cases so far, while tragic, are inconsequential compared to Africa as recently as 2011 when four countries leapt from zero cases to 41. The same year, China saw an unprecedented 21 cases. No emergency.

Polio does not even merit consideration for emergency status. Swine flu occasioned WHO’s last emergency declaration in 2009, prompted by a rapid accumulation of 1,003 cases in 20 countries on four continents. Flu can spread swiftly, directly from human to human, unlike polio which usually comes from contact with feces-contaminated water. Wealthy nations are already highly vaccinated against polio whereas swine flu vaccination necessarily followed the discovery of the new virus, H1N1. In the United States, the Centers for Disease Control (CDC) estimated there were 57 million H1N1 infections resulting in 11,000 deaths. Polio rarely kills.

However, eradication efforts cost $1 billion a year, a sizeable piece of the $30 billion spent on global health annually. Eradication dollars could be spent on increasing coverage of routine vaccinations, building hospitals and health systems, or providing clean water. But Bill Gates champions polio eradication. It is “the single thing I work on the most,” according to Gates. And it’s his show: Gates, not WHO, orchestrated funding of the $5.5 billion effort to eradicate polio by 2018. “We’ve raised three-quarters of that money,” Gates reported in 2013. But the Gates-approved plan calls for ending transmission by 2014, already impossible. Eradication has never been closer, but the schedule is at risk. Thus the theater of polio public health emergency.

As the Gates Foundation blog notes, “The sounding of an emergency often is seen as a sign of distress, and news of this announcement certainly communicated that.” Indeed, the announcement fueled headlines like “Polio, Spreading Abroad, Threatens US.” However, “what this alarm really signals,” continued the foundation’s blog, is doing “what it takes to end this disease as quickly as possible,” which includes stoking false fear. The CDC isn’t stockpiling oral polio vaccine to extinguish outbreaks. Instead, the CDC said of the polio declaration: “we do not believe this reflects an increased risk to the US.” But with deadlines looming, a WHO spokesperson stated: “we need to pull out all the stops, which is what the emergency should help us to do.”

The International Health Regulations on emergencies emphasize “public health risk,” not schedule risk. Whether technically legitimate or not, the polio “emergency” hides its real motivation and makes people afraid when actual polio risks are close to the lowest level in all of human history.

Eradicating polio, while a noble intention, distorts rational global health priority-setting. Eradication gives the wealthy world a trophy to brandish before its own citizens and taxpayers while ignoring and overriding the priorities of the developing world. The polio emergency wraps this distortion in deception. Bill Gates believes eradication will serves as a symbol and portent of further triumphs. But he has substituted symbol manipulation for the pursuit of optimal global health policy in open society. 

Polio in Nigeria: at the cusp of the cusp

Immunization coverage for polio continues to climb in Nigeria. The most recent campaigns in April reached more children than ever and continue a solid upward trend over the last two years. The key threshold of 80% coverage has been reached. That level, sustained over time, usually crushes polio inexorably.

India, in 2011, stood in similar circumstances just prior to the high season--and knocked polio out, enduringly. Nigeria has a chance as the high season approaches, beginning around July. However, elimination poses different challenges in every country. In Nigeria, not only widely-publicized security issues obstruct. But upcoming elections might also impinge on sustaining coverage gains. With luck, Nigeria might stop polio transmission this year. But the World Health Organization's Sona Bari cautions that India at this point, "was in a far stronger position in terms of surveillance quality, immunity levels and political commitment." Most likely, Nigeria is at the cusp of the cusp

Outbreak Emphasis (Again) Obscures Polio Progress

Polio in Syria and the spread of a single case to Iraq "signal an absolute failure of the global eradication effort," according to an expert quoted by the New York Times. A Guardian headline described the new obstacles as the "most challenging in history." Even global health bloggers concluded eradication is "further off than it had been just a year ago." Actually, eradication is closer than ever. 

Outbreaks, while tragic and not to be taken lightly, are a spectacular side show. There are already five in 2014, equaling the total for all of 2013. But 19 outbreaks hammered the eradication project in 2009, clearly short of any breaking point. Polio coverage emphasizing outbreaks has completely missed that two of the three remaining endemic countries, Nigeria and Afghanistan, have seen only a single indigenous case of the disease this year. 

Nigeria has been steadily raising vaccination coverage in key high risk areas, accounting for the drop in cases. If coverage continues to climb, transmission might be interrupted and polio eliminated from the country. High season, which generally begins in July and extends through September, will be a major test. Any number of factors might derail progress. Still, today polio teeters closer than ever to extinction in Nigeria. 

In Afghanistan, all polio cases this year have been in eastern in provinces near Pakistan, and sequencing shows similarity to strains from from across the border. 

Pakistan performs much worse than the other two endemic nations, but despite even the targeting and killing of polio vaccinators, Pakistan's case level is not extraordinarily high by historical standards.

Choking off endemic sources stops outbreaks from occurring to begin with. Outbreaks plummeted after India knocked out polio at the end of 2010. The Global Polio Eradication Initiative has stamped out every single polio outbreak there has ever been; today there are five more that must also be dispatched. In Syria, the 41 cases so far and emergence of a single related case in Iraq is concerning. But a 2013 outbreak hit Somalia with 194 cases and spread a further two dozen cases to Kenya and Ethiopia. Nonetheless, that fire is now out and probably will remain far larger and thus more difficult than reckoning with the smaller (to this point) recrudescence in Syria. 

War in Syria undoubtedly complicates vaccination efforts there. But in Somalia, kidnappings and killings forced Médecins Sans Frontières to leave the country in the middle of the polio outbreak after more than two decades in the country.

Polio eradication, in retrospect, is not a good idea. "Vertical," single-disease campaigns are inferior to building health systems, and polio has never been as deadly as say, diarrhea. Eradication is extremely costly.

Regardless, however, polio eradication is succeeding. Local news reporting on fires and gunshots distorts the reality of less crime and fewer fires. Similarly, despite media coverage, eradication of polio has never been so near.

If this continues, polio in Nigeria won't

This is why polio cases in Nigeria are now hovering near zero. According to the Global Polio Eradication Initiative (3.12.2014):

...almost 90% of Local Government Areas (LGAs) in the 11 high-risk states achieved coverage of at least 80% during last week’s conducted IPDs. This compares to less than 65% of LGAs in these same states achieving the same level of coverage just 12 months ago.

If 80% coverage continues and expands geographically, endemic circulation of polio in Nigeria will likely end. 


Eradication Effort Cornering Polio in Pakistan

As 2013 becomes history, efforts to combat polio have pushed the disease closer to a permanent place in the past. In the last tally of the year, only Pakistan reported new cases. Excepting eleven cases originating from Pakistan, Afghanistan experienced no polio in 2013. And Nigeria, which led the world in cases last year, has reported none since early October, a string of zeroes unprecedented in this century. [Update: Nigeria has subsequently reported a single case that dates to December 15.] Nigeria might also have recorded the world’s last case of type 3 polio more than a year ago, in November 2012; no type 3 cases have been reported anywhere since. Type 2 was eradicated in 1999, leaving only type 1 of the wild polio virus.

The spectacular outbreaks in Syria and Somalia, afflicting hundreds with polio-induced paralysis, originated from Pakistan and Nigeria respectively. A handful of cases in Cameroon also trace back to Nigeria. Until India snuffed out polio, about one year ago, the disease leapt to places as far away as Angola. But when the reservoirs are extinguished, the outbreaks cease. 

Although Nigeria has yet to run the mid-year gauntlet where cases have peaked over the last several years (see graph below), the multibillion dollar eradication program might now have polio cornered in Pakistan.


Somali Outbreak Obscuring Progress Against Polio

A spectacular polio outbreak—over 100 cases in Somalia—is obscuring progress in eradicating the disease. It’s not the first time. 2010 saw an even larger outbreak, 460 cases in Tajikistan.  Yet the next year, cases went to zero in India which once led the world in polio.

Today the good news is that the type three strain of polio might be gone forever, joining type two in oblivion and leaving only type one to reckon with.  There have been no type three cases detected in the world since last November.  However, because type three polio is less paralytic than type one, it is harder to detect. But surveillance is bulked up in places where type three has appeared previously. And, encouragingly, sewage samples have been negative suggesting an absence of asymptomatic circulation. Type two polio was driven to extinction in 1999, the last case appearing in India. The disappearance of type three would represent “another proof-of-principle, like the eradication of [type two],” according to WHO spokesperson Sona Bari. The virus is under pressure. “If [type three] can be interrupted, it gives us more evidence that [type one] eradication is not far behind.” Bari emphasizes, however, that “we are still holding our breath” to see if type three is really gone.

The Somali outbreak has little impact on the main eradication fronts: Nigeria, Pakistan and Afghanistan. Afghanistan has pushed cases down to just four this year, historic lows reached not with the help of chance as in the past but improvement in the quality of immunization campaigns, according to Apoorva Mallya, program officer at the Bill & Melinda Gates Foundation. The number of children never receiving vaccine is down. Because more children are being vaccinated, population immunity is up.

The gains in Afghanistan come against a backdrop of insecurity not unlike that in Somalia. Somalia suffered an outbreak of over 100 cases in 2005 but was polio free again by the end of 2007. The country has since served as the exemplar for smashing the virus despite instability. 

The eradication program doesn’t take the Somali outbreak lightly, but it is “nothing to detract from the 2018 timeline,” said Mallya of the plan to complete eradication. “Outbreaks are going to happen,” he said. The current eradication plan anticipates and budgets for them. Global capacity for rapidly subduing outbreaks has never been better. Indeed, the Somali outbreak could have received a different storyline, one of rapid and courageous response to a crisis.

Nigeria and Pakistan loom as far larger problems than outbreaks. It is not clear that case trajectories point enduringly down in those two countries. So far this year, cases number in the dozens, not the single digits that might augur eradication. And although Afghanistan represents a bright spot, it is inextricably tied to progress across borders with Pakistan where deadly attacks have been orchestrated against vaccinators.  

The remaining obstacles are daunting but of a kind that have been overcome before. Even with outbreaks, eradication can and likely will be done.