Malaria-resistant red blood cells for malaria patients?

[Seeking MD Perspective]

Infectious disease docs,

Do you recommend transfusion / exchange transfusion of malaria-resistant RBCs for Plasmodium falciparum malaria patients (especially now that parasites are becoming drug-resistant)?

Some background for those unfamiliar with malaria: Type O RBCs (universal donor RBCs) are malaria-resistant along with sickle trait RBCs and many others. Evolution selected for type O RBCs and sickle cell trait RBCs due to a survival advantage with Pf malaria. These RBCs are found in blood banks, because individuals with these blood types can donate blood in the US and in other countries. These blood types do not face the challenge of drug-resistance.

So, do you utilize exchange transfusion, in which parasitized RBCs are removed and replaced with malaria-resistant (type O) RBCs, for your malaria patients?

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[gutonc]

Is there data to support this as an effective therapy? Or is this just hypothetical?

Also, how many drug resistant malaria patients do you think the average physician in the US comes across each year?

 

[Seeking MD Perspective]

Is there data to support this as an effective therapy? Or is this just hypothetical?

Also, how many drug resistant malaria patients do you think the average physician in the US comes across each year?

I am not aware of a single case in which type O or sickle cell trait RBC units were deliberately transfused / exchange transfused to save the life of an an individual with Pf malaria. And, I really want to know why! Currently, this is an idea, based on the fact that people with type O and sickle-cell trait have higher survival rates with Pf malaria. If interested, lookup the prevalences of these blood types in malaria hot zones of Africa.

Also, it may help to consider the term "fraction of cells remaining" (FCR) - this refers to the fraction of the patient's RBCs remaining after RBC exchange. For patients with sickle cell disease (HbSS), the goal is usually to get the FCR below 30%... thus 70% of the RBCs in the patient should be transfused (non-HbSS) RBCs. I have seen FCRs in the single digits. In other words, it would be very feasible to replace parasitized RBCs with malaria-resistant (type O) RBCs.

According to the WHO, there were 228,000,000 cases of malaria in year 2018. In the USA, the CDC states that there are about 1,700 cases per year. Such a therapy could be used to treat severe or drug-resistant malaria cases in the US and overseas. Thus, I would expect that such a therapy could help save a life in the USA and definitely in other countries (developed world and developing world).

 

[gutonc]

I assume you understand the geographic and socioeconomic realities of malaria as well as the healthcare economics of exchange transfusion. If you understand those, you will easily understand why this is not done. The fact that it's just a theory you seem to have without any scientific or experimental data to support it may explain part of it as well.

 

[Seeking MD Perspective]

I assume you understand the geographic and socioeconomic realities of malaria as well as the healthcare economics of exchange transfusion. If you understand those, you will easily understand why this is not done. The fact that it's just a theory you seem to have without any scientific or experimental data to support it may explain part of it as well.

Cost of Malaria: The WHO reported that there were 405,000 deaths from malaria in year 2018. Also, there can be long-term disability in patients that recover from severe malaria. The problem is really amplified by the fact that most deaths are children (less than 5 years of age). Thus, there is a significant "human cost" to malaria.

Cost of Therapy: RBC exchange / whole blood exchange is not very expensive - in fact it can be done manually using a syringe - known as the "push-pull method" (without a machine). Also, because children have small bodies, they have small blood volumes (another benefit). Of note, the procedure is performed in Africa (and in the USA).

Cost / Benefit: If transfusing / exchange transfusing malaria-resistant RBCs can prevent death / long-term disability, then to me it is "worth the cost". But, everyone has their own view of cost-benefit when it comes to human health / life.

"First, do not harm": There is also a "flip side". Instead of the burden resting on the idea that malaria-resistant (type O) RBCs can help malaria patients, maybe the burden should be on the practice of using malaria-promoting (type A, B, AB) RBCs to help malaria patients. It reminds me of the phrase "first, do no harm".

Common Ground: I think that the exchange transfusing malaria-resistant RBCs should be used - that way the benefit can be clearly measured. I think that is the starting point.

 

[tsip]

The CDC used to recommend exchange transfusions for select patients, but changed their policy in 2013.

CDC - Malaria - Exchange Transfusion

Malaria is a mosquito-borne disease caused by a parasite. CDC provides scientific leadership in fighting malaria at home and around the globe.

www.cdc.gov

This is a very interesting topic but it seems that the current consensus is that the risk/cost/effort of exchange transfusion is not worth the benefit for the vast majority of patients, even those with high parasite burden or cerebral malaria.

This would make a great plot line for some medical show, however. Too bad House MD is over. But one of those new shows could use it.

 

[Seeking MD Perspective]

The CDC used to recommend exchange transfusions for select patients, but changed their policy in 2013.

CDC - Malaria - Exchange Transfusion

Malaria is a mosquito-borne disease caused by a parasite. CDC provides scientific leadership in fighting malaria at home and around the globe.

www.cdc.gov

This is a very interesting topic but it seems that the current consensus is that the risk/cost/effort of exchange transfusion is not worth the benefit for the vast majority of patients, even those with high parasite burden or cerebral malaria.

This would make a great plot line for some medical show, however. Too bad House MD is over. But one of those new shows could use it.

The American Guidelines for RBC Exchange (including for malaria) can be found here Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society fo... - PubMed - NCBI

These Guidelines describe some of the major problems with CDC's analysis. The CDC study was underpowered, ignored data / variables (about the procedure, parasitemia, survival), excluded survival cases, and improperly matched cases and controls.

The bottom line: CDC's study had major flaws - so it is not the final word on the topic.

 

[tsip]

The American Guidelines for RBC Exchange (including for malaria) can be found here Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society fo... - PubMed - NCBI

These Guidelines describe some of the major problems with CDC's analysis. The CDC study was underpowered, ignored data / variables (about the procedure, parasitemia, survival), excluded survival cases, and improperly matched cases and controls.

The bottom line: CDC's study had major flaws - so it is not the final word on the topic.

If Malaria was more prevalent in wealthy countries then I think that there would be some more interest in using this treatment. But right now I think the major push is on putting money towards prevention.

Interesting stuff, however. I know that Bill Gates has put a lot of money towards Malaria eradication, maybe his foundation has thought about performing more studies to see if this treatment is worthwhile.

 

[Seeking MD Perspective]

If Malaria was more prevalent in wealthy countries then I think that there would be some more interest in using this treatment. But right now I think the major push is on putting money towards prevention.

Interesting stuff, however. I know that Bill Gates has put a lot of money towards Malaria eradication, maybe his foundation has thought about performing more studies to see if this treatment is worthwhile.

I agree.

To me, this is a feasible (ready-for clinic) therapy in either the developed or developing world. Unlike pharmaceutical drugs, there is no money to be made with malaria-resistant RBC units. Thus, there is no marketing / promotion of such a therapy.

I am optimistic that one day this therapy will be tried and then reported in the medical literarure.

 

[Hospitalist12345]

This is way too theoretical and really low yield in wealthier countries as mentioned before. There is little to no place for this in the practical care of malaria patients. Why do exchange when we have a RCTs showing the benefit of antimalarials already? Until there are more studies on this, the role of exchange is not clear and should not even be considered unless for severe cases or truly resistant cases ( which are so few in number at this time ).

 

[Seeking MD Perspective]

This is way too theoretical and really low yield in wealthier countries as mentioned before. There is little to no place for this in the practical care of malaria patients. Why do exchange when we have a RCTs showing the benefit of antimalarials already? Until there are more studies on this, the role of exchange is not clear and should not even be considered unless for severe cases or truly resistant cases ( which are so few in number at this time ).

In the malaria hot-zones of Africa, such as Southeast Nigeria, the prevalence of type O RBCs is almost ~90%. (Of note, as you move to malaria non-endemic areas of the world, type A blood dominates). Similarly, conditions such as sickle cell trait are most prevalent in malaria-endemic nations. Why is this true? It is because these conditions confer survival-protection against P. falciparum malaria. So, the "clinical trial" was done by nature through a process known as evolution, and the result is that individuals with type O and sickle cell trait survive P falciparum malaria while those without these conditions have much lower survival. But, don't believe me - read it for yourself in this famous article in the journal Blood. The ABO blood group system and Plasmodium falciparum malaria. - PubMed - NCBI

Furthermore, here is a different article by completely different authors which describes how type O blood protects against severe P falciparum malaria.

Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting

Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe malaria, ...

www.ncbi.nlm.nih.gov

Summary: To help your patients with P falciparum malaria, ask for type O RBCs (universal blood), rather than malaria-promoting RBCs (type A, B, AB). It is not difficult to simply request "using only malaria-resistant type O RBCs for RBC exchange". RBC exchange has the ability to replace 90% or more of a patient's RBCs, thus it has the ability to temporarily convert a patient from a malaria-susceptible phenotype (type A) to a malaria-resistant phenotype (type O). In my view, the use of malaria-promoting RBCs to treat malaria is not in the patient's best interest.

 

[Seeking MD Perspective]

This is way too theoretical and really low yield in wealthier countries as mentioned before. There is little to no place for this in the practical care of malaria patients. Why do exchange when we have a RCTs showing the benefit of antimalarials already? Until there are more studies on this, the role of exchange is not clear and should not even be considered unless for severe cases or truly resistant cases ( which are so few in number at this time ).

Additional comments:

1.) P falciparum parasitized RBCs are "sticky" (technical term is cytoadherence). Even when anti-malarial medications kill the parasites inside of RBCs, the parasitized RBCs remain "sticky" and this contributes to the disease process.
2.) Anti-malarials are not always effective for many reasons. As you mentioned, drug-resistance is a major problem. Of course, Americans travel to malaria-endemic nations and then return home. So, American physicians are facing this challenge.
3.) This treatment option is not "either or". Anti-malarials are first-line therapy, and RBC exchange using malaria-resistant RBCs can be an additional therapy to help patients. Both are feasible in today's world.

Bottom line: Consider using malaria-resistant RBCs to treat malaria.

 

[Hospitalist12345]

You are missing the point here. This is not how clinical medicine / patient care works.
Your description of the pathophysiology is irrelevant to my decision in adopting a therapy. Until you have some kind of real evidence showing that it has been used in x number of patients and it has produced y outcome then we can talk.

I think the perspective you should be looking for is that of a clinical researcher who will actually consider testing this idea.

 

[Hospitalist12345]

And another thing- american physicians are not facing this challenge, please don’t make bogus claims like that. Most physicians in the US rarely see malaria at all. There is no unmet need here in the US.

 

[Seeking MD Perspective]

You are missing the point here. This is not how clinical medicine / patient care works.
Your description of the pathophysiology is irrelevant to my decision in adopting a therapy. Until you have some kind of real evidence showing that it has been used in x number of patients and it has produced y outcome then we can talk.

I think the perspective you should be looking for is that of a clinical researcher who will actually consider testing this idea.

I think we are saying the same thing. In order to demonstrate the efficacy of such a new therapy, it must be performed in patients. For RBC exchange, efficacy is demonstrated through case reports and case series (almost never by a clinical trial). Thus, physicians need to perform the procedure and report the results / outcomes in case reports. When enough cases are reported, then a cost-benefit analysis can be done. So, the procedure must be done in patients for its efficacy to be determined. But, any physician that performs even a single procedure and reports it will contribute to the dataset.

 

[Seeking MD Perspective]

And another thing- american physicians are not facing this challenge, please don’t make bogus claims like that. Most physicians in the US rarely see malaria at all. There is no unmet need here in the US.

The Centers for Disease Control and Prevention (CDC) publishes data regarding malaria cases in the USA. Here is one of their articles:

Malaria Surveillance — United States, 2015

Excerpts from the article:

• CDC received reports of 1,517 confirmed malaria cases, including one congenital case, with an onset of symptoms in 2015 among persons who received their diagnoses in the United States.
• Among all reported cases in 2015, 17.1% were classified as severe illnesses and 11 persons died.
• CDC provided diagnostic assistance for 13.1% of patients with confirmed cases and tested 15.0% of P. falciparum specimens for antimalarial resistance markers.
• In 2015, CDC received 153 P. falciparum-positive samples for surveillance of antimalarial resistance markers (although certain loci were untestable for some samples); genetic polymorphisms associated with resistance to pyrimethamine were identified in 132 (86.3%), to sulfadoxine in 112 (73.7%), to chloroquine in 48 (31.4%), to mefloquine in six (4.3%), and to artemisinin in one (<1%), and no sample had resistance to atovaquone.

Thus, drug-resistant cases of P falciparum are in the US and are a challenge to US physicians.

 

[gutonc]

The Centers for Disease Control and Prevention (CDC) publishes data regarding malaria cases in the USA. Here is one of their articles:

Malaria Surveillance — United States, 2015

Excerpts from the article:

• CDC received reports of 1,517 confirmed malaria cases, including one congenital case, with an onset of symptoms in 2015 among persons who received their diagnoses in the United States.
• Among all reported cases in 2015, 17.1% were classified as severe illnesses and 11 persons died.
• CDC provided diagnostic assistance for 13.1% of patients with confirmed cases and tested 15.0% of P. falciparum specimens for antimalarial resistance markers.
• In 2015, CDC received 153 P. falciparum-positive samples for surveillance of antimalarial resistance markers (although certain loci were untestable for some samples); genetic polymorphisms associated with resistance to pyrimethamine were identified in 132 (86.3%), to sulfadoxine in 112 (73.7%), to chloroquine in 48 (31.4%), to mefloquine in six (4.3%), and to artemisinin in one (<1%), and no sample had resistance to atovaquone.

Thus, drug-resistant cases of P falciparum are in the US and are a challenge to US physicians.

1500 total cases of the disease a year (10% of which were drug resistant) does not make the disease a "challenge to US physicians". It doesn't even rate as a disease that you will even see in an entire career outside of a very small number of geographic areas (mostly related to immigration).

I saw 3 cases as a med student in Brooklyn, all of whom were either returning to the US after a visit home, or came to stay with family in the US when they got sick.

I've been in training/practice for the last 15 years and haven't seen a case since.

Please stop trying to make your pet project a bigger deal than it is. In the grand scheme of medicine in the US, malaria is nothing.

 

[Seeking MD Perspective]

1500 total cases of the disease a year (10% of which were drug resistant) does not make the disease a "challenge to US physicians". It doesn't even rate as a disease that you will even see in an entire career outside of a very small number of geographic areas (mostly related to immigration).

I saw 3 cases as a med student in Brooklyn, all of whom were either returning to the US after a visit home, or came to stay with family in the US when they got sick.

I've been in training/practice for the last 15 years and haven't seen a case since.

Please stop trying to make your pet project a bigger deal than it is. In the grand scheme of medicine in the US, malaria is nothing.

You are correct. In the US there are ~1500 cases of malaria per year, compared to more than 200 million per year globally. But, every patient matters. As my boss would say "the most important patient is the one in front of you". I guess we could say that malaria is a rare disease in the US, but rare diseases still matter. I see this as an opportunity to improve parient outcomes, and that is what medicine is all about.

One small point... Of the 153 P. falciparum samples tested by CDC, more than 85% were drug-resistant. Thus, drugs are not always effective therapy. So, the use of malaria-resistant RBCs as non-drug therapy for malaria seems useful.

 

[Hospitalist12345]

“Every patient matters“ does not equal a “challenge to physicians”.

Please don’t speak for us if you aren’t a physician yourself. Your whole communication strategy really falls short of what physicians actually care about. I am actually appalled by this post. You employ way too many is-ought fallacies in your posts. Your thinking is actually quite dangerous, and I am reassured that no doctor would actually take you seriously.

I am not knocking any of the background science you have presented. I am knocking the way you communicate it, all the unnecessary moral qualifiers you place on the science, and the huge mental disconnect you seem to have with theoretical science and patient care.

I really think you need to find a different audience, not practicing ID physicians. Our patients are not a means to test your theories. This is not how medicine works.

 

[Seeking MD Perspective]

“Every patient matters“ does not equal a “challenge to physicians”.

Please don’t speak for us if you aren’t a physician yourself. Your whole communication strategy really falls short of what physicians actually care about. I am actually appalled by this post. You employ way too many is-ought fallacies in your posts. Your thinking is actually quite dangerous, and I am reassured that no doctor would actually take you seriously.

I am not knocking any of the background science you have presented. I am knocking the way you communicate it, all the unnecessary moral qualifiers you place on the science, and the huge mental disconnect you seem to have with theoretical science and patient care.

I really think you need to find a different audience, not practicing ID physicians. Our patients are not a means to test your theories. This is not how medicine works.

I stated the following: "Thus, drug-resistant cases of P falciparum are in the US and are a challenge to US physicians." Data from the CDC demonstrate that US physicians have to treat drug-resistant malaria - that is all I mean. I am not trying to say that malaria is the same challenge as opioid abuse (much larger problem).

Every drug / therapy starts as an idea. Then, it must be tried and evaluated. The same holds true for using malaria-resistant RBCs to treat malaria. This therapy must be tried (by physicians) and reported (one case at a time). Then, an analysis of its efficacy can be made. This is how almost all apheresis procedures (including RBC exchange) are evaluated - rarely is a clinical trial performed.

It is ok if you don't want to try such an approach - totally fine. Maybe some ID physicians on SDN might be curious / interested? Let's see.