Does the Thalassemia Trait Protect Against SARS-COVID-19?

Foggy Countryside in Thailand
thailand Hot_and_fog_in_the_Thai_countryside JosH.film 4.0.jpg
Image credit: JosH.film. Used under a CC 4.0 license An article in the journal, "Southeast Asian J Trop Med Public Health" (1992) reported that "at the junction of Thailand, Laos, and Cambodia" 60 different thalassemia syndromes have been detected in the population. These genetic mutations affect as much as 60% of the people in the area.

The virus that causes SARS-COVID-19 (hereinafter referred to as COVID-19) is a puzzle. Although researchers understand more today than they did when the virus was first discovered, they are still trying to understand circumstances which promote replication and circumstances which impede replication of the virus. Some interesting, and perhaps (eventually) productive studies have shown a connection between hemoglobin and replication. Since this research, or at least the implication of the research, is still speculative, I will simply try to summarize some of the intriguing findings surrounding the virus and hemoglobin.

Respirator Delivers Oxygen to a Patient Experiencing Hypoxia, a Common Presentation in Patients with COVID-19
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Image credit: Blogotron. Used under a CC 1.0 license (public domain.

Thalassemia Trait in Italy
In the spring of 2020, a paper published in the journal Medical Hypotheses suggested that the thalassemia trait might offer immunity against COVID-19. Since my maternal forebears immigrated from the Mediterranean region, where thalassemia trait is quite common, the article naturally caught my eye.

In the article, the authors note that areas in three Italian regions (Puglia, Sardinia and Sicily) where there is a high incidence of "betathalassemic heterozygote population", there is a corresponding low incidence of COVID-19/severe COVID-19.

Another paper from Italy, this one published in Frontiers in Immunology (December, 2020) found in Sardinia the same correlation between the occurrence of thalassemia trait and a reduction in COVID-19/severe COVID-19.

Beach in Sardinia
Sardinia beach credit MrArifnajafov 3.0.JPG
Image credit: MrArifnajafov. Used under a CC 3.0 license. A 1978 article in the"Journal of Medical Genetics" reports that about 19% of the population in Sardinia carries some form of the thalassemia mutation.

Puglia, Sardinia and Sicily: Relationship Between the Thalassemia Mutation and SARS-COVID-19

puglia, sicily, sardinia.jpg

Image credit: Map derived from Flanker Public domain. Information about Puglia derived from Wandering Italy. I colored in the three regions, approximately.

The phrase 'betathalassemic heterozygote population' (referred to above) indicates that people who fall in this category have inherited the thalassemia trait from one parent, but not the other. If someone inherits the trait from both parents, the term used to describe that person would be homozygote. That would result in a full-blown thalassemia, which is a serious medical condition.

When I first read about the possible relationship between COVID-19 and thalassemia trait, the idea was considered highly speculative. But, it was a line of inquiry that suggested possible productive research.

Since then, I've read about more research from Southeast Asia, in which the same correlation was detected between heterozygote thalassemic people and reduced incidence of covid-19 infection/covid-19 mortality. The authors of this study plotted infection rates and death rates from COVID-19 against the occurrence of heterozygote thalassemia. Their findings:"COVID-19 infection/death appear to be inversely correlated with the trait".

After reading about the findings in Southeast Asia, I was really interested in the connection between the thalassemia trait and COVID-19. So I did a little poking around.

What is Thalassemia?

Microcytosis as Might Be Seen in the Blood of Someone with Thalassemia Trait
red blood cells Iron_Deficiency_7 Osaretin 4.0 0r 3.0.jpg
Image credit: Osaretin. Used under a CC 4.0 license.

The image above shows red blood cells that are smaller and paler than normal. This might be seen in several iron-deficient conditions, including in people who have the thalassemia trait. However, there are people with the thalassemia trait who do not show evidence of microcytes.

Thalassemia is a genetically transmitted disorder that ranges in severity from inconsequential to life altering and even life-threatening. Thalassemia falls in the broad category of hematopathologies-- disorders of the blood. There are many different kinds of thalassemia. Two major categories are beta and alpha, and within each there are varieties.

It is estimated that 5% of all the people in the world carry the trait for thalassemia. However, only about 1.7% of the world's population evinces symptoms because of the disorder.

Blood Types: Thalassemia Major May Require Transfusions Throughout the Individual's Life
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Image credit:InvictaHOG. Public domain

Since thalassemia is passed through generations on a recessive gene, it is possible to have the trait and not the disease. As stated above, this is true for most people who carry the mutated gene. People who carry the trait but have no or few symptoms are classified as thalassemia minor. People who have inherited the mutation from both parents are classified as thalassemia major, or thalassemia intermedia. Usually people who have thalassemia major need intermittent blood transfusions, and those who have thalassemia intermedia do not. Sometimes full-blown thalassemia can have serious consequences, including early death, growth retardation,and splenectomy.

In relation to COVID-19, people with full-blown thalassemia major are at increased risk of severe disease and death.

Origins of the Thalassemia Mutation
It is believed this genetic mutation evolved to protect against malaria. The distribution map where thalassemia is prevalent overlaps with areas where malaria is endemic.
Old World Map of Red Blood Cell Abnormalities Overlapping with Areas of Endemic Malaria
Red_Blood_Cell_abnormalities Armando Moreno Vranich public.jpg
Image credit: Armando Moreno Vranich. Public domain.

The thalassemia mutation makes it difficult for the malaria parasite to penetrate and hitch a ride in red blood cells. It is suggested, in research I have referred to earlier in this blog, that the mutation also makes it difficult for the COVID-19 virus to attach to hemoglobin.

The authors of one paper (in Medical Hypotheses) explain why it would be difficult for a COVID-19 virus to latch onto a hemoglobin molecule affected by the thalassemia trait:

"A recent PRE-print study has showed a heme attack on the 1-beta chain of hemoglobin by COVID19. Beta-thalassemia results of a default in the hemoglobin beta-chain synthesis."

Pattern of Gene Transmission in Thalassemia
Thalassemia beta NIH free.jpg
Image credit: NIH. Copyright free.The mutation is a recessive gene and is carried on chromosome 11 or 16.

Covid 19 Virus Spikes Bind to Hemoglobin

The research to which the quote above refers, is likely the research on COVID-19 done at Cold Spring Harbor Laboratories. There, scientists observed Covid-19 binding to hemin (related to heme) and hemoglobin. Hemin is a constituent of hemoglobin, and it binds to oxygen. Hemoglobin carries oxygen in the bloodstream.

An intriguing, and possibly productive, aspect of the Cold Spring Harbor findings is that, although COVID-19 binds to hemoglobin, free hemin floating around in the bloodstream seems to depress replication of the virus. The authors state:

"Notably, free Hb (Hemoglobin) suppressed viral entry by interaction with the RBD (Receptor Binding area) region in the Spike protein and reduced viral replication."

This is an exciting observation. The authors suggest that it might be possible to develop a therapy based on the inhibitory action of free hemin on COVID-19 replication.

Hemogloblin, Oxygen and COVID-19
A September 2020 paper published in the Annals of Hematology draws a relationship between low hemoglobin counts and poor COVID-19 outcomes. Because hemoglobin carries oxygen, a low hemoglobin count is also associated with hypoxia (low oxygen). And, hypoxia is significant indicator of poor outcome in COVID-19.

Conclusion
There is no definitive finding about COVID-19, hemoglobin and virus replication described in this blog, or any of the papers I cite. However, the associations between thalassemia trait, and COVID-19/hemoglobin binding is highly suggestive of a promising line of inquiry. Will it lead to better understanding the virus? Will it lead to a cure, or preventative intervention? Let's hope so.

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