Written by: David Clark, PhD, chair of the Coalition for Hemophilia B

NOTE: This article is not intended as medical advice. Readers should seek the advice of their own physician. Because information regarding COVID-19 (novel coronavirus) is ever changing, readers are also asked to check for frequent updates on our website.

We still don’t know the cause of death in cases of COVID-19. Doctors have been assuming that it is pneumonia, which is an inflammation of the lungs, and/or acute respiratory distress syndrome (ARDS), which goes beyond pneumonia as the lungs begin to fill up with fluid, making breathing impossible. However, over the past few days, several doctors in China, Italy, and New York have speculated that something else might be going on. The cause of death might actually be hypoxia—a lack of oxygen.

The lungs are marvelously complex “machines” that transfer oxygen from the air we breathe into red blood cells (RBCs) that can then move that oxygen throughout the body to the tissues that need it. At the same time, the RBCs move carbon dioxide (CO2), which is a waste product, from the tissues back to the lungs where it is exhaled. When something goes wrong and the body is not getting enough oxygen, we tend to first suspect the lungs. For one thing, because the lungs behave like machines, we can more easily understand how they work. The rest of the process of moving oxygen and CO2 is all chemistry, so takes more effort to tease out what’s actually going on.

Something else might be going on in COVID-19 patients. The cause of death might actually be hypoxia—a lack of oxygen.

One aspect of the pandemic is that doctors are being reassigned to work in different areas. A doctor in the emergency room (ER) usually only sees patients that come in with problems. However, when the doctor is reassigned to work in the intensive care unit (ICU), he may see some of his original ER patients and get a better idea of the whole course of their illness. This has been happening all over the world with several doctors realizing that these patients don’t seem like your typical pneumonia patients; they look more like patients with altitude sickness. Altitude sickness is caused by a lack of oxygen from breathing the thin air at high altitudes.

The oxygen level in the blood is usually measured by pulse oximetry. If you go to the doctor’s office and they clamp a small device on your finger to measure your blood oxygen level, that’s pulse oximetry. It measures the amount of hemoglobin in your blood that is bound to oxygen, compared with the amount that is oxygen-free. Hemoglobin is the molecule inside your red blood cells (RBCs) that carries oxygen. The RBCs pick up oxygen in the lungs and carry it around the body, releasing it to the cells and tissues that need it. The normal oxygen range for a health patient is 95–100%, which means that 95–100% of the hemoglobin in your blood has oxygen bound to it. Below about 89%, the body starts to have trouble from a lack of oxygen.

Severe COVID-19 patients have been developing very low apparent oxygen levels as measured by pulse oximetry. That is one of the reasons that they have been assumed to have pneumonia. However, doctors have reported that many of the patients with apparent low oxygen levels do not act like pneumonia patients. Most of the time, when patients have oxygen levels that low, they are in distress and they can barely talk; they can't say complete sentences. However, many of the COVID-19 patients presumed to have pneumonia are alert and talk easily.

This may be a limitation of pulse oximetry. These patients might not actually have oxygen levels as low as it seems. The test measures the difference in light absorption between hemoglobin that is bound to oxygen and hemoglobin that is oxygen-free. If something else is binding to the hemoglobin, that could throw off the test. That “something else” might be a result of COVID-19. Some other recent research has shown that a number of the proteins generated by the novel coronavirus can bind to hemoglobin. Those proteins might be not only be throwing off the oxygen test, they also might be interfering with the red blood cells’ ability to carry oxygen.

Some research has shown that a number of the proteins generated by the novel coronavirus can bind to hemoglobin. Those proteins might be throwing off the oxygen test and interfering with the red blood cells’ ability to carry oxygen. 

This is where the drugs hydroxychloroquine (HCQ) and chloroquine (CQ) might come in. These drugs are derivatives of quinine, which was the original treatment for malaria. The malaria parasite (not a virus) has developed resistance to all three of these drugs, so in many parts of the world these drugs are not used very much for treating malaria. However, HCQ has found uses in treating lupus and rheumatoid arthritis.

We still don’t fully know how these drugs work, but there is some speculation that they stabilize hemoglobin, among other things. The malaria parasite feeds on hemoglobin. One idea is that HCQ stabilizes the hemoglobin and starves the parasite.

HCQ is a licensed drug in the United States. It was originally developed by Sanofi but now is generic. Many doctors are already using it to treat COVID-19 patients, but there are no studies that show that it actually works. President Donald Trump keeps promoting it and saying that “It can’t hurt,” but it can. The drug can have some serious side effects—some fatal. Many people will not be able to take it. One problem is that the effective dose is not much lower than the toxic dose, so patients need to be followed closely.

People talk about the French study of HCQ in 20 COVID-19 patients. Sixteen of the patients recovered, but no one mentions the other patients. The investigators also said this: “Of concern, six patients dropped out and were not considered in the reported efficacy rates. Three went to intensive care; one died; one left the hospital testing negative, and one opted out due to nausea.” The problem is that we don’t know whether HCQ actually helped the patients who recovered. They might have recovered anyway. It is also possible that they would have recovered more quickly if they hadn’t been given HCQ.

A follow-up French study showed no beneficial effect of HCQ but was criticized for studying too few patients. Other studies have also shown mixed results. Several new randomized controlled studies are now underway. We really need more research before recommending this drug and there are a number of other promising drugs currently in the pipeline. We don’t want to risk lives with HCQ if there is another drug that would work better. We also don’t want to risk lives with another drug if HCQ works better. This is the dilemma of researchers in a pandemic. They have to experiment to understand what’s really happening while also protecting patients from further harm.

This is the dilemma of researchers in a pandemic. They have to experiment to understand what’s really happening while also protecting patients from further harm.

People seem to have a fascination with experimental drugs. There is always the hope that something will be the next big breakthrough. However, they need to understand that only about 10% of experimental drugs are successful in clinical trials. Most experimental drugs fail. Just because someone has an idea that seems to make sense doesn’t mean it will pan out.

Please note that much of the above information is speculation. Things are moving rapidly, but we are still in the dark about a lot of it. Although this all might be a breakthrough, it also could be all for naught. In my next post, we’ll talk about some of the other treatments being explored.