During a March 19 press conference, President Trump announced that chloroquine, a drug long used to treat malaria, was going to be made available for those stricken with COVID-19. This followed news of preliminary research, including a limited study in Australia, in which chloroquine showed promise in eradicating the coronavirus in some patients. Chinese research published in February suggested efficacy and safety of chloroquine in treating pneumonia associated with COVID-19. A subsequent Chinese study involving the use of both chloroquine and its molecular cousin, hydroxychloroquine, determined that hydroxychloroquine is the more potent of these two drugs in its inhibition of this novel coronavirus.
Controversy enveloped the announcement by the president, especially after he indicated that chloroquine has already been approved for this use by the FDA. The agency's commissioner, Stephen Hahn, MD, quickly clarified that larger studies still need to be conducted to determine the safety and effectiveness of chloroquine for treating COVID-19. Much of the discussion that continued in the media throughout the day concerned whether the drug will truly prove effective and, if so, how long will it be until this medication gets the green light for patient use. There was also confusion as to which drug is under consideration since some reports, and the president himself, made mention of hydroxychloroquine as well. The distinction is important, as will be seen shortly.
While others are focusing on the drug effectiveness component in this debate, I am more concerned about the safety with regard to chloroquine. What I haven't seen mentioned is the contraindication for use of the drug in people who have glucose-6-phosphate dehydrogenase (G6PD) deficiency. For those who need a refresher from medical school, G6PD deficiency is an X-linked recessive genetic condition, and therefore almost always occurs in males. It is found predominantly in people of African or Mediterranean origin. As a result of mutations in the G6PD gene, the amount of G6PD is either reduced or its structure is significantly altered so that it cannot perform its usual enzymatic functions.
G6PD has two primary functions: it plays a role in carbohydrate processing and, important for this discussion, it helps protect cells from the harmful effects of free oxygen radicals. These reactive oxygen molecules are byproducts of normal cell function. G6PD is involved in a chemical reaction known as the pentose phosphate pathway and produces another molecule called NADPH. The latter has a direct role in ridding cells of the free oxygen radicals before they build up to toxic levels. This function is especially essential for red blood cells, which, unlike other cells in the body, lack additional NADPH-producing enzymes.
In the presence of a buildup of reactive oxygen species, red blood cells are prematurely destroyed, causing a condition called hemolytic anemia. This can result in jaundice, shortness of breath (from decreased oxygen carrying capacity of the remaining red blood cells), and tachycardia. In severe cases, it can cause acute kidney failure and death. However, many people with G6PD deficiency are asymptomatic and not aware that they have it until something triggers an episode of hemolytic anemia. Common triggers include bacterial or viral infections and treatment with certain drugs. One drug commonly associated with hemolytic anemia in G6PD deficiency is ... chloroquine.
Should this be a concern in the present debate over treating COVID-19 patients? In my opinion, yes. G6PD deficiency is rather common; in fact, it is the second most common human enzyme defect, affecting some 400 million people worldwide. It affects 1 in 10 African-American males in the U.S. It is common enough that it was written into an episode of the long-running TV series M*A*S*H. In this episode, the character Corporal Klinger, who was of Mediterranean descent, became seriously ill after being given an anti-malarial drug. He was found to have hemolytic anemia and an association was made with the drug. The ending credits included a brief commentary on G6PD deficiency.
Given the challenges of knowing who may or may not have G6PD deficiency, it would seem prudent not to use chloroquine to treat COVID-19 patients who may be at risk for this genetic condition. The last thing they need is to have a serious respiratory disease compounded by hemolytic anemia, resulting in further loss of oxygenation.
Hydroxychloroquine, on the other hand, does not induce hemolytic anemia in people with G6PD deficiency despite the molecular similarity to chloroquine. It has shown effectiveness in inhibiting the pandemic coronavirus during in vitro testing. Perhaps this is the drug to which the president and Hahn were referring. Hydroxychloroquine is where the FDA should direct its testing efforts, and quickly, to determine whether this may be the silver bullet for treating COVID-19.
Dan J. Vick, MD, DHA, MBA, CPE, a pathologist and former hospital executive, is a member of the graduate teaching faculty in the Master of Health Administration Program, School of Health Sciences, in the Herbert H. & Grace A. Dow College of Health Professions at Central Michigan University in Mount Pleasant.