Chloroquine (CQ) and hydroxychloroquine (HCQ) are showing promise as therapeutic treatments for COVID-19 infections. These drugs are widely used for the treatment of malaria, and their use against COVID-19 was a source of some controversy in the early stages of the current pandemic. Nevertheless, the FDA has recently given emergency approval to what had long been a common off-use application for treatment of viral infections. This approval was granted in light of a long history of using CQ and HCQ as antiviral drugs, including during past coronavirus epidemics. Furthermore, informal reports coming from emergency and critical care clinics indicate they are effective against COVID-19, particularly when combined with antiviral agents and antibiotics.
This raises an interesting question. The malaria parasite is a radically different disease agent compared to the cause of COVID-19, SARS-CoV-2. The malaria parasite, from the genus Plasmodium, is a nucleated organism, similar to the amoeba. SARS-CoV-2, in contrast, is an RNA virus, a snippet of RNA wrapped in a protein coat that facilitates the introduction of the viral RNA into the epithelial cells of the lung. Why should one drug be effective against these very different organisms? There is a subsidiary question. How did one use for these drugs—the treatment of malaria—come to have official approval, while the other use—treatment of coronavirus infection—resided for so long in regulatory limbo?
For both questions, part of the answer lies in history. CQ and HCQ are chemically related to quinine, an alkaloid extract from the dried bark of the cinchona trees of the genus Cinchona. The more than two dozen species of Cinchona are found throughout South America, Central America, the Caribbean Islands, and West Africa. They are part of a large group of so-called fever trees that found widespread use by indigenous healers to treat fever. Cinchona’s most common traditional use was as a muscle relaxant, to ease shivering from cold. Ironically, treatment of malaria was an early off-use of the material: malarial fevers are accompanied by violent shivering, which cinchona bark could relieve. No one then could know why, of course—malaria was established as a parasite disease only in 1897. But cinchona bark eased the shivering because it killed the Plasmodium parasite.1
By the time of the Spanish conquest, malaria had long been present in South America, brought there by human migration into the New World, mostly from Asia and the Pacific Islands.2 The Spanish conquest brought with it a new species of Plasmodium that had been endemic in Southern Europe. The introduction of a new malaria parasite resulted in serious local outbreaks, in both indigenous and European populations. The discovery that the bark of a common indigenous plant could relieve malaria set off a scramble by the Europeans to domesticate and cultivate cinchona. Eventually, one species, Cinchona ledgeriana, was identified as the best source of the healing bark, which led to large-scale cultivation. Growers could not keep up with the rising demand for the antimalarial drug though. In 1820, chemists learned to extract usable chemicals from the cinchona bark, identifying roughly two dozen alkaloids. Four of these, notably quinine, seemed to be the effective agents against malaria. Synthesis of quinine was eventually accomplished, but only in 1944, and it was costly and complex, ensuring that extract of cinchona bark remained, and remains to this day, the only economically viable source of quinine. More promising were synthetic analogues of quinine, which also had powerful antimalarial action. CQ was first synthesized in 1934 and was immediately put to use as an antimalarial agent. HCQ was synthesized in 1955 and immediately used to treat an emerging CQ-resistant form of malaria.3
Doubts about using HCQ to treat COVID-19 were based largely in its status as a drug officially approved for treating malaria. The use of CQ and HCQ as antiviral drugs was not officially approved. They were most frequently resorted to in emergency situations when a patient’s health had already deteriorated significantly. When it came to treating COVID-19, the concern was that this off-use of HCQ posed an unknown risk to patients already at high risk from the viral infection. The debate missed two important points. First, the ad hoc use of CQ and HCQ as antiviral drugs has a history going back nearly forty years, including in the last major coronavirus pandemic of 2002–2003 known as SARS, for Severe Acute Respiratory Syndrome. Second, no one really understands why the quinine family of alkaloids is an effective treatment for malaria.4 For that matter, nobody really understands why CQ and HCQ are effective agents against coronavirus. If this were not enough, CQ and HCQ have also been shown to be effective in a broad spectrum of disorders, including several autoimmune diseases such as lupus and rheumatoid arthritis, diabetes, blood clotting disorders, lymphoma and other blood cancers, and sensory neuropathy. Nobody really understands why CQ and HCQ are effective therapeutic agents for these disorders either.
For the malaria parasite, the most widely accepted theory for how CQ and HCQ work is that they interfere with the parasite’s ability to feed off its host. Plasmodium in humans is a blood parasite. The parasite is introduced into a human host through a mosquito bite and establishes itself by taking up residence within the red blood cell. There, the parasite grows and multiplies by digesting the red cell’s hemoglobin. Once the hemoglobin is exhausted, the parasites escape, either to infect new red cells or to take up residence in cells of the liver. Eventually, the parasite is transmitted back to the mosquito in a blood meal.5
The parasite digests hemoglobin by ingesting it into a compartment within the cell called the digestive vacuole (DV). Contained within the DV are enzymes that digest the protein into amino acids, which can nourish the parasite. Hemoglobin digestion also produces toxic end products, which the parasite detoxifies in the DV. CQ and HCQ interfere with the parasite’s ability to detoxify these end products. These then accumulate and poison the parasite. The antimalarial action of the quinine family probably extends beyond this narrow mechanism of action. The pathology of malaria, most notably intense and sometimes fatal fevers, hypertrophy of the spleen, tissue necrosis, and thrombotic injury such as infarction or stroke, indicate the disease is a broader disorder of the immune response to the parasite. It may not be the parasite per se that causes the disease of malaria; rather, the disease may be a disorder of the body’s own immune system.6
Such an anomalous immune response may also be at the heart of the pathology of COVID-19.7 Coronaviruses are actually common human pathogens that the body usually weathers with mild or no frank symptoms. The common cold, for example, is a coronavirus infection. What makes COVID-19 dangerous is the body’s own intense immune response, especially in the deep tissues of the lungs, which causes a potentially fatal pneumonia.
CQ and HCQ may be effective for both malaria and COVID-19 because they treat a common link between the two diseases. That common link is probably a modulation of the body’s immune response. CQ and HCQ exhibit a broad spectrum of proximate effects on various aspects of the immune system. They act as a general anti-inflammatory agent, through inhibiting the production and release of prostaglandins, which mediate fevers and inflammation. Aspirin reduces fever and pain through the same mechanism. CQ and HCQ also modulate how antigens, such as proteins from the coronavirus, are presented to the immune cells that mediate antibody production. These immune cells are used to mark cells for destruction by macrophages, another of the multiple types of cells involved in the immune response.
The effects of CQ and HCQ on the macrophages may be crucial to their effectiveness against COVID-19. The most dangerous aspect of anomalous immune responses is the phenomenon of the cytokine storm, in which the macrophages release a variety of small proteins, or cytokines, that mobilize and modulate the inflammatory response. Cytokine storms are what turn syndromes such as toxic shock or sepsis into sudden killers. A cytokine storm produces a fulminating and massive inflammatory response, especially in the lungs, which can rapidly fill with fluid, suffocating the patient. Once begun, cytokine storms are very hard to bring under control. At that point, the only option left to a physician is to put the patient on life support, such as artificial ventilation, which must be continued until the storm passes. This may not be sufficient to save the patient. It is probably a cytokine storm that is at the heart of COVID-19 pathology.
Cytokine storms are difficult to manage because their dynamics are unclear.8 The immune system is characterized by a complex web of feedbacks among the system’s components. Normally, these systems operate within a certain range of perturbation, and this determines whether an infection is benign or fatal. A coronavirus-induced common cold, for example, is benign because all the components of the immune response operate within their physiological limits. Cytokines are released, and all the other immune components come into play, but these are self-regulated. When the regulatory limits are exceeded, however, anomalous and unpredictable results can follow, including a potentially fatal cytokine storm.
Emergency medicine ultimately involves managing these regulatory feedbacks, and doing so is a delicate art. The immune system can be pushed up against its limits, but at the extremes, the feedbacks can easily be pushed into derangements—a cytokine storm being one. Part of the art of treating patients in this condition is to dampen the immune response, to draw the patient a little way back from the precipice of initiating a cytokine storm. This is why anti-inflammatory agents such as corticosteroids are a common tool of the emergency room physician.
Chloroquine and hydroxychloroquine are promising drugs for COVID-19 because they provide the physician another tool in the anti-inflammatory armamentarium. This is why a seemingly anomalous and potentially risky therapy for COVID-19 can, in the hands of an experienced physician, make the difference between life and death.
