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4.3. Possible Reasons for Methemoglobinemia in COVID-19 Patients There are several factors relevant to explain why methemoglobinemia and carboxyhemoglobinemia can be present in COVID-19 patients. The SARS-CoV-2 infection, the individual constitution and the medical treatment seem to be the major ones. It is well known that several medical drugs can increase MetHb concentration in the blood as a side-effect [26,27]. A recent review reports the early recognition, pathophysiology, and management of methemoglobinemia in the intensive care unit [28]. Chloroquine is such a drug for which reports were published regarding induced methemoglobinemia due to its intake [29,30,31]. Both chloroquine and hydroxychloroquine (a derivative of chloroquine) are currently used to treat COVID-19, while debate is ongoing about their effectiveness and safety [32,33,34,35,36,37,38,39]. Moderately certain evidence suggests that hydroxychloroquine lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19 or at risk of hospitalization in outpatients with COVID-19. A G6PD deficiency can enhance the probability of methemoglobinemia induced by oxidizing drugs, such as hydroxychloroquine [40]. However, a very recent experimental animal study suggests that short-course high doses of hydroxychloroquine do not induce methemoglobinemia or clinically significant hemolytic anemia or organ damage in a murine model of G6PD deficiency [41]. Clinically, chronic hemolytic anemia associated with G6PD deficiency is rare [42]. So far, no evidence of hemolysis was observed in patients with G6PD deficiency when exposed to low doses of hydroxychloroquine [43]. The first case of severe hemolytic crisis was found in a seriously ill COVID-19 patient with G6PD deficiency following treatment with high doses of hydroxychloroquine [44]. Several other cases have subsequently been reported by others [45,46,47]. Nevertheless, Mastroianni et al. [47] and Afra [48], concerning hydroxychloroquine use in G6PD-deficient patients, have indicated that it is difficult to assess the relationship between hydroxychloroquine and hemolysis in COVID-19 patients. With the global spread of COVID-19, especially in regions with a high prevalence of G6PD deficiency, these cases should alert physicians to the possible correlation between G6PD-deficiency and hydroxychloroquine treatment. In the reports on MetHb and COVID-19 summarized in Section 3.2, the use of chloroquine or hydroxychloroquine is described. In the case reported by Kuipers et al. [17], the subject received chloroquine and had a G6PD deficiency; hydroxychloroquine was administered to the subject reported by Faisal et al. [20] (the G6PD status was not reported); and in the three cases reported by Naymagon et al. [18] all received hydroxychloroquine, while one subject was tested for G6PD deficiency and was positive. In the cases reported by Al-Aamri et al. [23] and Palmer et al. [22], the patients did not receive chloroquine and hydroxychloroquine, but the patient described by Al-Aamri et al. had a G6PD deficiency. A G6PD deficiency is not only relevant with respect to the reaction to antiviral oxidizing drugs, but also for the effects of the drug methylene blue administered to treat the methemoglobinemia. Methylene blue may be ineffective in patients with a G6PD deficiency since they lack sufficient reduced nicotinamide adenine dinucleotide phosphate (NADPH) to reduce methylene blue to leuko-methylene [49,50]. Despite the obvious effect of oxidizing drugs on the formation of MetHb, it can also be formed as a byproduct of a physiological reaction in the form of an adaptive increased nitric oxide (NO) signaling due to an acute anemia [51]. Anemia can be associated with an infection and/or a systemic inflammatory reaction, termed “anemia of inflammation”, as part of the physiological reaction to the disease [52,53]. According to a study by Bellmann-Weiler et al. [54] on 259 hospitalized patients with COVID-19, 24.7% were anemic on admission, with the majority suffering from anemia of inflammation (68.8%). During hospitalization, the percentage of patients with anemia increased (around 68.8% at day 7). A significantly higher mortality during hospitalization was also found in those with anemia upon admission. Anemia is associated with an increased NO expression, leading to vasodilation and thus preventing tissue hypoxia, but also causing increased NO-based oxidation of Hb to MetHb [51]. Interestingly, anemia, and drops in total Hb (tHb), have been reported in COVID-19 patients [22,55,56]. An anticorrelated development of tHb levels and MetHb levels in a COVID-19 patient has been reported [22], in line with the pathway described by Hare et al. [51] of an NO-induced MetHb increase caused by anemia. The role of MetHb as a marker of anemic stress has been also been validated in a study investigating MetHb changes in patients undergoing heart surgery [57]. While “anemia of inflammation” is associated with methemoglobinemia, iron-deficient anemia seems to be a further risk factor for acquired methemoglobinemia by enhancing red blood cell oxidative stress [58]. The occurrence of methemoglobinemia due to a viral infection has been reported for several types of infection [59,60,61]. For example, the activity of MetHb reductase has been shown to be negatively affected by infections with Plasmodium yoelii nigeriensis [62,63] or Plasmodium knowlesi [61]. The fact that the severity of the methemoglobinemia observed in COVID-19 patients was dependent on the subject firstly reflects the different disease severities of the patients but is also most probably due to the physiological constitution of the subjects before the disease, related to their medical history, their overall fitness and age. The age factor seems to be of particular interest since, for example, erythrocytes from elderly humans are more easily affected by oxidative stress, facilitating the formation of MetHb [64]. MetHb can have proinflammatory properties. For example, it activates the NF-κB pathway in endothelial cells associated with chemokine (IL-8) and cytokine (IL-6) production [65]. The activation of the NF-κB and MAPK pathways with subsequent release of the chemokines IL-8 and the chemokine monocyte chemoattractant protein-1 (MCP-1) has also been observed in endothelial cells exposed to MetHb [66]. This underlines that an elevation of MetHb in the blood has an effect on cytokine/chemokine production—a fact that might be of particular relevance for COVID-19 since a “cytokine storm” has been observed in severe courses of the disease [67,68,69,70]. At the same time, it must also be borne in mind that hypoxia also causes the production of cytokines and cytokines, like IL-8 and IL-6 [71,72].