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To the contrary, the information presented by Knobeloch et al. (1) support my conclusions (2). Knobeloch et al. (1) described two purported cases of infantile methemoglobinemia in their paper. The diagnosis of methemoglobinemia in case 1, however, is completely speculative: a doctor did not examine the infant, and blood methemoglobin concentrations were not measured during the observed anoxia. It seems ill considered, therefore, to include this case in a serious discussion of the causes of methemoglobinemia. Knobeloch et al. (1) placed undue importance on my discussion of infectious illness as a potential factor in methemoglobinemia (2), and their conclusion implies that I limited my discussion and conclusions to infectious illness. This is erroneous. As I discussed in my review (2), the case literature amply demonstrates that, along with gastrointestinal and urinary tract infections, a number of noninfectious gastrointestinal disturbances can directly cause methemoglobinemia in infants without exposure to exogenous nitrates in food or water, including copper toxicity (3), protein intolerance (4), and nonspecific diarrhea (5,6). Although Knobeloch et al. (1) acknowledge that studies show “infants with diarrhea are at risk of developing methemoglobinemia, even in the absence of dietary nitrate exposure,” they state that “only a small percentage of infants in these cohorts had clinically significant methemoglobin levels.” This statement seriously understates the potential severity of methemoglobinemia caused solely by diarrhea and other gastrointestinal illnesses; I found eight cases reported in the literature in which methemoglobin levels were > 34%, and three of these were > 55% (4,7–12). Contrary to the claims of Knobeloch et al. (1), secondary risk factors, such as nitratecontaminated water, oxidant drug exposure, and inherited enzyme deficiencies, were ruled out in all of these cases, as well as in dozens of additional cases caused by diarrhea. In fact, Knobeloch (13) has acknowledged that diarrhea was observed during hospitalization in case 2 of their report, undermining the conclusion that nitrates from drinking water played a critical role in this case. Knobeloch has suggested that the observed diarrhea was merely the result of the severe anoxia suffered by this infant (91.2% methemoglobin concentration) (13). However, the anoxia in this case was life threatening and resolved quickly following methylene blue treatment immediately after admission to the hospital. Therefore, if anoxia were the cause of the diarrhea, the diarrhea would not be expected to persist during hospitalization. Moreover, diarrhea has not been reported in cases of anoxia and methemoglobinemia caused by oxidant drug or chemical exposure. Knobeloch et al. (1) stated that “infectious illnesses apparently did not contribute to her illness,” yet they failed to mention the infant’s diarrhea in their paper. It is worth noting that the well water in case 2 tested positive for Escherichia coli. Knobeloch et al. (1) also failed to discuss the lengthy hospitalization of case 2. The authors stated that the infant “responded rapidly to treatment with methylene blue,” yet the infant remained hospitalized for 17 days. What other health problems existed that required such a lengthy hospitalization? Could these health problems have contributed to the methemoglobinemia? Unfortunately, on several occasions Knobeloch has refused to discuss the specifics of this case with me. Regardless, the diarrhea, the extremely high methemoglobin level, and the lengthy hospitalization indicate that the infant in case 2 was suffering from more than simple chemical nitrate poisoning. This raises an important question, in fact, the question at the heart of my original review: What are the factors that contribute to methemoglobinemia in infants? Exposure to even high levels of exogenous nitrates in drinking water is insufficient, by itself, to cause methemoglobinemia. This was demonstrated conclusively by experiments conducted with human infants in the 1940s (14). Four healthy infants ranging from 2 days to 6 months of age were fed formula prepared with water containing ~100 ppm nitrate–nitrogen (nitrate-N). Despite ingesting such highly contaminated formula for more than a week, the highest methemoglobin level observed was 7.5%, with no cyanosis evident in any of the patients. Even when nitrate-contaminated formula was fed to several infants hospitalized for methemoglobinemia ostensibly linked to nitrate-contaminated water, the highest methemoglobin level recorded was 11% (14). As these researchers noted, It appeared that there were other factors in addition to the quantity of nitrate ion ingested that determined whether or not an infant became cyanotic.

Cause of methemoglobinemia: illness versus nitrate exposure.