Mystery of Saturation Gap in a Young Boy Dapsone-induced Methemoglobinemia
Year: 2026
Type: article
Abstract: Dear Editor, Autoimmune blistering disorders are a heterogeneous group of diseases characterized by appearance of blisters involving either skin or mucous membrane. It occurs due to formation of autoantibodies against structural proteins of skin and are treated with corticosteroids, immunomodulatory drugs, biologics, etc., Dapsone is an antibacterial medication of sulfonamide class of antibiotics that is used in bullous disorders for its anti-inflammatory action and suppression of neutrophil migration.[1] About 15% of patients develop dapsone-induced methemoglobinemia on standard doses (2 mg/kg/day) for a prolonged duration or at higher doses in a short time only.[2] A 15-year-old male, diagnosed case of pemphigus vulgaris on the basis of clinical presentation, histopathology, and direct immunofluorescence was started on oral prednisolone 40 mg. After 2 weeks, there was minimal improvement, so dapsone 100 mg was added as an adjunct to therapy after normal Glucose-6 Phosphate Dehydrogenase analysis. Further on, there was minimal improvement with treatment due to which he was planned for an injection of Rituximab infusion. On admission, his SpO2 was 89% on pulse oximetry before infusion could be started without any signs of dyspnea, cyanosis, lightheadedness, fatigue, palpitations, or lethargy. All other vital parameters of the patient were normal. He was evaluated for evidence of congenital heart disease or lung disease, but the investigations were within the normal limits; there was no history of consanguinity, previous episodes of dyspnea or cyanosis, family history of methemoglobinemia, any other topical or oral drug intake, any contact with fertilizers or history suggestive of well water intake. Patient was given 4–5 L of oxygen in view of decreased SpO2. Rituximab infusion was completed slowly under close monitoring of the vitals as there was no contraindication. Blood sample was also sent for arterial blood gas (ABG) analysis which showed a pH of 7.44, pCO2 of 48.2, pO2 of 60.1, SaO2 of 95.4%, and methemoglobin (MetHb) levels of 8.5% [Figure 1]. Even 6-min walk test revealed a lower than estimated distance covered (372 m) with below normal oxygen saturation (6-min walk test is a standardized tool used to objectively assess functional exercise capacity and hypoxemia). After this, Dapsone was stopped and oral lycopene and vitamin C were added. On a follow-up visit after 10 days, SpO2 returned to normal, confirming dapsone-induced methemoglobinemia to be the cause.Figure 1: (a) Crusting on lower lip with ulceration and white deposits on lower surface of tongue (b) Arterial Blood Gas analysis of the patient showing a pH of 7.44, pCO2 of 48.2, pO2 of 60.1, SaO2 of 95.4%, and Met Hb levels of 8.5 % suggestive of discrepancy from the pulse oximetry findings. (c) 6-Minute Walk Test shows a below average distance covered along with lower than normal SpO2 values suggestive of MethemoglobinemiaDapsone or diaminodiphenyl sulfone (DDS) is a sulfone antibiotic used therapeutically as a first-line agent for leprosy and for several other dermatologic conditions, including pyoderma gangrenosum, dermatitis herpetiformis, treatment of Pneumocystis jiroveci pneumonia, bullous systemic lupus erythematosus, and severe aphthous ulcers.[3] Owing to its immunosuppressive properties, it has also been used as an adjuvant in pemphigus vulgaris. Dapsone is metabolized via two pathways: nitrogen (N)-acetylation and N-hydroxylation, former being the major route of its metabolism. N-hydroxylation of Dapsone is mediated by hepatic cytochrome P450 isoforms (e.g., CYP3A4), forming metabolites such as dapsone hydroxylamine, and monoacetyl dapsone hydroxylamine, which are in turn responsible for the oxidation of Fe2+ to Fe3+ in hemoglobin, resulting in the formation of methemoglobin (an altered state of hemoglobin in which heme iron is present in oxidized form) in patients receiving this drug.[4] Clinical risk factors for dapsone-induced methemoglobinemia include renal failure, co-administration of other drugs causing methemoglobinemia (lidocaine, benzocaine, prilocaine, and acetaminophen), slow N-acetyltransferase 2 activity, and decreased G6PD activity.[5] Methemoglobin formation hampers the oxygen delivery to tissues leading to a leftward shift of the oxygen dissociation curve creating a state of functional anemia in the patient. Standard colorimetric pulse oximeters show inaccurately low readings in mild toxicity and falsely high readings in severe toxicity by giving a consistently lower reading around 80s in the presence of methemoglobin. Furthermore, ABG analyzers determine the oxygen saturation using PaO2 that gives falsely high values. This “saturation gap” which is the difference between the pulse oximeter’s recorded saturation and the ABG saturation may be detected, which points toward a diagnosis of presence of abnormal hemoglobin, for example, methemoglobinemia in cases of high index of suspicion.[4] As per the literature, healthy patients with normal hemoglobin concentrations develop cyanosis at MetHb level of 15%–20%, lightheadedness, fatigue, tachycardia, dyspnea, lethargy at 20%–50%, respiratory depression, altered sensorium, coma, shock, and seizures at 50%–70%, and death if levels are more than 70%. In case methemoglobinemia is detected, primary step is to prevent the causative agent’s further exposure and assess the severity. Levels more than 10%–30% of MetHb are considered alarming where therapy needs to be started with oxygen supplementation and 1% methylene blue at a starting dose of 1–2 mg/kg that can be upgraded if no response occurs within half an hour. Hyperbaric oxygen therapy and exchange transfusion are reserved for recalcitrant cases. Mild cases are just managed with close monitoring, oxygen supplementation, and ascorbic acid. Hayama et al. in 2020 described a 93-year-old male patient suffering from bullous pemphigoid who presented with dyspnea that developed due to dapsone-induced methemoglobinemia.[6] We are reporting this case to highlight the importance of saturation gap and regular SpO2 monitoring, even during the outpatient department visits, keeping a high index of suspicion of methemoglobinemia if these are altered. A simple test can enable us to quickly intervene and save the patient from grave unwanted side effects. Authors’ contributions Literature search: S, Manuscript preparation: N.K.K, Manuscript editing: R.B Manuscript review: A.B. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Source: Clinical Dermatology Review
Institution: All India Institute of Medical Sciences Rishikesh
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7119550681