Methylene blue: a controversial diagnostic acid and medication?

A narrative review of the literature was conducted to determine if the administration of methylene blue (MB) in humans has potential risks. Studies were identified from MEDLINE, Web of Science, Scopus, and Cochrane. MB is a diagnostic substance used during some diagnostic procedures and also a part of the treatment of several diseases including methemoglobinemia, vasoplegic syndrome, fosfamide-induced encephalopathy, and cyanide intoxication, and the detection of leaks or position of parathyroid corpuscles during surgery. Although the use of MB is historically justified, and it ought to be safe, because it originated as a diagnostic material, the basic toxicological characteristics of this substance are unknown. Despite reports of severe adverse effects of MB, which could significantly exceed any possible benefits evaluated for the given indication. Therefore, the clinical use of MB currently represents a controversial problem given the heterogeneity of available data and the lack of preclinical data. This is in conflict with standards of safe use of such substances in human medicinal practice. The toxic effects of the application of MB are dose-dependent and include serious symptoms such as hemolysis, methemoglobinemia, nausea and vomitus, chest pain, dyspnoea, and hypertension. Some countries regard MB as harmful because of the resulting skin irritation and triggering of an adverse inflammatory response. MB induced serotoninergic toxicity clinically manifests as neuromuscular hyperactivity. This review aims to summarize the current understanding concerning the indications for MB administration and define the potential adverse effects of MB.

SARS-CoV-2 and methemoglobinemia in the neonatal period. Case report

INTRODUCCTION: Methemoglobinemia (MetaHb) is a condition where the erythrocyte is unable to release oxygen into tissues causing tissue hypoxia and metabolic acidosis with high lactate. In adult patients with SARS-CoV2 infection, some cases of coexistence of MetaHb and refractory hypoxemia have been reported;although there are no reports of this association in the neonatal stage. CLINICAL CASES: We show two cases of premature newborns with SARS-CoV-2 infection who had multisystemic deterioration and MetaHb in the second to the thrid week of life, without microbiological isolation, or temperary relationship with known MetaHb triggers, normal G6PD levels, and partial response to exchange transfusion or infusion of methylene blue. CONCLUSION: The relationship between MetaHb and SARS-CoV-2 infection is still unknown, but its pro-inflammatory activity has recently been documented, which can increase cytokine storm and worsen the evolution and prognosis of the patient with moderate to severe infection. Further studies of these associations are therefore necessary to enable timely interventions. © 2023 Instituto Nacional de Pediatria. All rights reserved.

Co-Occurring Hemolysis and Methemoglobinemia After COVID-19 Infection in Patient With G6PD Deficiency.

Hemolytic anemia and methemoglobinemia are known complications in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. They can be elicited by various oxidative stressors. Here we report a case of an adult with the first episode of G6PD deficiency associated hemolysis and methemoglobinemia after acquiring COVID-19 infection, who had no recent exposure to oxidative drugs or fava beans. A 52-year-old gentleman known to have myocardial bridging on aspirin and beta-blocker, with no other medical illnesses, developed anemia symptoms, jaundice, and hypoxia after contracting COVID-19 infection. Further laboratory work revealed non-immune hemolytic anemia, methemoglobinemia, and a positive G6PD screen test. He was treated conservatively with a blood transfusion, and his oxygen saturation improved thereafter. With the widespread COVID-19 infection and its morbidity worldwide, it is crucial to consider methemoglobinemia in the differential diagnosis of hypoxia. Testing for G6PD is an essential next step in such cases, as starting methylene blue in G6PD deficiency can worsen hemolysis. Apart from COVID-19, there is no other identified trigger for the acute event in this patient. It is not known whether COVID-19 infection alone is enough to result in G6PD deficiency-associated hemolysis and methemoglobinemia simultaneously.

REFRACTORY HYPOXEMIA: A CASE OF DAPSONE-INDUCED METHEMOGLOBINEMIA IN A PATIENT WITH COVID-19

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Methemoglobinemia is an increase in methemoglobin (mHb) level characterized by functional anemia and tissue hypoxia. It can be caused by congenital enzymes deficiencies, but it is usually acquired. Dapsone, an oxidizing agent, is a medication commonly associated with acquired methemoglobinemia (1). We describe the diagnosis and management of a COVID-19 patient with acquired methemoglobinemia due to Dapsone. CASE PRESENTATION: 84-year-old female with history of MPO-ANCA vasculitis with renal involvement, CKD4 and anemia of chronic disease presented with shortness of breath, lethargy and weakness. Initially, the patient was saturating (SpO2) 80% on room air and was placed on 4L nasal cannula (NC) with improvement to 92%. CT of the chest showed b/l GGOs consistent with atypical pneumonia and patient tested positive for COVID-19. About 4 months prior, she had received 2 doses of Rituximab and on high steroid therapy that was tapered to 5mg of prednisone daily. She has been on Trimethoprim/Sulfamethoxazole for PJP prophylaxis, but due to hyperkalemia the medication was stopped. After confirming no G6PD deficiency, she was started on Dapsone 100mg daily. During hospitalization, she was given dexamethasone 6 mg daily and Dapsone was continued. On hospital stay day 6, a rapid response was called after oxygen dropped to 78% while walking on 6L NC. She was placed on high flow NC 100% and SpO2 went up to 90%. An arterial blood gas (ABG) was then obtained showing pO2 of 334, oxyhemoglobin (oxyHb) of 83 and mHb of 17.4. The SpO2-PaO2 gap and elevated mHb lead to the diagnosis of Dapsone-induced methemoglobinemia. Dapsone was discontinued. Patient received a one-time dose of 1mg/kg IV of methylene blue. One hour later her dyspnea had improved and was on 3L NC. Repeat ABG showed improvement of oxyHb (98) and decreased mHb (2.2). DISCUSSION: Physiologically, mHb is less than 1% of total Hb (1) and occurs when the iron in the porphyrin group of heme is oxidized from ferrous to the ferric form (2). Ferric heme binds oxygen irreversibly causing a left shift of the oxygen-hemoglobin dissociation curve. Clinical presentation tends to correlate with mHb levels, and it varies from being asymptomatic to fatigue, dyspnea, confusion, seizure, cyanosis resistant to oxygen therapy (mHb > 15%) and death. Methylene blue is safe and can be consider when mHb level is greater than 10 to 20% (2). Methylene blue was administer to our patient given the presence of COVID (leaving patient more susceptible to medication-induced methemoglobinemia (3)) and chronic anemia which made her less likely to tolerate state of reduced oxygen delivery. CONCLUSIONS: The diagnosis of methemoglobinemia is a rare cause of hypoxemia that is often overlooked. In patients with risk factors (COVID, medication exposure) a high index of suspicion is needed when interpreting an ABG (SpO2-PaO2 gap) for correct diagnosis and appropriate treatment. Reference #1: Toker, Ibrahim, et al. "Methemoglobinemia Caused by Dapsone Overdose: Which Treatment Is Best?” Turkish Journal of Emergency Medicine, vol. 15, no. 4, Dec. 2015, pp. 182–184, 10.1016/j.tjem.2014.09.002. Accessed 31 Aug. 2020. Reference #2: Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth. 2014 Aug;28(4):1043-7. doi: 10.1053/j.jvca.2013.02.005. Epub 2013 Aug 13. PMID: 23953868. Reference #3: Naymagon, Leonard, et al. "The Emergence of Methemoglobinemia amidst the COVID -19 Pandemic.” American Journal of Hematology, vol. 95, no. 8, 3 June 2020, 10.1002/ajh.25868. Accessed 3 Mar. 2021. DISCLOSURES: No relevant relationships by Mileydis Alonso No relevant relationships by Samantha Gillenwater No relevant relationships by Christine Girard No relevant relationships by Sikandar Khan No relevant relationships by Jose Rivera No relevant relationships by Frederick Ross

DAPSONE-INDUCED METHEMOGLOBINEMIA IN COVID-19: A MIMIC OF “HAPPY HYPOXIA”

SESSION TITLE: Drug-Induced Lung Injury and Disease SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: COVID-19 has been notorious to cause "happy hypoxia” or presentation with profound hypoxia yet without proportional signs of respiratory distress. Methemoglobinemia is a rare and potentially life threatening condition characterized by an inability of hemoglobin to bind oxygen leading to diffuse tissue hypoxia. Diagnosis of methemoglobinemia in a patient with COVID-19 may be masked if the index of suspicion is low. We present such case of dapsone-induced methemoglobinemia in the setting of COVID-19. CASE PRESENTATION: A 64-year-old male presented to the hospital with fatigue. His past medical history included Type 1 Diabetes Mellitus (DM), hypertension and dermatitis herpetiformis. He also reported a 6 day history of testing positive for COVID-19 as an outpatient. His initial vital signs were stable and his peripheral oximeter showed a 96% saturation on 2L O2. Physical exam was unremarkable without any signs of respiratory distress. His labs were notable for blood glucose of 500, high anion gap metabolic acidosis concerning for diabetic ketoacidosis (DKA). A chest X-ray (CXR) revealed bilateral infiltrates. He was initiated on insulin drip and per hospital protocol initiated on Remdesevir and Decadron for COVID-19 treatment. Patient's DKA subsequently resolved. However on Day 4, patient's oxygen saturation decreased suddenly to the 80s without any signs of respiratory distress. Infectious workup including CBC, sputum culture, antigen for streptococcus, legionella returned negative. His CXR remained unchanged. Arterial blood gas (ABG) demonstrated pH of 7.45, pCo2 46mm Hg, pO2 157 mm Hg. Methemoglobin level was found to be 14.1%. He was given methylene blue 1 mg/kg and dapsone was discontinued. His methemoglobin level improved to 3.4% the next day. He was subsequently discharged home without need for supplemental oxygen. DISCUSSION: Methemoglobinemia can be acquired through drugs that oxidize the ferrous hemoglobin to ferric form. Dapsone is one such agent commonly used for dermatological conditions and opportunistic infection prophylaxis. The oxidative stress caused due to COVID-19 coupled with Dapsone use may have precipitated methemoglobinemia in our patient. Since the presentation can easily mimic "happy hypoxia", index of suspicion for methemoglobinemia can be low and thus can have profound consequences if undetected and not treated. CONCLUSIONS: In the setting of COVID-19 pneumonia with refractory hypoxemia, clinicians should have a high index of suspicion for methemoglobinemia especially in patients on highly oxidative medications. Reference #1: Burke P, et al. Dapsone-induced methemoglobinemia: case of the blue lady. Can Fam Physician. 2013 Sep;59(9):958-61. Reference #2: Naymagon L., Berwick S., Kessler A., et al. The emergence of methemoglobinemia amidst the COVID-19 pandemic. Am. J. Hematol. 2020;95: E196-E197 https://doi.org/10.1002/ajh.25868 Reference #3: Faisal H, Bloom A, Gaber AO. Unexplained Methemoglobinemia in Coronavirus Disease 2019: A Case Report. A&A Pract. 2020;14(9):e01287. doi:10.1213/XAA.0000000000001287 DISCLOSURES: No relevant relationships by Syed Azharuddin Speaker/Speaker's Bureau relationship with gsk Please note: 2020-present by Tariq Cheema, value=Honoraria Speaker/Speaker's Bureau relationship with GSK Please note: 2020 Added 04/14/2022 by Tariq Cheema, value=Honoraria Removed 04/14/2022 by Tariq Cheema Speaker/Speaker's Bureau relationship with BI Please note: 2020-PRESENT Added 04/14/2022 by Tariq Cheema, value=Honoraria Speaker/Speaker's Bureau relationship with astra zeneca Please note: 2020-Present Added 04/14/2022 by Tariq Cheema, value=Honoraria Speaker/Speaker's Bureau relationship with regeneron Please note: 2021-Present Added 04/14/2022 by Tariq Cheema, value=Honoraria No relevant relationships by Deeksha Ramanujam No relevant relationships by Alisha Sharma

CONSOLIDATION OF ERN-EUROBLOODNET: THE EUROPEAN REFERENCE NETWORK ON RARE HEMATOLOGICAL DISEASES FIRST 5 YEARS OF IMPLEMENTATION

Background: ERN-EuroBloodNet was established in 2017 as the European Reference Network on Rare Hematological Disorders (RHDs) bringing together nationally recognized centres of excellence with the goal of promoting EU best health care in RHDs. ERN-EuroBloodNet has been recently enlarged integrating 103 HCP from 24 EU-MS. Aims: ERN-EuroBloodNet was conceived to contribute to innovative, efficient and sustainable health systems and facilitate access to better and safer healthcare for EU citizens while decreasing the cross-border health barriers. Methods: Since 2017, ERN-EuroBloodNet established the state-of-the art of RHD allowing the implementation of transversal and disease-specific strategies, where actions on very rare RHD were prioritized. Results: Profile. 182 expert profiles were created freely accessible. Expert centers follow 65,000 RHD patients and treat 5,000 new patients per year, while 24 patients requested support for cross-border health assistance. Expertise. The need to improve access to next-generation sequencing for non-oncological RHD and bone marrow transplantation for sickle cell disease (SCD) was identified. Also, significant disparities in the clinical practice of primary vitreoretinal lymphoma were found and we demonstrated that less than 30% of children with SCD benefit from adequate annual stroke risk monitoring. Guidelines. A repository of 68 Clinical Practice Guidelines (CPG) classified on quality of evidence and consensus approach was created. Recommendations for diagnosis and treatment of methemoglobinemia was published in collaboration with EHA. A CPG on Adult Burkitt Lymphoma is under development. Next topics focus long-term complications in hemoglobinopathies and patients' pathways&summary. Education. ERN-EuroBloodNet Webinars were launched for professionals with 26 Thursdays Webinars and 3 EBAH accredited Topic on Focus on Cutaneous Lymphoma, Thrombotic Microangiopathies, and Bone Marrow Failures. A collaboration was established for EHA & ERN-EuroBloodNet Spotlight on Castleman Disease. For patients, 3 Topic on Focus were launched for Myelodysplastic syndromes, SCD, and Cutaneous lymphoma. Past webinars are available at EuroBloodNet EDU Youtube channel. Preceptorships on SCD will be launched soon. Telemedicine. 43 complex cases have been inter-professionally discussed in the Clinical Patient Management System with 21 outcome reports delivered. Registries. 184 Registries were identified through the European Rare Blood Diseases Platform (ENROL), endorsed by the EHA. The ENROL project, which includes rare anemias, dendritic cell leukemia and von Villebrand's disease pilots, aims to collect exhaustive and therefore epidemiological data for RHDs. The final objective is a possibility of EU health planningl and the promotion of research by identifying cohorts of patients. ERNEuroBloodNet launched the collaborative platform on patients with red blood cells and COVID-19 containing so far 373 patients. Collaborations. collaborative research projects were encouraged like EC-funded projects i.e., genomics and personalized medicine in hematological diseases (GenoMed4All) and the properties and viability of erythrocytes (EVIDENCE), or the International Hemoglobinopathy Research Network (INHERENT) for genomic and phenotypic correlations. Summary/Conclusion: The implementation of well-defined strategies but above all adapted to the specific and not yet covered needs of RHD has led to the realization of concrete projects. This has laid the foundations to strengthen health systems in the field of RHD and allow them to flourish under the new EU4Health programme.

Comparison of the Efficacy of Tocilizumab and Itolizumab for the Treatment of Severe Covid-19: A Retrospective Cohort Study

Aim and background: Alcohol intoxication can complicate detection and timely management of poisoning. Case report: A 52-year-old male was found unconscious at home following heavy alcohol drinking. He presented in emergency department in the gasping state, with hypoglycemia and un-recordable BP. He had tension pneumothorax which was managed accordingly and put into mechanical ventilation, resuscitated with fluids and dextrose. However, in view of persistent hemodynamic instability needing triple inotropes, refractory hypoxemia with cyanosis on a mechanical ventilator and dark brown colored blood co-oximetry was done which showed severe methemoglobinemia. Patient was treated with intravenous methylene blue which led to a dramatic recovery. The inciting event came out to be the ingestion of paintthinner liquid under the influence of alcohol. Conclusion: We report a case of severe methemoglobinemia due to paint-thinner ingestion. High index of suspicion and timely management with methylene blue can save patients of severe methemoglobinemia.

A review on microgreens as an emerging food for health benefits

Microgreens became evident specialty food product that attains quality and higher attention these days. Young foliaged greens are relished as a delicacy for its color, crunchiness and flavor. Microgreens are a novel category of wholesome vegetables which can be harvested after the emergence of primary leaves. Microgreens have fresh aroma and used as freshly made ingredients. By and large, they are used as salads and garnishing for wide variety of dishes. These microgreens have high nutritional value as it contains ample amount of antioxidants, vitamins, minerals and nourishes the human health. Generally, cultivated microgreens are peas, kale, beets, radish, sunflower and arugula. However, they ordinarily enclose a quick fundamental measure because of speedy product deterioration. On examination, microgreens and mature greens, microgreens were the richest sources of water-soluble vitamin and zinc, which are suggested to spice up the immunity of the body throughout the current state of affairs of COVID-19 threat. Hence, these could also be observed as natural supplements. This paper aims to furnish an outline of the organic process facts, their comparison with sprouts, potential bioactive compounds, and cultivation, harvesting, and promoting of microgreens at the side of their future perspective.

Untangling a rare case of hypoxia

Introduction: Hypoxia is a very common symptom during this COVID-19 pandemic. Detailed history, clinical examination and relevant investigations are important in distinguishing rare causes from commonest. Case Report: 52-year-old lady presented to emergency room with sudden onset breathlessness. She was recently diagnosed with Idiopathic Thrombocytopenic Purpura (ITP). She was found to be hypoxic with a room air saturation of 82% in pulse oximeter. She was started on high flow oxygen. But her saturation didn't improve. Chest X-ray showed normal lung fields and bedside echocardiography revealed normal cardiac status. Point of care blood gas analysis (ABG) revealed a normal partial pressure of oxygen (Pao2-100). The discrepancy between oxygen saturation recorded in pulse oximetry and PaO2 in blood gas analysis tempted us to relook the ABG. It was found that the methaemoglobin level in ABG was 10.7%. When we analysed her drug history, we found that there was dapsone intake for the treatment of ITP which strongly supported us to reach the diagnosis of methemoglobinemia. She was then treated with intravenous methylene blue in the emergency room. She responded well and her repeated ABG revealed normalized level of methaemoglobin. Her hypoxia also resolved. Dapsone was later removed from her regular medications. Conclusion: Methemoglobinemia is an extremely rare cause for hypoxia. Though rare its potentially life threatening if not identified on time. Refractory hypoxia with a discrepancy in spo2 and PaO2 should raise the suspicion of methemoglobinemia. IV methylene blue is the recommended treatment for methemoglobinemia.

Occurrence of Methemoglobinemia due to COVID-19: A Case Report.

Methemoglobinemia (MetHb) is a rare, life-threatening condition that occurs when the body is exposed to oxidative stress. It is typically corrected through the glucose-6-phosphate dehydrogenase (G6PD)-dependent shunt. G6PD deficiency is the most common enzymatic deficiency worldwide. This genetic disorder makes patients susceptible to oxidative stress and reduces the expected life span of erythrocytes (red blood cells (RBCs)) among other cells. G6PD deficiency is asymptomatic in most cases unless exogenous stressors are introduced, whether they are dietary, iatrogenic, or infections, such as the highly transmissible serotype of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report a case of an 11-year-old male with known insulin-dependent diabetes mellitus (IDDM) and glucose-6-phosphate dehydrogenase (G6PD) deficiency, who was found to develop methemoglobinemia after being infected by the SARS-CoV-2 virus. The direct effects of COVID-19 on children were reported to be lower than on adults. However, the effects of COVID-19 on children with comorbidities, such as G6PD deficiency in our patient, are understood only to a minimal extent. Moreover, identifying cases of G6PD deficiency prior to initiating treatment with methylene blue, hydroxychloroquine (HCQ), or other contraindicated agents is essential to prevent further deterioration in symptoms.

Paracetamol (acetaminophen) toxicisis in companion animals

Paracetamol is an analgesic and antipyretic with less anti-inflammatory properties than non-steroidal anti-inflammatory drugs, indicated in the symptomatic treatment of mild to moderate pain and the symptomatic treatment of fever. It is found in a variety of over-the-counter analgesic combinations (tablets, suppositories, children's syrups). Poisoning is due to use by pet (dogs, kats) owners without veterinary advice. The risk is high at present due to movement restrictions on people imposed by the Covid pandemic. Cats are the most susceptible. Poisoning is manifested by methaemoglobinaemia, haemolytic anaemia or toxic hepatosis.

Blue despite O2: A rare case of methemoglobinemia

INTRODUCTION: The diagnosis of methemoglobinemia is infrequently thought of in cases of hypoxia, given its rarity. The most common inciting factor is an exposure to oxidizing agents, such as various antibiotics (sulfonamides, trimethoprim, and dapsone), local anesthetics, nitrites, and aniline dyes. This is a case of methemoglobinemia in a patient who was initially treated for COVID 19 with outpatient vitamin infusions. DESCRIPTION: A 76-year-old man was brought to the emergency department after collapsing at home. He was treated for COVID-19 the week prior with ivermectin and vitamin infusions, however developed high fevers, up to 102 F, with worsening cough and fatigue. On arrival his oxygen saturation was 50%, which improved with non-rebreather. Chest CT revealed multifocal ground glass opacities, consistent with COVID pneumonia. Shortly after admission, a rapid response was initiated as the patient was becoming more hypoxic with worsening altered mental status. Pulse oximetry revealed oxygen saturation of 60%;the patient was quickly intubated and transferred to the intensive care unit - oxygen saturation continued to read 70% despite a FiO2 100%. An arterial blood gas appeared brown in color and revealed a normal paO2 and pCO2. The patient was found to have a methemoglobin level of 21%. The patient underwent exchange transfusion of 7 units, with subsequent resolution of his hypoxia. DISCUSSION: Methemoglobinemia is a life threatening disorder, and diagnosis is dependent on a high degree of clinical suspicion. Patients typically present with shortness of breath, fatigue, cyanosis, and can ultimately develop loss of consciousness. An arterial blood gas, with its classic chocolate-brown appearance, a normal Po2, and CO-oximetry panel confirms diagnosis. Methemoglobinemia is routinely treated with methylene blue and, in severe cases, requires red cell exchange. There are reports that have shown benefits of high-dose vitamin C for safe and effective treatment of methemoglobinemia in centers with no access to methylene blue, through its anti-oxidant effect. Interestingly, this patient developed this condition after being treated for COVID 19 with vitamin infusions. This case highlights the importance of careful history taking, as certain medications can have unknown and fatal side effects.

Glucose-6-Phosphate Dehydrogenase Deficiency-Associated Hemolytic Anemia and Methemoglobinemia in a Patient Treated With Hydroxychloroquine in the Era of COVID-19.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells worldwide. The severity of hemolytic anemia varies among individuals with G6PD deficiency, depending on the genetic variant in the G6PD gene; this makes the diagnosis of the condition more challenging in some cases. In this report, we present a case of severe hemolytic anemia and methemoglobinemia in a patient with G6PD deficiency who had been exposed to hydroxychloroquine prescribed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To the best of our knowledge and based on a literature search, this is one of the first case reports in the literature about hemolytic crisis and methemoglobinemia in a patient with critical illness due to severe coronavirus disease 2019 (COVID-19) who was exposed to hydroxychloroquine. It is critical for physicians and caregivers to recognize the effects of oxidative stressors such as hydroxychloroquine, particularly in this era of the COVID-19 pandemic and in regions with a high prevalence of G6PD deficiency, for the appropriate management of this unique subset of patients.

Reactive nitrogen compounds and their influence on human health: an overview.

Nitrogen (N) is a critical component of food security, economy and planetary health. Human production of reactive nitrogen (Nr) via Haber-Bosch process and cultivation-induced biological N2 fixation (BNF) has doubled global N cycling over the last century. The most important beneficial effect of Nr is augmenting global food supplies due to increased crop yields. However, increased circulation of Nr in the environment is responsible for serious human health effects such as methemoglobinemia ("blue baby syndrome") and eutrophication of coastal and inland waters. Furthermore, ammonia (NH3) emission mainly from farming and animal husbandary impacts not only human health causing chronic lung disease, inflammation of human airways and irritation of eyes, sinuses and skin but is also involved in the formation of secondary particulate matter (PM) that plays a critical role in environment and human health. Nr also affects human health via global warming, depletion of stratospheric ozone layer resulting in greater intensity of ultra violet B rays (UVB) on the Earth's surface, and creation of ground-level ozone (through reaction of NO2 with O2). The consequential indirect human health effects of Nr include the spread of vector-borne pathogens, increased incidence of skin cancer, development of cataracts, and serious respiratory diseases, besides land degradation. Evidently, the strategies to reduce Nr and mitigate adverse environmental and human health impacts include plugging pathways of nitrogen transport and loss through runoff, leaching and emissions of NH3, nitrogen oxides (NO x ), and other N compounds; improving fertilizer N use efficiency; reducing regional disparity in access to N fertilizers; enhancing BNF to decrease dependence on chemical fertilizers; replacing animal-based proteins with plant-based proteins; adopting improved methods of livestock raising and manure management; reducing air pollution and secondary PM formation; and subjecting industrial and vehicular NO x emission to pollution control laws. Strategic implementation of all these presents a major challenge across the fields of agriculture, ecology and public health. Recent observations on the reduction of air pollution in the COVID-19 lockdown period in several world regions provide an insight into the achievability of long-term air quality improvement. In this review, we focus on complex relationships between Nr and human health, highlighting a wide range of beneficial and detrimental effects.

The Role of Methemoglobin and Carboxyhemoglobin in COVID-19: A Review.

Following the outbreak of a novel coronavirus (SARS-CoV-2) associated with pneumonia in China (Corona Virus Disease 2019, COVID-19) at the end of 2019, the world is currently facing a global pandemic of infections with SARS-CoV-2 and cases of COVID-19. Since severely ill patients often show elevated methemoglobin (MetHb) and carboxyhemoglobin (COHb) concentrations in their blood as a marker of disease severity, we aimed to summarize the currently available published study results (case reports and cross-sectional studies) on MetHb and COHb concentrations in the blood of COVID-19 patients. To this end, a systematic literature research was performed. For the case of MetHb, seven publications were identified (five case reports and two cross-sectional studies), and for the case of COHb, three studies were found (two cross-sectional studies and one case report). The findings reported in the publications show that an increase in MetHb and COHb can happen in COVID-19 patients, especially in critically ill ones, and that MetHb and COHb can increase to dangerously high levels during the course of the disease in some patients. The medications given to the patient and the patient's glucose-6-phospate dehydrogenase (G6PD) status seem to be important factors determining the severity of the methemoglobinemia and carboxyhemoglobinemia. Therefore, G6PD status should be determined before medications such as hydroxychloroquine are administered. In conclusion, MetHb and COHb can be elevated in COVID-19 patients and should be checked routinely in order to provide adequate medical treatment as well as to avoid misinterpretation of fingertip pulse oximetry readings, which can be inaccurate and unreliable in case of elevated MetHb and COHb levels in the blood.

Methemoglobinemia and hemolytic anemia after COVID-19 infection without identifiable eliciting drug: A case-report.

We report a second case of methemoglobinemia and non-autoimmune hemolytic anemia after contracting the SARS-CoV-2 infection in the absence of an identifiable eliciting drug. A 35-year old male without previous known comorbidities was admitted after he was diagnosed with the COVID-19 infection and had large pulmonary involvement. Seven days later, he desaturated but was without any signs of respiratory distress. A check of arterial blood gas revealed normal partial pressure of oxygen and follow-up tests confirmed a methemoglobinemia diagnosis. Over the next few days, hemolysis was established after decreased levels of hemoglobin and increased levels of indirect bilirubin and lactate dehydrogenase. A hemolytic anemia investigation panel came back normal, including G6PD. A second G6PD test was ordered at the 5-month follow-up appointment and revealed decreased levels. Clinicians should thus be aware of possible false negative tests when testing for G6PD during hemolytic crisis. In addition, whether the COVID-19 infection alone would be responsible for this chain of events remains a challenging question.

Methemoglobinemia in Patient with G6PD Deficiency and SARS-CoV-2 Infection.

We report a case of intravascular hemolysis and methemoglobinemia, precipitated by severe acute respiratory syndrome coronavirus 2 infection, in a patient with undiagnosed glucose-6-phosphate dehydrogenase deficiency. Clinicians should be aware of this complication of coronavirus disease as a cause of error in pulse oximetry and a potential risk for drug-induced hemolysis.