Breathlessness in a 32-Year-Old Female: Clinical Presentation and Evaluation

BREATHLESS WITH A CLEAR CHEST! Clinical Club 10/06/2022 SHIFA c

32 years, female, homemaker Presenting Complaint Worsening of breathlessness ( NYHA Gr IV dyspnoea)*1 week H/O Present Illness Pre-existing dyspnoea on exertion *1 year, gradually progressive, worsened over past few weeks, now breathless even at rest for past 1 week. No h/o orthopnoea or PND. No h/o cough/rhinitis/fever/significant loss of weight/appetite.

No h/o chest pain or hemoptysis. No h/o skin/ mucosal bleeding/ GI bleed. No h/o calf pain / recent surgery /immobilisation.

PAST H/O ILLNESS Diagnosed c/o immune thrombocytopenia ( 3 years back following evaluation for echymotic patches) Was on oral prednisolone. Later started on dapsone 100 mg BD*5 months. H/O anemia in the past, had taken iron tablets for few months one year back. FAMILY HISTORY No h/o similar illness, bleeding disorders/ malignancies.

MENSTRUAL & MARITAL HISTORY Menarche at 13 years, irregular cycles, polymenorrhoea and heavy menstrual bleeding+ Married @ 24 years P1L1, Full term delivery by emergency LSCS at 25 years of age( protracted labour) No h/o PPH, no h/o blood transfusions, no h/o erythroblastosis foetalis( O +ve blood group)

EXAMINATION FINDINGS Conscious,oriented, co-operative Dark complexion, not visibly cyanosed PR- 90/ BP-130/80 RR-26/ SpO2 84%RA, 88% with full flow O2 via face mask No calf muscle tenderness

Chest clear , Vesicular breath sounds B/L CVS S1S2 heard, no murmurs Abdomen soft, no organomegaly Nervous system Normal,no focal deficits

Hb- 10gm% Plt-79,000 MCV -78 ESR-10 S.Ferritin -9.5 S.Bilirubin -1.2 P.smear microcytic hypochromic anemia Stool occult blood neg Direct Coomb s test neg ANA, anti-dsDNA- neg IgG H.pylori - positive

D-Dimer neg COVID -19 RTPCR Neg Chest Xray normal HRCT thorax normal ECHO ( + Bubble contrast) - normal

ABG no acidosis, SaO2 - 99.6 ! Saturation Gap!! Peripheral blood darker, did not brighten on air exposure as compared to control. Owing to h/o dapsone intake, methhemoglobinemia was suspected. Co-oximetry - Not done, not available @ hospital lab, no insurance, financially drained.

WHY SATURATION GAP? The difference between calculated oxygen saturation from the ABG & the reading from a pulse oximeter. Traditional dual length pulse oximeters measure absorbance of light at 2 wavelengths -660 & 940 nm can detect deoxyHb & oxyHb. MetHb absorbs light at both these gives a false high reading. Upto 20 % metHb SaO2 drops by half of the methemoglobin percent, after that- around 85% regardless of the true percentage. Co-oximetry- use multiple wavelengths of light can detect oxy, deoxy, carboxy & methemoglobins.

Here, Dx Dapsone induced Methhemoglobinemia, immune thrombocytopenia, iron deficiency anemia( menstrual blood loss). Clues : 1.Drug history (dapsone) 2.Dyspnoea out of proportion to anemia 3.Saturation fall not improving with O2 in the absence of cardiac cause. 4.Saturation Gap in ABG 5. Darker blood ,not brightening on exposure to air compared to control.

MANAGEMENT O2 by face mask Stopped Dapsone, continued steroids. 1 pint PRC transfused. Oral ascorbic acid 500 mg BD Oral riboflavin Oral N-acetyl cysteine Symptoms & SpO2 improved -94% RA by Day-4.

HOW IS SHE NOW? Sent home on steroids, Oral iron. Later underwent splenectomy. Now, 5 months after splenectomy- not dyspnoeic, SpO2-99% RA, Hb-11.6, Platelet 3 lakhs, not on steroids.

DISCUSSION WHAT IS METHEMOGLOBIN Methemoglobin by oxidation of heme iron to Fe3+ - reduced O2 carrying capacity & high O2 affinity Left shift in O2 dissociation curve- no tissue delivery functional anemia. >50-60% MetHb is fatal.

MetHb is Normally Present. Normal levels <1% formed by autooxidation, endogenous & exogenous free radicals & oxidizing agents. Kept @ <1% by enzymatic activity in RBCs Cyb5R 1. NADPH Methemoglobin reductase (G6PD in the HMP shunt) activated by extrinsic electron acceptors like methylene blue, riboflavin. 2. Other pathways electron donors like ascorbic acid, reduced glutathione, riboflavin, cysteine, tetrahydropterin, 3-hydroxyanthranilic acid,3-hydroxykynurenine. 3.

Elevation in Methemoglobin: 1. Congenital enzyme deficiencies 2.Exogeneous oxidizing agents. Congenital Methemoglobinemia 1. Cyb5R deficiency AR 2. Hb M disease AD 3. Cytochrome b5 deficiency - rare

ACQUIRED CAUSES Often iatrogenic Dapsone Topical anaesthetics (benzocaine, lidocaine, prilocaine) Anti-malarials ( chloroquine, primaquine, diaminodiphenylsulphone) Inhaled NO Nitrates & nitrites intestinal bacteria convert nitrates to nitrites sepsis, infants more prone well water (blue baby syndrome), root vegetables, frozen-foods preservative, illicit drugs (poppers) Aniline dyes, chlorhexidine.

DAPSONE Sulfone antibiotic & anti-inflammatory agent. In liver- CytP450- to potent antioxidants. Enterohepatic circulation long half-life (30 hrs). Used in - Leprosy, acne vulgaris, dermatitis herpetiformis, prophylaxis for P.jiroveci pneumonia , ITP In a case series-138 cases dapsone accounted for 42 % - mean methemoglobin level of 7.6% (range 2-34%) In a case series of 167 children with hematologic malignancy/aplastic anemia-on PCP prophylaxis 19% (32) developed methemoglobinemia,

WHEN TO SUSPECT? When the usual search within the airways & thorax of your dyspnoeic patient yields no clue, one has to search beyond that box. Methemoglobinemia suspect when dyspnoea / cyanosis & hypoxemia that is refractory to supplemental oxygen, especially when there is exposure to an oxidizing agent. CYANOSIS IS NOT SPECIFIC 5g% of deoxyhemoglobin, 0.5g% of sulfhemoglobin, 1.5g% of methemoglobin.

WHAT IF THERE IS NO CYANOSIS? In methemoglobinemia, development of cyanosis correlates with the total amount of methemoglobin. i.e. {Total hemoglobin*percent methemoglobin} - not the percentage of methemoglobin! Total methemoglobin>1.5g% usually causes cyanosis. For the same percentage of methemoglobin, anemia can mask cyanosis & erythrocytosis will accentuate cyanosis.

Since anemic persons have a reduced baseline oxygen carrying capacity, they can be quite sick despite lack of cyanosis! Appearance of cyanosis can also be affected by skin pigmentation & dermal thickness.

Here, menstrual blood loss caused a mild anemia of HB 10. This when coupled with increasing concentration of MetHb owing to continuous Dapsone intake the functional HB level will be much lower. Hence the dyspnoea out of proportion to the degree of anemia.

TAKE HOME MESSAGE Eliciting proper history ( including relevant drug history,) is often the key to diagnosis in confusing cases, as in this case. Here, co-oximetry was not available diagnosing with available clues might be the only option in resources limited settings.

REFERENCES P.Burke et al.Dapsone induced methemoglobinemia.Can Fam Physician.2013 Sep;59(9) Shenouda M,Padilla M, Silva J,et al.Dapsone-induced methemoglobinemia:A case report.Cureus 14(2):e22466.Feb 2022 Singh S,Sethi N,Padith S,Ramesh G.Dapsone induced methemoglobinemia:Saturation Gap- The key to diagnosis.J Anaesthesiol Clin Pharmacol.2014 Jan-Mar;30(1):86-88 L.Shobhavat,A.D Costa,K.Shroff.Anemia That Presented with Desaturation:A Focus on Core Concepts.Case Reports inPaediatrics,vol.2021 Up-to-date