PathoBiocheModel of the double-edged sword of glucocorticoids: a case report of COVID-19 management of an outpatient with sarcoidosis
Case Report

PathoBiocheModel of the double-edged sword of glucocorticoids: a case report of COVID-19 management of an outpatient with sarcoidosis

Yuliya Buinitskaya1 ORCID logo, Clifford G. Wlodaver2 ORCID logo, Roman Gurinovich1 ORCID logo, Siarhei Kastsiuchenka3 ORCID logo

1Sci.AI, Agavai Tech Ltd., Hadera, Israel; 2Private Practice, Midwest City, OK, USA; 3Anesthesiology Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates

Contributions: (I) Conception and design: All authors; (II) Administrative support: CG Wlodaver; (III) Provision of study materials or patients: Y Buinitskaya, CG Wlodaver, S Kastsiuchenka; (IV) Collection and assembly of data: R Gurinovich; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Yuliya Buinitskaya, MD. Sci.AI, Agavai Tech Ltd., Adnei Paz 46, Hadera 3831005, Israel. Email: julia@sci.ai.

Background: For coronavirus disease 2019 (COVID-19), glucocorticoids are accepted treatment against its attendant inflammation. However, their use has side effects raising the possibility that they may be harmful in its management. Following the principle of primum non nocere, we used biochemical pathways to model a complicated patient’s condition to predict this eventuality.

Case Description: We present the case of a 60-year-old man with progressive sarcoidosis who was receiving glucocorticoids and contracted COVID-19. He was admitted to a hospital, stabilized, discharged and then worsened. He declined re-admission and was managed at home by family members under the tele-supervision of an intensivist. To individualize management, we modelled his biochemical pathogenesis graphically in the form of a PathoBiocheModel, emphasizing the roles of glucose-6-phosphate dehydrogenase (G6PD) and triiodothyronine (T3). It was developed using his personal data—clinical course and laboratory biomarkers—and published data that was extracted and integrated by sci.AI machine reasoning methods. Based on the PathoBiocheModel—which was validated by the group of our authors—we recognized an underlying insulin resistance which affected the patient’s G6PD status, and therapeutic interventions were modified. The patient successfully recovered. Inspired by his good outcome, we discuss our insights, using biochemical rationale, on the benefits and risks of glucocorticoid use in COVID-19.

Conclusions: While glucocorticoids are used for COVID-19, in our case report we demonstrated that they were harmful. They aggravated an underlying insulin resistance and G6PD deficiency, as a consequence, that potentiates COVID-19. And, interestingly, this was reflected by T3 levels used as a biomarker.

Keywords: Coronavirus disease 2019 (COVID-19); glucocorticoids; sarcoidosis; glucose-6-phosphate dehydrogenase activity (G6PD activity); case report

Received: 12 January 2024; Accepted: 14 June 2024; Published online: 13 August 2024.

doi: 10.21037/jmai-24-8

Highlight box

Key findings

• In patients with an underlying insulin resistance with an affected glucose-6-phosphate dehydrogenase (G6PD) status, glucocorticoids can potentiate coronavirus disease 2019 (COVID-19) and decreased T3 levels can be used as practical biomarker to navigate glucocorticoid therapy in COVID-19.

What is known and what is new?

• Systemic glucocorticoid therapy improves clinical outcomes and reduces mortality in patients with COVID-19 who require supplemental oxygen.

• The PathoBiocheModel approach recognized a condition, an underlying insulin resistance with an affected G6PD status, where risks of glucocorticoid use outweigh its benefits.

What is the implication, and what should change now?

• The PathoBiocheModel in clinical practice can be used in real time to individualize recommended general guidelines and predict their potential adverse effects.

Introduction

Previously, we showed a potential mechanism of how insulin resistance (IR) affects glucose-6-phosphate dehydrogenase (G6PD) status which has a central role in coronavirus disease 2019 (COVID-19) pathogenesis (1,2). Multiple randomized trials indicate that systemic glucocorticoid therapy improves clinical outcomes and reduces mortality in patients with COVID-19 who require supplemental O2 (3). In the era of personalized medicine, general guidelines have to be individualized based on the global biomedical literature. Here we show the PathoBiocheModel of a COVID-19 outpatient with sarcoidosis as an example of how to individualize management using the Sci.AI-based approach (1) in clinical practice. In our case, the PathoBiocheModel approach recognized a condition, in particular, an underlying IR with affected G6PD status, where the risks of glucocorticoid use outweigh its benefits for the management of COVID-19. We present this case in accordance with the CARE reporting checklist (available at https://jmai.amegroups.com/article/view/10.21037/jmai-24-8/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A 60-year-old man with sarcoidosis, stage II: pulmonary and mediastinal involvement, for which he was receiving methylprednisolone 10 mg daily for 6 months, developed progressive respiratory insufficiency and fever. While it was initially thought that this was an exacerbation of his sarcoidosis, he tested positive for COVID-19 which then became the apparent diagnosis. He was hospitalized.

Inpatient management included the following: dexamethasone intravenously (IV), dalteparin (fragmin) subcutaneously (SQ) and aspirin orally (PO). Additionally, he received supplemental O2, 30% by nasal prongs, to maintain a haemoglobin O2 saturation of 90% by pulse oximetry (SpO2). His respiratory status was stable and his fever responded to the anti-inflammatory drugs. After 7 days he was discharged home. However, on the following day, his respiratory status worsened but he declined re-admission, so he was managed at home by tele-supervision. This was facilitated by the patient’s home already equipped with pulse oximetry and home O2 for his sarcoidosis. A visiting nurse and family members managed the therapy as discussed below and monitored the biomarkers shown in Table 1. Clinically, the patient progressively recovered over a week.

Table 1

The trend of the patient’s biomarkers

Biomarkers Day 1 Day 4 Day 9 Day 35 Normal range
Ferritin, ng/mL 1,247 568 341 – 30–400
CRP, mg/L 182 67 10 0.6 <5
ESR, mm/h 40 25 8 – 2–20
Lymphocytes, /L 0.9 1 1.9 4 1.2–3×109
Glucose, mmol/L 4.6 4.2 4.6 4.9 3.5–5.5
HbA1c, % 5.7 – – – <5
T3, pmol/L 2.7 – 2.5 4.3 3.1–6.8
HDL, mmol/L – – 0.8 1.7 >1.45
Fibrinogen, g/L – 7.2 – – 1.5–6.5
D-dimer, mcg/mL – 1.1 0.7 0.11 <0.5

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; T3, triiodothyronine; HDL, high-density lipoprotein.

The patient shared his perspective: “I thought that I was dead at some point because everything was black outside. I asked for a priest. While I was waiting, I felt a light in my chest.”

Discussion

Li et al. reported glucocorticoid-associated adverse outcomes in COVID-19 management (4). Our model may offer an explanation of their observations on a molecular level.

We combined the patient’s clinical data, the COVID-19 pathogenesis (1,2) and guidelines (5) to model his PathoBiochemical-based therapy as depicted in Figure 1.

Figure 1 PathoBiocheModel of COVID-19 patient with sarcoidosis. COVID-19, coronavirus disease 2019; TNFα, tumor necrosis factor-alpha; ChREBP, carbohydrate response element binding protein; NSAID, nonsteroidal anti-inflammatory drug; GSH, glutathione; GSSG, glutathione disulfide; NADPH, nicotinamide adenine dinucleotide phosphate; FAD, flavin adenine dinucleotide; ATP, adenosine triphosphate; T3, triiodothyronine; HDL, high-density lipoprotein; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Sarcoidosis pathogenesis is mediated by tumor necrosis factor-alpha (TNFα) production triggering chronic inflammation (6). In macrophages, TNFα induces production of oxidants (O2−) (7). The antioxidants glutathione (GSH) neutralizes and nitric oxide (NO) suppresses their production (8). Both pathways are dependent on the co-factor nicotinamide adenine dinucleotide phosphate (NADPH) that is produced by G6PD (9). In sarcoidosis, G6PD activity and NADPH production are compromised (10). A proposed mechanism for this is insulin receptor resistance (1,11) which is triggered by TNFα (12). In addition, decreased intracellular glucose leads to decreased production of adenosine triphosphate (ATP) which is required for GSH production (13). The test for G6PD deficiency is falsely negative due to hemolysis in critically ill patients (14) and NADPH cannot be measured in clinical practice. However, triiodothyronine (T3) levels can be used as a surrogate biomarker for these because its production also requires NADPH (15). Moreover, T3 mediates the co-factor flavin adenine dinucleotide (FAD) production from riboflavin (16) that is also required for both GSH and NO pathways (17).

COVID-19 induces TNFα, triggering acute O2− production (18); and it also suppresses NO production through the ACE2-eNOS pathway (19). Furthermore, it aggravates NADPH deficiency by diminishing absorption of its prerequisites, tryptophan, the precursor of niacin, through ACE2 inhibition in the small intestine (20). Interestingly, tryptophan is the precursor of serotonin, the deficiency of which can be responsible for post-COVID-19 depression.

In summary, the preexisting chronic inflammation from sarcoidosis and the acute inflammation from COVID-19 can act synergistically, converting the COVID-19 infection into its clinical syndrome.

In addition, we have modelled the pathways to explain the potential adverse effects of glucocorticoids in this case. Although glucocorticoids are used to suppress inflammatory TNFα activity (21), they interfere with oxidative phosphorylation, increasing O2− production and cause IR (22), decreasing G6PD and NADPH levels (23) and, as a result, GSH and NO systems are additively compromised. Moreover, they induce apoptosis of lymphocytes, decreasing their amount (24).

Altogether, there are three key issues: excessive O2− production, decreased O2− neutralization and decreased NO production.

Excessive O2− production

The biomarkers C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and ferritin were used to estimate O2− production (25) and to navigate the following therapeutic interventions:

  • O2 was supplied when the SpO2 level was lower than 86%, while acknowledging that the results of pulse oximetry can be falsely low due to methemoglobinemia (26).
  • We continued methylprednisolone 10 mg PO daily. We did not continue the stress dose of glucocorticoids used in the hospital because of his depleted lymphocyte count.
  • Fever and pain were controlled with physical methods such as head cooling and body warming for skin vessel dilation to maintain heat transmission into conditioned cool air as well as body repositioning techniques. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol were avoided because they interfere with oxidative phosphorylation and GSH synthesis resulting in increase O2− production and decrease in O2− neutralization, respectively (27).

Decreased O2− neutralization

Sarcoidosis triggers TNFα-mediated IR. Glucocorticoids potentiate this condition. We used the long-term biomarker HbA1c to define the status of his IR and the short-term biomarker T3, as noted above, to navigate the following therapeutic interventions:

  • Glucose IV was avoided and intervals between meals were prolonged to increase the sensitivity of insulin receptors (28).
  • Thiamine (Vitamin B1) 100 mg 2×/day IV to up-regulate pyruvate dehydrogenase complex for ATP production (29).
  • Niacin (Vitamin B3) 500 mg 1×/day PO to up-regulate production of NADPH and high-density lipoprotein (HDL) cholesterol that is oxidized during oxidative stress (30).
  • Tryptophan 500 mg 1×/day PO to up-regulate niacin and serotonin production (31).
  • N-acetyl cysteine (NAC) 600 mg 3×/day PO and glycine 300 mg 3×/day to up-regulate GSH synthesis (32).
  • Ascorbic acid (Vitamin C) 2,000 mg 2×/day IV and 1,000 mg 1×/day PO between infusions for O2− neutralization (33).

Decreased NO production

COVID-19 suppresses the canonical pathway of NO production. However, the alternative pathway, which is mediated by xanthine oxidoreductase (XOR), is intact. Since NO balances coagulation, the biomarkers fibrinogen and D-dimer were used to estimate the coagulation status as well as inflammation and navigate the following therapeutic interventions to maintain the alternative pathway:

  • Nitroglycerin 0.6 mg 5×/day sublingual (SL) and beetroot fresh juice 200 mL 2×/day to supply nitrites and nitrates (NO2/NO3) for XOR reduction to NO.
  • O2 was supplied when SpO2 was less 86% to maintain XOR activity (34).
  • NAC and food sources of H2S such as garlic and onion were used to activate XOR (35).

Conclusions

We constructed a PathoBiocheModel to individualize management of a COVID-19 patient with sarcoidosis. Scrutinizing the molecular interplay between the endogenous and exogenous factors in these two diseases enabled us to recognize, explain and predict their potential adverse effects, respecting primum non nocere. Extrapolating from our experience, we suggest that, in patients with an underlying IR with an affected G6PD status, glucocorticoids can potentiate COVID-19 and that decreased T3 levels can be used as a practical biomarker for glucocorticoid therapy in patients with COVID-19.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jmai.amegroups.com/article/view/10.21037/jmai-24-8/rc

Peer Review File: Available at https://jmai.amegroups.com/article/view/10.21037/jmai-24-8/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jmai.amegroups.com/article/view/10.21037/jmai-24-8/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/jmai-24-8
Cite this article as: Buinitskaya Y, Wlodaver CG, Gurinovich R, Kastsiuchenka S. PathoBiocheModel of the double-edged sword of glucocorticoids: a case report of COVID-19 management of an outpatient with sarcoidosis. J Med Artif Intell 2024;7:40.

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