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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 5
| Issue : 1 | Page : 25 |
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Correlation of the severity of mucormycosis with levels of inflammatory markers in COVID-19 patients
S Kruthika, N Inchara, Poojitha Madala
Department of Ophthalmology, Sri Devaraj Urs Medical College, SDUAHER, Kolar, Karnataka, India
| Date of Submission | 18-Apr-2023 |
| Date of Decision | 04-May-2023 |
| Date of Acceptance | 08-May-2023 |
| Date of Web Publication | 27-Jun-2023 |
Correspondence Address:
N Inchara
House No. 01, G Block, Staff Quarters, SDUMC Campus, Tamaka, Kolar - 563 103, Karnataka
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/pajo.pajo_24_23
Purpose: The purpose of the study is to explore the clinical spectrum of rhino-orbital cerebral mucormycosis (ROCM) and to correlate its severity with the levels of inflammatory markers of COVID-19 patients.
Materials and Methods: It is an observational analytical study. Clinical and laboratory data of the patients with mucormycosis admitted in COVID-19 wards in a notified nodal tertiary care center were collected and stratified clinically according to the severity of ROCM. Serum ferritin, serum lactate dehydrogenase (LDH), D-dimer, total count, neutrophils, and lymphocyte count were considered primary outcome variables. The severity of the ROCM (Stage II, Stage III, and Stage IV mucormycosis) was considered the primary explanatory variable.
Results: Forty-five participants were included, of which 38 (84%) were male and 7 (16%) were female. The mean age was 48.71 ± 10.71 years, which ranged from 29 to 75 years. In people with the severity of the ROCM, 26 (58%) were in Stage II, 15 (33%) were in Stage III, and 4 (9%) were in Stage IV. The mean serum ferritin, mean serum LDH, and D-dimer across the severity of ROCM were statistically significant. The median total count, mean neutrophils, and mean lymphocytes across the severity of ROCM were not statistically significant.
Conclusion: The study shows that raised serum ferritin, LDH, and D-dimer levels at admission significantly predict disease severity in COVID-19 patients with mucormycosis. Mucormycosis and its severity are associated with higher inflammatory markers levels than the mild disease in COVID-19 patients. Tracking these markers may allow early identification or even prediction of disease progression.
Keywords: COVID-19, D-dimer, inflammatory markers, lactate dehydrogenase, mucormycosis, rhino-orbital-cerebral mucormycosis, serum ferritin
How to cite this article:
Kruthika S, Inchara N, Madala P. Correlation of the severity of mucormycosis with levels of inflammatory markers in COVID-19 patients. Pan Am J Ophthalmol 2023;5:25 |
How to cite this URL:
Kruthika S, Inchara N, Madala P. Correlation of the severity of mucormycosis with levels of inflammatory markers in COVID-19 patients. Pan Am J Ophthalmol [serial online] 2023 [cited 2023 Sep 21];5:25. Available from: https://www.thepajo.org/text.asp?2023/5/1/25/379759 |
| Introduction | |  |
COVID-19 is caused due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Besides, COVID-19 has been associated with a wide range of opportunistic bacterial and fungal infections ranging from mild upper respiratory tract infections to fatal pneumonia.[1],[2] This dreaded disease, along with the involvement of the respiratory system, induces an inflammatory response triggered by the rapid viral replication of SARS-CoV-2. Cellular destruction can recruit macrophages and monocytes and induce the release of cytokines and chemokines.[3],[4]
Lately, worldwide, particularly in India, several cases of mucormycosis have been increasingly reported in patients with COVID-19 infection.[5],[6] During this period, a Tertiary Care Teaching Hospital in South India, a notified nodal center for diagnosis and management of “Black Fungus,” has witnessed a sudden rise in cases of invasive fungal sinusitis, with mucormycosis features needing emergency interventions.
Mucormycosis belongs to the order Mucorales, and the most common presentation is rhino-orbital-cerebral mucormycosis (ROCM) conventionally and in COVID-19 patients. The upsurge of mucormycosis amidst the ongoing pandemic was hypothesized to be driven by the interplay between host factors such as weakened immunity following COVID-19, poorly controlled diabetes mellitus, rampant use of steroids/immunomodulators, and other factors such as a prolonged hospital stay, continuous oxygen support, poor hospital infection control, and nursing care practices.[7] Mortality is high with invasive mucormycosis by its complication such as intracranial involvement, cavernous sinus thrombosis, and osteomyelitis. In extremely rare situations, such infections can be seen in immunocompetent patients.[8] They cause tissue necrosis which leads to severe morbidity and mortality by angioinvasion and thromboembolism.[9],[10] Clinically, ROCM presents with atypical signs and symptoms similar to complicated sinusitis, including nasal blockade, crusting, proptosis, facial pain, edema, ptosis, chemosis, and even ophthalmoplegia, with headache and fever. Rapid disease progression may occur, with reported mortality rates of 50%–80% from intra-orbital and intracranial complications without early diagnosis and treatment.[11]
We carried out this study to explore and correlate the inflammatory markers and severity of mucormycosis in COVID-19 patients, which can help to decide on early intervention to prevent morbidity and mortality among these patients.
| Materials and Methods | | |
Study setting and design
An observational analytical study was conducted at the notified nodal Tertiary Care Center for Black Fungus cases in Kolar District, Karnataka, India, for 3 months, from April 2021 to June 2021.
Inclusion criteria
Patients with a history of COVID-19 infection with proven fungal elements in fungal culture or histopathological examination belonging to the Mucorales family were included in the study.
Exclusion criteria
Those with no history of COVID-19 infection and a history of surgical debridement elsewhere were excluded from the study.
Study population and sample size
Nodal center had 98 cases of invasive ROCM during the second wave of the COVID-19 pandemic. Forty-five patients admitted to the hospital with COVID-19-positive infection with proven fungal culture belonging to Mucorales during the period were included in the study using nonprobability sampling.
Data collection
Clinical history and inflammatory laboratory parameters (including serum ferritin, serum lactate dehydrogenase (LDH), D-dimer, and total and differential white blood cell [WBC] count) were recorded. A detailed ophthalmological examination was performed, and the findings were noted.
Statistical analysis
We considered inflammatory markers as primary outcome variables. Whereas the severity of the ROCM (Stage II, Stage III, and Stage IV) from the Directorate of Medical Education guidelines, the proposed staging of post-COVID-19 ROCM suggested by the Government of Tamil Nadu, India, was considered as a primary explanatory variable.[12],[13] The proposed staging is Stage I – Involvement of the nasal mucosa, Stage II – Involvement of the paranasal sinus, Stage III – Involvement of the orbit, and Stage IV – Involvement of the central nervous system.[14],[15],[16] We conducted a descriptive analysis using mean and standard deviation for quantitative variables and proportion for categorical variables. Data were checked for normal distribution, and the data with normally distributed quantitative parameters and the mean values were compared between study groups using the ANOVA test. For nonnormally distributed quantitative parameters, descriptive analysis was measured using medians and interquartile range (IQR). The comparison between study groups was tested using the Kruskal–Wallis test with a statistically significant P < 0.05. Data were analyzed using SPSS software, version 22.0 (Chicago, IL, USA).
Ethics approval and confidentiality
The Institutional Ethics Review Committee approved this study. The patient's identity and privacy were concealed, and confidentiality of data was ensured during the study.
| Results | | |
A total of 45 participants were included in the final analysis. Majority were male, 38 (84%), and 7 (16%) were female. The mean age was 48.71 ± 10.71 years, ranging from 29 to 75. In people with the severity of the ROCM, 26 (58%) were in Stage II, 15 (33%) were in Stage III, and 4 (9%) were in Stage IV. The mean serum ferritin was 491.48 ± 320.46 ng/mL, ranging from 46.80 to 1000; the mean serum LDH (IU/L) was 416.91 ± 221.24, ranging from 100 to 897; the mean D-dimer (ng/mL) was 1248.67 ± 2117.29, ranging from 53.10 to 10,000; the mean total count (/μL) was 15.77 ± 11.81, ranging from 5.61 to 87; the mean neutrophils (%) was 78.55 ± 8.51 ranging from 56 to 94; the mean lymphocytes (%) was 12.30 ± 6.71 ranging from 2.10 to 31.40. Among the study participants, 25 (56%) had high levels of serum ferritin (ng/mL), 20 (44%) had a normal level, 30 (67%) had a high level of serum LDH (IU/L), and 15 (33%) had a normal level, 34 (76%) had high-level D-dimer (ng/mL), and 11 (24%) had a normal level, 39 (87%) had high total WBC count (/μL), and 6 (13%) had normal count, 44 (98%) had high neutrophils (%) count, and 1 (2%) had normal count, 41 (91%) had low lymphocytes count, and 4 (9%) had normal count. A summary of the demographic and baseline characteristics is given in [Table 1]. | Table 1: Demographic and baseline characteristics of the subjects (n=45)
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The mean serum ferritin (ng/mL) with the severity of the ROCM in Stage II was 397.94 ± 268.73, it was 592.07 ± 311.76 in Stage III, and it was 682 ± 251.33 in Stage IV, the mean difference of serum ferritin across the severity of ROCM was statistically significant [P = 0.048, [Figure 1]]. | Figure 1: Serum ferritin level versus ROCM stage. ROCM: Rhino-orbital-cerebral mucormycosis
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The mean serum LDH (IU/L) with the severity of the ROCM in Stage II was 327.27 ± 180.15, it was 563.13 ± 211.23 in Stage III, and it was 451.25 ± 247.18 in Stage IV, a mean difference of serum LDH across the severity of ROCM was statistically significant [P = 0.003, [Figure 2]]. | Figure 2: Serum LDH level versus ROCM stage. LDH: Lactate dehydrogenase, ROCM: Rhino-orbital-cerebral mucormycosis
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The mean D-dimer (ng/mL) with the severity of the ROCM in Stage II was 614.6 ± 272.36, was 776.79 ± 241.05 in Stage III, and it was 901.42 ± 158.45 in Stage IV, the mean difference of D-dimer across the severity of ROCM was statistically significant [P = 0.044, [Figure 3]]. | Figure 3: D-dimer level versus ROCM stage. ROCM: Rhino-orbital-cerebral mucormycosis
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The median total count (/μL) was 13.61 (IQR 12.18, 16.04) in Stage II, 12.20 (IQR 10.50, 14.90) in Stage III and 18.56 (IQR 11.47, 29.97). The difference in the median total count across the severity of the ROCM was not statistically significant [P = 0.323, [Table 2]]. | Table 2: Comparison of mean laboratory parameters across the severity of the rhino-orbital-cerebral mucormycosis (n=45)*
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The mean neutrophils (%) with the severity of the ROCM in Stage II was 78.72 ± 8.98, it was 77.26 ± 7.9 in Stage III, and it was 82.28 ± 8.44 in Stage IV, the mean difference of neutrophils across the severity of ROCM was not statistically significant [P = 0.581, [Table 2]].
The mean lymphocytes (%) with the severity of the ROCM in Stage II was 11.62 ± 7.33, it was 14.4 ± 5.5 in Stage III, and it was 8.88 ± 5.53 in Stage IV, the mean difference of lymphocytes across the severity of ROCM was not statistically significant [P = 0.254, [Table 2]].
| Discussion | | |
COVID-19, during the second wave in early 2021, has caused an alarming increase in cases encountering health infrastructure inadequacy and demand for hospital beds, drugs, vaccines, and oxygen adding more burden to such a challenging situation, mucormycosis created chaos.[17] Patients with SARS-CoV-2 infection appear in large numbers with various clinical symptoms, from asymptomatic manifestations to life-threatening illnesses like acute respiratory distress syndrome.[5]
India had been significantly impacted by COVID-19, which also posed a fatal risk of mucormycosis. Historically, the prevalence ranged from 0.005 to 1.7/million people worldwide. However, following COVID-19, the frequency has increased to 1.4/1000 in India alone.[5],[6] In India, there have been 25,000 instances reported over 3 months during the pandemic.[18] Our institute experienced a dramatic increase in mucormycosis cases during the final 3 months of the second wave of the pandemic.
Initial ocular issues in ROCM are brought on by tissue inflammation and necrosis of the surrounding orbital tissue and decreased blood supply. Occlusion of the retina's central artery and infarction of the orbit, which also affects the optic nerve, are two potentially serious ophthalmic issues related to ROCM that could ultimately result in total blindness. ROCM can move from the orbit to the brain through the cribriform plate and orbital apex, resulting in potential problems such as internal carotid artery occlusion, cranial nerve palsy, chiasmal infarction, intracranial aneurysm, fungal meningitis, and even death.
Several previous studies have reported hyperglycemia and the use of systemic corticosteroids as the main risk factors for the development of COVID-19-associated ROCM.
Irrespective of hospitalization for COVID-19, hyperglycemia is an independent risk factor. Published reports indicate that COVID-19 is associated with hyperglycemia in general. Hyperglycemia or new-onset diabetes mellitus has been observed with COVID-19 and is hypothesized to predispose to ROCM through phagocyte dysfunction, defective chemotaxis, and impaired intracellular killing of Mucorales.[19],[20] Hyperglycemia during COVID-19 could be due to SARS-CoV-2 infection per se and steroid usage during treatment of COVID-19.[17] COVID-19 infection is a pro-inflammatory disease characterized by an excessive release of inflammatory molecules. A catecholamines, cytokines, and cortisol surge promotes glucagon production and gluconeogenesis, resulting in hyperglycemia.[21] This emphasizes tight monitoring of plasma glucose, even among nondiabetic COVID-19 patients. Our finding is consistent with published studies reporting a higher risk of mucormycosis among people with diabetes and more so after COVID-19.
In this study, we documented substantial steroid usage among all COVID-19 patients and more so among the never-hospitalized group indicating irrational and unmonitored use. Poor adherence to the guidelines on steroid use for COVID-19 has been reported widely in India.[22] Hyperglycemia is a known side effect of steroid intake.[23] Before COVID-19, steroid usage was not considered an independent risk factor for mucormycosis. However, studies on COVID-19-associated mucormycosis have reported steroids as an important predisposing factor.[24],[25] Mucormycosis among steroid users has been mediated through macrophages/neutrophil dysfunction or hyperglycemia.[26] The viral-induced lymphopenia and endothelitis add to the favorable environment produced by steroids, diabetes mellitus, and hyperglycemia, causing COVID-19-associated ROCM. Therefore, COVID-19 patients on steroid treatment must be monitored for their glycemic status and educated to recognize and report symptoms and signs of ROCM. Further, prescribing steroids for COVID-19 patients in home isolation or nonhospital care centers needs to be done rationally, along with stringent monitoring and control of plasma glucose levels.
In our study, there was a male preponderance of 38 (84.44%) which was consistent with other studies in the literature.[27],[28],[29]
The mean age group of patients with COVID-19 ROCM was 48.71 ± 10.71 years. Because COVID-19 afflicted comparatively more young persons during the second wave, there was a substantial percentage of younger patients and adults between the ages of 29 and 75.
The higher mean serum D-dimer, ferritin, and LDH levels were discovered to be significantly associated with concurrent COVID-19 with ROCM patients in our investigation and were also suggested by Godatti et al.[30] COVID-19-mediated tissue damage and inflammation might increase free iron levels in the serum and cause a concomitant increase in serum ferritin levels.[30] Since iron metabolism is vital for mucorale growth, the release of iron in patients following tissue damage from SARS-CoV-2 infection might be one of the major factors determining the establishment of mucorale infection suggested by Sharma et al.[31],[32] Patients with elevated levels of free iron (not bound to transferrin) are uniquely susceptible to Rhizopus oryzae and other Zygomycetes infections but not other pathogenic fungi, such as candida or aspergillosis.[33] However, the research on the interaction between the COVID-19 ROCM and inflammatory markers could not be located.
D-dimer, a protein fragment, is a fibrin degradation product in the blood after a blood clot is degraded by fibrinolysis. In the present study, the mean difference of D-dimer across the severity of ROCM has seen a statistically significant increasing trend. The rise in the D-dimer level has been attributed to endothelialitis, endothelial damage, and dysfunction of the hemostatic system leading to a hypercoagulable state induced by the virus.[28] In a study by Pal et al. of 10 patients and He et al., D-dimer was raised in all cases.[34],[35],[36]
In the current study, LDH has seen an increasing trend with the severity of ROCM. LDH is usually released from the cytosolic compartment of injured or dead cells, revealing a significantly elevated component in Mucorales infection.[37],[38]
The study by Bhadania et al. suggested that hyperferritinemia presents a systemic inflammatory process in COVID-19 but also indicates increased free iron, which thereby aids the growth and extent of involvement by the R. oryzae.[39]
Strengths and limitations
The strength of this study is that the data are representative of the entire district as it was conducted in a notified nodal center during the COVID-19 pandemic. The study is limited due to the cross-sectional nature of the data and sample size. A comparative study with non-COVID-19 ROCM and longitudinal data could have given a more realistic and causal direction to disease progression and the natural history of the disease.
| Conclusion | | |
This study shows that increased levels of various inflammatory indicators, including serum ferritin, LDH, D-dimer, total neutrophils, and lymphocytes, have been strongly related to the increased risks of developing rhino-ocular-cerebral mucormycosis and its progression. Considering the high morbidity and mortality, especially in a pandemic, tracking these markers may allow early identification, prediction of disease progression, and intervention.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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