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Background: Surge in invasive fungal rhino-sinusitis during COVID-19 pandemic imposed as life-threatening complication. Even after overcoming pandemic, there is definite rise in cases compared to pre-pandemic incidence. Emergence of newer variants will only make conditions worse as population is already heavily burdened with exposure to previous variants, COVID-19 vaccines, injudicious steroids, anti-fungal and antibiotics usage, uncontrolled diabetes, hypertension. Methodology: Case series on 8 microbiologically confirmed cases of invasive fungal rhino-sinusitis amongst 25 clinically suspected who attended ENT OPD or were admitted in inpatient department for span of six months, i.e. from October 2023 to March 2024. We aim to identify risk factors for sudden surge, microorganism prevalence pattern and associated co-infection patterns. Results: 3 males and 5 females of age group 20 - 70 years old were studied. 7 had uncontrolled diabetes with average Hba1c level of 11. All were completely vaccinated for COVID-19 and 4 were previously COVID infected. Mucor group found to be predominant, followed by Aspergillus affecting primarily inferior turbinate, majorly maxillary and ethmoid sinuses. Disease extension for all were rhino-orbital with lateral rectus palsy and few with co-infection of Acinetobacter species. Conclusions: A significant surge in cases from pre-pandemic incidence of 14% to currently 32%. Major risk factor included uncontrolled diabetes, previous history of COVID infection and steroid usage. Vaccination against COVID didn’t seem to play protective role, however data is too less to make adequate conclusion. The disease is of utmost importance due to increased burden of mortality, hence timely diagnosis, surgical and medical management is crucial.
Acute invasive fungal rhino sinusitis, earlier infrequent, however during and post COVID – 19 pandemic, has seen a sudden surge in its occurrence. [1, 10, 11, 13, 14] It is associated with high morbidity and mortality due to its direct invasive nature and capability to spread rapidly to bones, blood vessels and nerves, if not diagnosed early and treated effectively. [1, 3, 12, 15]. As we step into the world of medical advancements, we also notice the rise in comorbid conditions, immunocompromised status in the population, changing microbiome, making the disease more penetrative and also a cause of concern. [1, 11, 13, 15]. It may also be noted that post COVID – 19 pandemic, the awareness regarding the disease amidst the medical fraternity, health care system and also amongst general population has increased. [2, 15] However, having stated that, it also quite manageable and carries good prognosis with timely and successful intervention, making it crucial. [1, 15]. The most common causative agents of acute invasive fungal rhino sinusitis includes organisms like Mucor spp., Aspergillus spp., and Rhizopus spp. with a typical hypha - type morphology and saprophytic existence. [10, 14, 15]. We witnessed a sudden surge in incidence of cases in comparison to pre pandemic state even after overcoming COVID – 19 for quite some time now. Hence we aimed to identify risk factors for this sudden surge, causative microorganism prevalence pattern and associated co-infection patterns with a thorough comparative analysis of actual situation between pre pandemic, during pandemic and post pandemic timeline.
This is a prospective case series, conducted in Dr. Shankarrao Chavhan Government Medical College and Hospital, Nanded, Maharashtra, India. The study was conducted for the period of six months, i.e. from October 2023 to March 2024. This case series includes samples of all clinically suspected cases who attended ENT OPD or were admitted in ENT in patient department in our hospital. A total of 25 samples were received, out of which 8 were KOH positive and culture positive and the remaining 17 were KOH negative. Informed consent was taken from patients for all samples processed. Approval of institution ethics committee was obtained.
Prior to processing of all samples, detailed clinical history, with special emphasis on comorbidities, previous COVID – 19 infection status and use of steroids for treatment, previous treatment with iron therapy, current signs and symptoms, ongoing treatment modality was recorded All available previous and current laboratory and radiological findings were taken into consideration for proper and adequate clinical correlation and precise reporting purpose. Patient outcome was also recorded.
Patients were categorized by age groups, gender, occupational risk groups, comorbidities to analyze predisposition pattern. Patients presented with long standing, persistent nasal discharge, distorted sense of smell, nasal obstruction, facial pain, headache, periorbital swelling, distorted vision and numbness in the affected areas along with blackish discoloration. Diagnostic nasal endoscopy was done for all to identify associated sinus and turbinate involvement. Disease extension for all the cases were rhino – orbital with complications including orbital cellulitis and orbital nerve palsy.
Nasal crust / tissue of suspected patient was studied which either was sent pre-operatively obtained during diagnostic nasal endoscopy or collected during surgical procedure and sent post-operatively. These were initially subjected to KOH mount study and checked for presence of fungal hyphae, its septation, size, branching, etc. This was followed by two set culture on Saboraud’s Dextrose Agar to achieve adequate growth of the fungi for further study. The cultures were incubated for 21 days at 25o and 37o Celsius respectively which was later then taken up for further study. However, in all our cases, the growth was achieved within 72 hours. The growth was studied by doing a tease mount preparation with Lacto phenol cotton blue stain for identification of the fungi. Mucor was identified with its typical presentation of broad hyphae, aseptate in nature, non-dichotomous branching, sometimes at right angles. However, Aspergillus was noted to be septate hyphae, dichotomous branching at acute angles, tendency to grow in radial pattern, hyphae nearly parallel to one another with a conidiophore. Rhizopus showed presence of rhizoids and its typical arrangement of sporangium and sporangiophores arising from stolons opposite rhizoids. All findings were reported and recorded for further analysis. All cases required surgical intervention followed by antifungal therapy. Amphotericin B was the mainstay of treatment post-surgery. The outcome was monitored and showed improvement in health condition of patients and alleviation of their symptoms.
A total of 25 samples were received by us for examination. Out of which, 8 were KOH positive and subsequently culture positive and the remaining 17 were KOH negative. Male: female preponderance was 1:1.7, i.e. 3 males and 5 females. The average age group was 51 years, with maximum cases ranging between 40 – 55 years with only a single case at the age group of 20 – 30 years.
7 out of 8 patients suffered from prolonged diabetes with a minimum duration of 10 years. The blood sugar levels ranged between 250 – 400 mg/dl. Diabetes as risk factor was found to be 87.5% with an average Hba1c level of 10.5. Patients with hypertension as comorbidity was 62% (however existing in conjunction with Diabetes and not individually). A single case of hyperthyroidism comorbidity was noted wherein the patient was on azathioprine and carbimazole. No cases of IHD, hypothyroidism, Hepatitis, CKD found. 3 out of 8 patients were anemic with hemoglobin levels ranging between 7.5 – 9.6 mg/dl and underwent treatment in private set up with iron therapy, i.e. 37.5%. Occupational hazard was found to be 50%, wherein 3 males and 1 female, were farmers and laborers. 50% of the patients were previously affected with COVID -19 and were subjected to corticosteroids at that time as a part of their treatment regime which is well established by a similar study conducted on cases of invasive fungal rhino sinusitis during the time of pandemic at our hospital. However, no active history of steroid use noted as such comorbidities not present in population. All our affected patients had completed full course of COVID vaccine, hence 100% affect rate.
Based upon the diagnostic nasal endoscopy and radiological findings, maxillary sinus most commonly involved (38%), followed by ethmoid sinus (25%). Frontal sinus was not individually affected, however was involved in combination with maxillary and ethmoid sinus in 2 cases. Most common turbinate involvement was noted to be inferior turbinate, followed by middle and superior turbinate respectively.
100% cases were managed with surgical debridement followed by Amphotericin B therapy. 75% of the cases required on Functional Endoscopic Sinus Surgery (FESS), however, the remaining 25% required FESS along with maxillectomy. Most common complication was noted to be orbital cellulitis and orbital cranial nerve palsies, specifically the lateral rectus palsies.
All the 8 KOH positive samples were culture positive, i.e. 100%. Amongst the SDA growth and post study of LPCB tease mount microscopy, it was found that Mucor spp. was predominant (50%), followed by Aspergillus spp. (37.5%) and a single case of Rhizopus.
We also did a simultaneously bacterial aerobic culture of the same samples and a co - infection predominance pattern of Acinetobacter baumanii was noted, i.e. 5 out of 8 cases (62.5%). All patients had recovered well with no mortality records.
Ace invasive fungal rhinosinusitis is a serious and time ticking condition associated with high mortality and morbidity [1, 10, 13, 14, 15] Over the last few years, the understanding of fungal rhinosinsusitis has exponentially improved and we are able to detect and diagnose cases quickly and efficiently. A similar study on invasive fungal rhinosinusitis by Samale et al [1] was undertaken in our hospital during COVID – 19 pandemic, i.e. March 2021 to May 2021, which will be taken up for comparative purpose of results between findings during pandemic and post pandemic for apt understanding. The most prevalent age group found in our study was between 40 – 55 years with an average age of 51 years. This is in line with study done by Samale et al done during pandemic wherein highest prevalence was noted in age group of 41 – 70 years [1] and also pre pandemic studies like Suresh et al and Cho et al, wherein it was noted to be in range of 31 – 50 years. [2,4] The male : female ratio in our study was noted to be 1:1.7 which is in contradiction to all other studies done prior to this. Samale et al reported this ratio to be 2.8:1 [1], while other studies like Maruf et al and Turner et al indicated it to be 1.4:1 [3,16]. The prevalence of fungal rhinosinusitis cases in our study was found to be 32% which is concordant to study done by Suresh et al stating 30% prevalence. [2]
Most common causative organism found in our study was Mucor spp., which was 50% of total samples received of suspected patients. Samale et all reported the most common organism to be Aspergillus spp. [1] Our findings were concordant with pandemic studies like Suresh et al, Lahane et al, El- Kholy et al, Singh et al. [2, 7, 8, 13]. Aspergillus spp. was found to be second largest contributor with 37.5%. Suresh et al and Singh et el reported similar finding with 43.3% [2, 13]. However, Samale et al reported Aspergillus spp. as most common causative microorganism i.e. 27%. [1]. Most commonly involved sinus in acute fungal rhinosinusitis was noted to be maxillary sinus (38%), followed by ethmoid sinus (25%) in our study. Samale et al reported maxillary sinus involvement as majority i.e. 97.7%, followed by ethmoid sinus (73.3%). [1] Study by Suresh et al and Maruf et al reported maxillary sinus involvement highest (46.6%) and ethmoid sinus involvement being second highest i.e. 40%. [2, 3] In our study, frontal sinus was not individually involved, however a mixed involvement with maxillary or ethmnoid sinus in 2 cases were reported. Frontal sinus involvement was noted to be least involved in both Samale et al and Suresh et al. [2, 3]
Our study could also identify in regards to occupational hazard of our patients involved. 50% of the study population were farmers, i.e. 3 males and 1 female affected. Suresh et al reported occupational hazard for development of the disease to be 52.3%. [2]
100% cases were managed with surgical debridement followed by Amphotericin B therapy. In Samale et al, only 77% required surgical intervention and the remaining 23% were solely managed on Amphotericin B therapy. [1]. A combination of surgical debridement and antifungal therapy was administered according to studies done by Ferguson et al, Gillespie et al, Suresh et al, Sharma et al, Singh et al. [2, 5, 6, 13, 17]. Most common complication noted in our study was orbital cellulitis with orbital cranial nerve palsy, especially lateral rectus palsy. 74% cases in Samale et al reported orbital extension of the infection [1], which was concordant with Cho et al [4].
87.5% of the study population had diabetes and 62% had hypertension, making diabetes as the most commonly involved risk factor.78% of the study population in Samale et al suffered from diabetes mellitus [1]. Diabetes was the major risk factor is various other studies like Cho et al, John et al, Sharma et al, Singh et al, Deutsch PG et al, Ebied et al with risk factor involvement from 50 – 95% of the study population [4, 9, 10, 13, 14, 15]. We had only 1 case with hyperthyroidism as a comorbidity. The patient was under treatment with azathioprine and carbimazole. No comorbid conditions like ischemic heart disease, hypothyroidism, hepatitis and chronic kidney disease were noted. However such comorbid conditions did exist in study population of Samale et al and Suresh et al [1, 2].
During COVID study of our hospital by Samale et al reported 87% of the study population being treated with corticosteroids. [1] 50% of or study population was previously affected with COVID – 19, hence chances of previous corticosteroid use in the very same population is present. However, we could not document it as no records available with patient. No active history of steroid use noted as such comorbidities not present in our study population. In Suresh et al, 10% of the study population were using long term steroid therapy for conditions such as glomerulonephritis and rheumatoid arthritis [2]. John et al reported 88% of their study population received corticosteroid therapy as a part of COVID 19 treatment [9]. Another study by Sharma et al, reporting 100% of their study population received steroid therapy during the pandemic [17].
50% of the patients were previously affected with COVID -19 in our study. Samale et al reported 100% COVID – 19 in their study population with 19 – 48% as concomitant cases and 52% as post COVID sequelae [1]. Singh et al reported it to be 59.4% [13], while Ismaiel et al reported it to be 62.1% [18]. In our study. 100% of the study population had completed their full course of COVID -19 vaccination. In Samale et al, 93% of the population was unvaccinated, 0.01% - fully vaccinated, 0.04% - partially vaccinated [1].
We noted Acinetobacter baumani coinfection in 62.5% of our cases. It could be hospital acquired due to patient’s prone nature in view of diabetes and provoking presence of fungal infection. Zeitler et al and Cha et al reported coinfection patterns with Klebsiella pneumonia, Staphylococcus spp, Pseudomonas aeroginosa respectively [11, 12]ut
A short summary of the results with comparative study is as below:
|
|
Findings in our current study |
Findings in study conducted in our college during COVID 19 (Samale et al) [1] |
Findings in previous study |
|
1. |
Average age group: 51 years, with maximum cases ranging between 40 – 55 years |
Highest prevalence: 41 – 70 years |
Highest prevalence in 31 – 50 years. (Suresh et al [2], Cho et al [4], Tuner et al[16]) |
|
2. |
Male : Female cases – 1:1.7 |
2.8 : 1 |
1.4 : 1 (Maruf et al [3], Turner et al [15]) |
|
3. |
Prevalence of rhinosinusitis - 32% |
No data available |
Prevalence : 30% (Suresh et al [2]) |
|
4. |
Most common causative organism – Mucor spp. (50%) |
Most common – Aspergillus group of fungi (46%). |
Mucor spp cases: 52% (Suresh et al [2], Lahane et al [8], El- Kholy et al [7], Singh et al [13]) |
|
5. |
Aspergillus was 2nd most common after Mucor spp. - 37.5% |
Mucor spp. – 27%. |
Aspergillus spp. - 43.3% (Suresh et al [2], Singh et al [13]) |
|
6. |
Maxillary sinus most commonly involved (38%), followed by ethmoid sinus (25%). |
Most common – Maxillary sinus (97.7%), followed by ethmoid sinus (73.3%) |
Maxillary sinus involvement – 46.6%, ethmoid sinus – 40%. (Suresh et al [2], Maruf et al [3]) |
|
7. |
Frontal sinus was not individually affected, however was involved in combination with maxillary and ethmoid sinus in 2 cases. |
Least involved – frontal sinus (70%) |
Frontal sinus was least involved (1%). (Suresh et al [2]) |
|
8. |
Occupational hazard – 50% 3 Males and 1 female, were farmers and labourers. |
No data available |
Occupational hazard – 52.3% (Suresh et al [2]) |
|
9. |
Management: 100% cases were managed with surgical debridement followed by Amphotericin B therapy |
77% - surgical debridement, 23% - cured with only Amphotericin B. |
Combination of surgical debridement and antifungal therapy (Ferguson et al [5], Gillespie et al [6], Suresh et al [2], Sharma et al [17], Singh et al [13]) |
|
10. |
Most common complication – orbital cellulitis and orbital cranial nerve palsies. |
74% cases with orbital .;extension of infection. |
Similar to previous studies (Cho et al [4]) |
|
11. |
Diabetes as risk factor – 87.5%. Hypertension – 62% (however existing in conjuction with Diabetes and not individually). Hyperthyroidism: only 1 case. Patient on azathioprine and carbimazole No cases of IHD, hypothyroidism, Hepatitis, CKD found. |
Diabetes – 78%. Involved cases of hypertension, hypothyroidism, IHD, Hepatitis, CKD |
Diabetes – 93% (Cho et al [4], John et al [9], Sharma et al [17], Singh et al [13], Deutsch PG et al [14], Ebied et al [10]) Involved cases of hypothyroidism, IHD, Hepatitis, CKD, rheumatic arthritis (Suresh et al [2]) |
|
12. |
History of corticosteroid use – As 50% population was affected with COVID previously, chances of previous use present, however no documents available as records. No active history of steroid use noted as such comorbidities not present in population |
87% - corticosteroids used against COVID 19 treatment. |
10% - long-term steroid therapy for conditions such as glomerulonephritis and rheumatoid arthritis. (Suresh et al [2]) 88% - cases had patients who received corticosteroid therapy for COVID 19 (John et al) and 100% cases (Sharma et al [17]) |
|
13. |
Cases post COVID – 19 or with past history of COVID – 19 infection: 50% |
100% cases affected with COVID 19 – 48% concomitant, 52% - post COVID sequelae |
Singh et al reported 59.4% [13], Ismaiel et al reported 62.1% [18] |
|
14. |
100% patient with completed dosing of COVID vaccine affected |
93% unvaccinated, 0.01% - fully vaccinated, 0.04% - partially vaccinated |
No study available for the purpose of comparision. |
|
15. |
Bacterial co-infection – Acinetobacter baumanii (62.5%) Could be hospital acquired due to patient’s prone nature in view of diabetes and provoking presence of fungal infection. |
No data available |
Bacterial co-infection noted, however it was Klebsiella pneumonia, Staphylococcus spp, Pseudomonas aeroginosa (Zeitler et al [12, Cha et al [11]) |
The selected cases of rhino sinusitis were at a single center. Incorporation of multicenter study modality would have further increase the sample size as well as geographical distribution. Our study population, primarily comprised of uncontrolled diabetic patients, hence growth of Zygomycetes family could have been more. Incidence of the 17 culture / KOH negative, however clinically suspected cases could have been due to fungal hyphae entrapment in mucin which prevent contact and growth in culture media along with inappropriate tissue sampling, as sometimes nasal secretions and swabs were sent. As sample size was small and due to lack of evidence relating to role of COVID vaccines, we are unable to comment on any role of it in invasive fungal rhino sinusitis. However, as per our study, we didn’t find any protective role, as all our patients were completely vaccinated. In spite of having patients who were anemic and had received iron therapy in recent past, we actually could not conclude whether iron overload was present or not since treatment taken was in rural set up with no prescription available with patients, hence cannot be commented upon. Due to timeline and geographical constraint, we could not assess effect of corticosteroids use as no associated comorbidity was found in our patients.
Invasive fungal rhino sinusitis cases have surged significantly in comparison to the pre COVID-19 pandemic timeline. We could identify numerous causes for this increased prevalence in the population. Sedentary lifestyle of the population leads to development of metabolic syndrome. More and more of the population is nowadays are suffering from diabetes mellitus, obesity and hypertension. In spite of the increased incidence of the comorbid conditions, there is indeed a casual attitude of patients towards diabetes and hypertension, leading to uncontrolled parameters. As the population is on the rise and education and job opportunities not being in par, low socioeconomic status seems to be quite well established in many areas which leads to poor hygiene, living conditions, poor nutritional conditions, lack of visiting doctors early and taking adequate treatment. Injudicious use of steroids during COVID – 19 pandemic has definitely left an after effect amidst the population. Antifungals and antibiotics are also injudiciously used and this has increased the overall microbial resistance patterns in the environment. Malnutrition is quite prevalent which is leading to anemia in our population. Many a times, non-cautious iron correction is done which is another risk factor for the sudden surge in cases. Previous COVID-19 infection amongst the population, definitely has an impact and are more to be affected with invasive fungal rhino sinusitis. Also we are observing an iceberg phenomenon as post COVID - 19, due to increased awareness regarding the disease, isolation of cases increased. It can be concluded that all comorbid conditions, like diabetes, hypertension, obesity, etc. needs to be detected at the earliest and regularly and stringently managed. Awareness regarding the comorbid diseases amongst general population is the need of the hour, especially in the rural segment for us keep a check on fungal rhino sinusitis. Steroids, antifungals and antibiotics usage should be limited and done under proper monitoring and surveillance. Only then, we can reduce the incidence of this life-threatening disease.
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