Emerging Therapies in the Medical Management of Allergic Fungal Rhinosinusitis

Abstract

A non-invasive type of chronic sinusitis named allergic fungal rhinosinusitis (AFRS), which is a variant of allergic bronchopulmonary aspergillosis with nasal obstruction, was first described in 1976. The goal of this article was to provide an overview of various treatment approaches and how they can be used to control AFRS. Since this is an inflammatory disease rather than an invasive fungal infection, the treatment tries to modulate inflammation and reduce disease burden. A comprehensive treatment strategy must incorporate medicinal, surgical, biological, and immunological techniques. Owing to the chronic nature of allergic fungal rhinosinusitis and its high propensity for flare-ups and recurrence, multiple procedures are frequently required. The most likely method of establishing a long-term disease control for AFRS is a comprehensive management strategy that integrates medical, surgical, and immunological care. However, there are still disagreements regarding the exact combinations. In this review, we have mentioned different modalities in the management of AFRS, such as monoclonal antibodies, probiotic Manuka honey, and aPDT among others, some of which are promising but require further research.

Introduction

The term allergic fungal rhinosinusitis (AFRS), a non-invasive form of allergic bronchopulmonary aspergillosis with nasal obstruction, was first established in 1976 [1].

The earliest AFRS diagnosis criteria were published in 1994 by Bent and Kuhn [1]. It consists of five components: type I hypersensitivity, nasal polyposis, radiographic abnormalities, eosinophilic mucus that doesn't penetrate the sinus tissue, and aspiration of the sinus contents that produces a positive fungal stain [1] (Table 1).

Table 1.

Bent and Kuhn diagnostic criteria for AFRS

Major criteria	Minor criteria
Type I hypersensitivity	Asthma
Nasal polyposis	Unilateral disease
Characteristic CT findings	Bone erosion
Eosinophilic mucin without invasion	Fungal cultures
Positive fungal stain	Charcot-Leyden crystals Serum eosinophilia

Although there have been a variety of modifications suggested for these elements, they are still recognized for diagnosis [2]; a fungal culture may be positive if done properly in 96% of patients with chronic rhinosinusitis [3]. The paper also described how to separate the fungus from the mucus and allergic mucin.

According to Kuhn and Swain11, AFRS is challenging to identify and treat for rhinologists [4].

Endoscopic sinus surgery is always performed in conjunction with an extended course of medical therapy, which may involve a mix of oral and nasal steroids, immunotherapy, antifungal medication, and novel biological treatments, as will be discussed below [2].

IgE-mediated type I hypersensitivity reactions and type III responses to fungal antigens cause fungal rhinosinusitis in patients with atopic disorders [2].

The pathogenesis of AFRS is still not well understood. The development of AFRS may be influenced by a number of factors, according to Manning et al.

A fungal antigen is presented to an atopic host, acting as an antigen stimulation. This leads to a type I hypersensitivity reaction mediated by IgE and a tissue inflammatory type III reaction. This pattern is known as self-perpetuation [2].

AFRS is more frequently observed in regions with higher levels of humidity and among young individuals, with a mean age at presentation of approximately 22 years [5].

In addition to other structural risk factors such as septal deviation or turbinate hypertrophy, this edema causes sinus blockage. As a result, fungal antigens become trapped in the mucosa, creating favorable conditions for further antigenic exposure and fungal proliferation [2].

Additionally, it leads to the accumulation of allergic mucin [2]. AFRS is the only condition with unique histological features and radiological symptoms of allergic mucin [2].

Grossly allergic fungal mucin is described as having a peanut-butter appearance and is thick, persistent, and exceedingly vicious [2].

On CT scans, the paranasal sinuses show heterogeneous areas of signal intensity due to the build-up of allergic fungal mucin, although this observation is not unique to AFS [2] (Fig. 1).

Fig. 1.

CT sagittal view and endoscopic view showed the bony erosions area caused by allergic fungal rhinosinusitis

Due to the accumulation of calcium crystals and heavy metals (iron and manganese) in the inspissated mucin, areas of significant attenuation can be seen only on a CT scan [2].

The allergic mucin area on MRI appears as a signal void (hypointense) on T2 imaging [2].

The expansile nature of the accumulated mucin results in expansion, remodeling or thinning of the affected sinus walls, which also causes bone erosion visible on a CT scan [2] (Figs. 2, 3). Cytokines found in allergic mucin are believed to cause bone resorption.

Fig. 2.

Different areas of bony erosions showed in different CT views

Fig. 3.

Sagittal CT scan showing skull base erosion in the clivus caused by Allergic Fungal Rhinosinusitis

The disease typically presents subtly, with symptoms lasting months or years [2].

Nasal polyps, hyposmia or anosmia, the presence of allergic fungal mucin, and increased IgE to at least one fungal antigen are all common features of the classic presentation [5].

Particularly, in children, the disease may present with symptoms of orbital involvement and bone erosion. Other symptoms may include headache, feeling of pressure and fullness in the face, purulent nasal discharge, asthma, or hyperactive airway disease [2].

Patients who visit the tertiary rhinology centers frequently have a history of several surgical procedures, excellent oral corticosteroid (OCS) response, and poor oral antibiotic response. Unilateral or bilateral nasal polyps are often present in this patient group [2].

For treating physicians, the identification of this clinical illness continues to have diagnostic and therapeutic challenges. Once AFRS is identified as the cause, the patients are enrolled in a dedicated, long-term therapy program that is thought to be essential for effective care [2].

Another difficulty with AFRS is its reported incidence, which can eventually exceed 60% [2].

For bilateral versus unilateral AFRS and recurrence, we recorded the recurrence rate in bilateral AFRS patients treated at our hospital, even though the data from these cases were outside the scope of this study [6].

Herzallah et al. reported that the recurrence rate in unilateral cases of AFRS was significantly lower than that in bilateral cases (18.8 vs. 61.1%; P = 0.007) [7].

However, the final requirement for a second surgical intervention did not substantially differ between unilateral and bilateral AFRS cases (43.8 vs. 61.1%, respectively; P = 0.24) due to the contralateral progression of the disease in 31.3% of the unilateral AFRS cases [7].

The requirement for a second surgery was not statistically significant in bilateral cases; however, the development of AFRS on the contralateral side had an impact on the clinical result [7].

Within 29 months of ESS, 12.5% of the patients also experienced ipsilateral recurrence, and another 25% experienced contralateral AFRS (mean, 15 months). Additionally, one (6.25%) patient had both ipsilateral and contralateral AFRS [7].

Although the cause of the contralateral development of AFRS remains unknown, it could be a natural disease process [7].

Conceivably, intraoperative, or postoperative irrigation could theoretically transmit fungal antigens from the diseased side to the healthy side, causing the contralateral development of AFRS [7].

However, this event should notify the surgeon that the pre-operative counseling for patients should include consideration of contralateral AFRS, if it develops in the future. Additionally, both sinonasal passageways should receive postoperative follow-up [7].

The goal of this article was to provide an overview of various treatment approaches and how they can be used to control AFS.

Management

The treatment aims to regulate inflammation and reduce the disease burden, as this condition is an inflammatory disease rather than an invasive fungal infection [1] (Table 2).

Table 2.

The treatment of AFS requires both medical and surgical treatment

Surgical	Medical
Functional endoscopic sinus surgery	Topical corticosteroid
	Oral corticosteroid
	Oral anti fungal
	Manuka honey
	Immunotherapy
	Monoclonal antibodies
	Probiotics

An all-encompassing treatment plan must include medical, surgical, biological agents, and immunotherapy approaches.

Surgical Treatment

The goal of the surgical procedure was to open the sinuses’ natural ostia to facilitate wider access for topical treatments to reach the sinuses, through the removal of fungal debris and allergic mucus, preservation of the mucosa, postoperative follow-up evaluation, early disease recurrence identification, and suitable care [2].

Postoperative follow-up with dedication on the part of the patient and the surgeon. Several case series have shown extremely high recurrence rates, ranging from 35 to 75% [2].

Oral Corticosteroids

Bent and Kuhn observed that the recurrence was unavoidable in patients who had not received oral corticosteroids [8].

OCT inhibits both type I and III hypersensitivity reactions while exerting potent anti-inflammatory and immunomodulatory effects against the fungus causing the disease [2].

However, the most successful treatment is the one that manages the condition with the lowest dose in a short term. No prospective trials have evaluated the doses and treatment durations of OCS [2].

They discovered that the mucosal staging and treatment outcome would deteriorate if the oral steroid dose was tapered off too rapidly [9].

A mucosal staging system was proposed by Philpott-javer et al. and it included Grade 0 (no edema), Grade 1–3 (Mucosal edema (mild/moderate/severe)), Grade 4–6 (Polypoid edema (mild/moderate/severe)) and Grade 7–9 (Frank polyps (mild/moderate/severe)).

Postoperatively, while the patients were on OCS, Kuhn and Javer showed an improvement in the mucosal stage and IgE levels [10].

Their original treatment plan required terminating the OCS after four months to maintain the patients at endoscopic Grade 0 [10]. After a major recurrence during the 4-month treatment period, this time period was later increased to 6 months [10].

The role of OCS in avoiding early recurrence has been identified through prospective randomized controlled studies [10].

Systemic steroids should only be administered during the perioperative phase and only in brief bursts to suppress the recurrent illness because prolonged steroid therapy causes both acute and long-term toxicity [2].

Pre-operative therapy, particularly with oral corticosteroids, is frequently used in patients with AFRS [5].

Pre-operative oral corticosteroids in patients with AFRS have demonstrated a greater reduction in inflammation and radiological and endoscopic scores when compared to individuals with CRSwNP [5].

According to a meta-analysis of 1148 patients, preoperative oral corticosteroids also reduce intraoperative blood loss and improve the surgical field’s quality [11].

However, it must be highlighted that using these drugs before to surgery may impact biopsies or mucous samples by misrepresenting the disease process at the time of operation [5].

In a retrospective review of 15 patients, Kinsella et al. found that none of the patients who received oral steroids experienced any recurrence; those who required revision surgery, however, did not receive oral steroids in the postoperative period [12].

However, oral steroids should only be used in patients with severe SNOT 22 scores and lung deterioration during acute exacerbations in the postsurgical period. These medications are associated with several adverse effects [5].

To monitor adrenal (HPA) axis suppression, it is necessary to record how frequently the patient requires oral steroids [5].

All alternative treatments should be tried before turning to oral steroids, especially in patients with osteoporosis, diabetes mellitus, hypertension, peptic ulcer disease, cataracts, and glaucoma. These include frequent flushing, application of topical medication, and other medical therapies listed below [5].

Topical Corticosteroids

Topical steroids are typically used to treat AFRS. These are essential for managing AFRS of longer duration [1].

The advantages include minimal adverse effects and absorption. They are advised for CRS, both with and without nasal polyposis, and have level A proof [13].

Non-standard, off-label topical steroid therapy, such as high-volume budesonide sinonasal irrigation, may have the advantage of providing a higher volume and concentration of steroids to the sinonasal mucosa, depending on the mode of administration [13] (Fig. 4).

Fig. 4.

The Pulmicort saline irrigation brochure for the patients

They are essential for the long-term management of AFRS [2]. As they entail a greater dispersion of medication over the sinus mucosa through the expanded ostia during the surgical phase, they are anticipated to be most effective during that time [2].

It is essential to use nasal sprays accurately to increase their effectiveness [2].

Using a concentrated budesonide solution to deliver the necessary dose in the sinus cavities eliminates the problem of nasal sprays, delivering insufficient doses to the paranasal sinuses [2].

Due to its significant first-pass metabolism of systemically absorbed drugs (80–90%) and dose-related decrease in plasma cortisol levels, budesonide has fewer adverse effects [2].

On a microgram scale, budesonide has a decreased suppressive effect on the HPA axis than that of other corticosteroids [2] (Fig. 4).

Budesonide has been established in numerous studies as a safe drug with fewer unfavorable systemic side effects in treating inflammatory airway conditions [2].

Additionally, the only corticosteroid with a pregnancy Category B rating is budesonide (both in intranasal and inhaled formulations) [2].

In a randomized control trial comparing 1 mg nasal budesonide nebulization to topical nasal sprays (n = 15), individuals utilizing budesonide had no disease recurrence over a mean follow-up duration of 18.5 months, but 26.67% of patients in the second group did [14].

The safety of the use of budesonide in the nasal cavity was assessed in two studies [15, 16].

One study examined the effects of using budesonide for a brief period (up to 2 months) and showed no consequences of continued use. Another study examined the effects of budesonide treatment over an extended period (> 6 months), and 3% of these patients showed a frequency of asymptomatic adrenal suppression [15, 16].

Oral Antifungals

Oral antifungals may help lower the fungal burden in these patients, which would minimize the immune-mediated response, claim proponents of their use in the management of AFRS. They insisted that these patients responded hypersensitively to fungus-related antigens [5].

There is insufficient research on the use of oral antifungals for the treatment of AFRS [17, 18]. Two of the three studies in the literature used oral itraconazole, while one used oral terbinafine [19].

The conclusions from this research have provided conflicting perspectives; however, the results are constrained by the small sample sizes. Six patients were enrolled in one study, of which three were administered itraconazole and the other three were administered a placebo [19].

While there was a similar deterioration in the control group, the study arm’s CT scores and eosinophil levels decreased. Itraconazole-related skin rashes caused two patients to discontinue treatment; however, no liver impairment was noted in this research [19].

A group of 32 patients from Javer et al.’s trial was resistant to oral prednisone, steroids, and amphotericin B nasal sprays [5].

Itraconazole was administered orally to these individuals for 3 months. The endoscopic and subjective ratings did not improve significantly [5].

Compared to pre-treatment levels, there was an increase in the post-treatment IgE levels. They found that a small proportion of their research group (38%) responded favorably to itraconazole [18]. One patient had to discontinue therapy due to increased liver enzymes.

Kennedy et al. conducted a randomized control experiment comparing a group of 26 patients receiving high-dose oral terbinafine with a similar group receiving a placebo, and they observed no radiological or symptomatic improvement after 6 weeks.

According to these small number of published trials, oral antifungals could be used in some resistant cases as adjuvant therapy in addition to topical steroids, even if they do not appear to significantly improve the radiological or symptomatic scores [5].

A specific cohort of individuals responds significantly better than others, suggesting that further endotyping and cytokine profiling of these patients may assist in identifying the group of patients who respond to antifungal treatment [5].

The data are currently restricted to a few studies with modest sample sizes. Monitoring of negative effects, such as skin rashes, increased liver enzyme levels, and cardiac side effects, must be performed with caution [5].

Immunotherapy

Research on non-steroidal therapy options has been sparked by the damaging consequences of steroids [2].

Immunotherapy is believed to work by increasing the synthesis of IgG4-blocking antibodies, which inhibit IgE antigen reactions while decreasing the development of allergen-specific IgE. The opponents of immunotherapy contend that the treatment might set off an immune complex-mediated reaction and lead to disease progression or deterioration [5].

Numerous clinical trials have been published in the literature that demonstrate the long-term effectiveness of immunotherapy, including the significant research by Mabry et al. [20].

In that study, nine AFS patients with the Bipolaris antigen received immunotherapy; patients in the immunotherapy group experienced a reduction in the recurrence of polyp, nasal crusting, and allergic mucin with no side effects and no long-term recurrences [20].

A study by Folker et al. compared 11 patients receiving. The control group received immunotherapy for at least a year, while the study group experienced statistically significant improvements in endoscopic and chronic sinusitis survey scores [21].

Similar findings from other studies suggest that immunotherapy improves patient outcomes by reducing the need for revision surgeries and oral and nasal steroids [21, 22].

One study also showed that these individuals required fewer postoperative follow-up visits [23].

None of the trials indicated significant negative effects associated with the use of fungal antigen immunotherapy [5].

A study by Greenhaw et al. with 14 individuals is noteworthy because it showed that high-dose immunotherapy did not increase the likelihood of local or systemic responses [24].

The ability of immunotherapy to complement surgery and other forms of treatment is one of its drawbacks [24]. It might not work if there is a fungal antigen load that is not treated surgically, and in such a case, it might even worsen the condition [25].

Monoclonal Antibodies

Biological agents are an attractive and emerging group of adjuvant therapies for the management of chronic rhinosinusitis, particularly in the context of comorbidities such as asthma.

They are favored because of their special receptor-level action, which reduces the severe systemic side effects of corticosteroids.

They decrease the need for steroids and antifungals by slowing and reversing the inflammatory process. Numerous studies using different biological drugs have been conducted to treat chronic rhinosinusitis [5].

Omalizumab

Since 2003, the US Food and Drug Administration (FDA) has approved the use of Omalizumab in patients aged < 12 years with moderate-to-severe allergic asthma, which is not controlled by a combination of inhaled corticosteroids and long-acting bronchodilators [26]. It also downregulates the Fc receptors on other cells such as mast cells, dendritic cells, and basophils [27].

Javer et al. published a retrospective record analysis of seven patients with refractory AFRS and asthma who were observed for 2 years. These individuals demonstrated a 31% improvement in their SNOT 22 scores and a 61% improvement in endoscopic grading after receiving an average dose of 287 mg of omalizumab [28].

Omalizumab has limited evidence supporting its routine use in AFRS, and more research with longer follow-up periods is necessary before it can be prescribed [5].

It cannot be administered to those without this comorbidity because it is only approved for patients with uncontrolled allergic asthma [5].

Dupilumab

Type 2 inflammatory-mediated conditions such as asthma and atopic dermatitis respond well to dupilumab, a completely human monoclonal antibody targeting the interleukin 4 (IL-4) receptor subunit [29, 30]. Additionally, it has been shown to be clinically effective in CRSwNP [31].

The use of biologic agents to treat refractory AFRS has not been supported in many studies. Very few isolated cases of AFRS with dupilumab treatment have been described in the literature [32, 33].

The disease is characterized by a high level of IgE, IL-4, and IL-5 and is caused by a type 2 inflammation. Dupilumab is effective in inhibiting type 2 inflammatory mediators such as IL-4, IL-13, and IgE by blocking the IL-4 receptor component [34].

The mechanism of action of dupilumab offers a strong justification for assessing its potential effectiveness in patients with AFRS [34].

Dupilumab is an effective therapy for various type 2 inflammation-mediated diseases such as atopic dermatitis, asthma, and eosinophilic esophagitis, in addition to CRSwNP [34].

Bulkhi et al. considered dupilumab as an option for therapy because of the notable rise in IgE and eosinophils in patients with type 2 inflammation, in addition to the presence of asthma and unfavorable results of the lung function test [34].

With a 5-month follow-up period, Bulkhi et al. discovered that clinical ratings significantly improved following dupilumab injection. Additionally, their asthma symptoms improved and they required less oral prednisolone and asthma drugs [34].

When compared to those after placebo or topical steroids, the pulmonary function test response after dupilumab significantly improved, according to the research by Iqbal et al. [35].

According to FEV1 and FEV1/FVC findings from pulmonary function testing, Bulkhi et al. demonstrated a notable improvement [34].

The duration for which dupilumab should be administered for CRSwNP remains unknown. The LIBERTY NP SINUS-24 trial found that the impact of dupilumab decreased after withdrawal at 24 weeks; therefore, the medication must be continued to achieve a long-term disease control.

The approach of Bulkhi et al. is to continue taking dupilumab for a year before deciding whether to continue the therapy further [34].

Dupilumab-treated patients with CRSwNP reported fewer side effects such as headaches, nasopharyngitis, and adverse injection site responses [36].

According to the LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 findings, the placebo group showed more side effects [34].

According to Bulkhi et al. no side effects were documented during the treatment with the biological agent, and the patients responded well to the treatment [34].

The use of dupilumab in resistant CRSwNP is supported by the advisory committees and expert groups from the Gulf Cooperation Council (GCC) nations, provided there is evidence of type 2 inflammation (e.g., total IgE, 100 or serum eosinophils, 250), diminished quality of life (SNOT-22, 40), and, preferably, concurrent asthma [34].

The Saudi population (as part of the Gulf countries] that satisfied the criteria showed positive results for the use of dupilumab in AFRS, as a subset of CRSwNP, in the current case series, with no noteworthy side effects [34].

Future research examining the use of biologics in AFRS should be conducted on a wider scale [34].

Manuka Honey

Due to its antibacterial characteristics, Manuka honey, which is a black, monofloral honey with a high phenolic content, is becoming increasingly popular [1].

Manuka honey kills bacteria using three different methods. First, the honey's high glucose content is supposed to provide phagocytes the energy they need to fight off microbes [37, 38].

Second, the organisms are known to be killed directly by acidic pH, and third, Manuka honey was once believed to create a chemical substance called “inhibin”, which has been found to be hydrogen peroxide [37, 38].

According to several studies, Manuka honey (extracted from Leptospermum scoparium), which has a 100-fold higher concentration of the active ingredient methylglyoxal than regular honey, is the most effective [39].

Yabes et al. compared the antifungal effects of polyhexamethylene biguanide and Manuka honey (PHMB). They discovered that the exposure time, and not dose, corresponded to the antifungal activity of both the drugs [40]. They claimed that after six hours, Manuka honey stopped the growth of the fungus [40].

When compared with other types of honey, Irish et al. indicated that Jarrah honey was the most effective against Candida species [41].

However, there is limited clinical evidence supporting its usage in AFRS [41].

According to a study by Thamboo et al. the endoscopic scores and culture results from the ethmoid sinuses did not significantly improve after 30 days of Manuka honey consumption; however, the SNOT 22 scores did [42].

The implication is that Manuka honey, which requires a surgically opened sinus with a low fungal load to function as a topical therapy, would not be beneficial alone but might be utilized as an adjuvant therapy with other forms of treatment [5].

Microbiome

A greater understanding of the microbiome's involvement in human health and disease is revolutionizing our perception of chronic illnesses, which has significant consequences for doctors [43].

The significance of bacterial populations found on all body surfaces and cavities has become clearer over the past 10 years [43].

The dysbiosis of the microbiome has a role in the persistence of the disease [43]. Surprisingly, this has more to do with the dearth (loss) of the beneficial bacteria needed for maintaining health, as opposed to the development of several infections and associated toxins [43]. Recently, the importance of the microbiome in maintaining the health in ENT has been recognized [44, 45].

Sinus cavities and nasal passageways are excellent potential targets for probiotic treatments [46, 47]. As a result of their documentation of microbiome dysbiosis in chronic rhinosinusitis and nasal allergies, some authors have suggested a potential for microbiome manipulation in these disorders.

Probiotics are the center of attention for nowadays. Because oral probiotic treatment for allergies and CRS has only had uneven success, the focus has mostly been on topical intranasal delivery of probiotics directly to the nasal passages by a nasal spray or irrigation [48].

According to Lynch et al. Lactobacillus sakei treatment in mice decreased the overgrowth of the purported pathogen Corynebacterium Tuberculostereaticum [14]. Despite this, no human trials were carried out as a result of this study [49]. Prior research suggests that this method is secure.

Mrtensson [50] first administered a nasal spray containing 40 million (106) colony-forming units (CFU), signifying the number of bacteria, LAB isolated from the honeybee to healthy volunteers, and showed that there were no side effects from the treatment.

They administered the same dosage to patients with CRS without nasal polyps in a follow-up study [51]. There were no unfavorable side effects, and no positive therapeutic benefits were found.

Probiotics may benefit nasal disease, according to a clinical trial with the probiotic Lactococcus lactis W136 in individuals with chronic sinusitis who also had or didn't have nasal polyposis and were resistant to treatment despite prior sinus surgery [52].

In this research, carried out by our group, 24 patients got nasal and sinus irrigation followed by 1.2 billion CFU of L. lactis W136 self-applied directly to the nasal and sinus passageways. For 14 days, this was applied twice daily [43].

The therapy was well tolerated and had positive effects on the endoscopic scores, quality of life indicators, and symptom severity [43].

Enhancing the epithelium repair and regeneration, as well as controlling the inflammation, was indicated by the gene expression profiling to identify relevant pathways. Using 16 s of technology, the microbiome analysis revealed a decrease in the pathogens Staphylococcus aureus, Peptostreptococcus, and Enterobacteriaceae [43]. Differences in the bacteria utilized and the experimental methodology may explain the variation in outcomes between the two trials [43]. The Mrtensson study utilized a bacillus or rod-shaped bacterium, in contrast to the L lactis W136, which is a coccus or spherical bacterium. The cocci comprise most of the typical flora of the nose [43].

Furthermore, the dosage was 30 times lower than it was in the L. lactis W136 study, and it was given as a nasal spray rather than a nasal irrigation, which had a lower level of intranasal penetration and deposition. These factors likely made the experiment less successful [43].

Health Canada has approved the probiotic nasal and sinus rinse, based on the probiotic Lactococcus lactis W136, as a natural treatment for the relief of chronic sinusitis, nasal polyposis, nasal obstruction, and nasal allergies. It has been available in the USA and Canada for 15 months [43].

Antimicrobial Photodynamic Therapy (aPDT)

Immunotherapy with Photodynamic Therapy (aPDT): a single treatment session of this recent mode of non-antibiotic broad-spectrum antimicrobial therapy can eliminate 99.99% of in vitro organisms [53].

There are no publications specifically mentioning AFRS in humans, although one paper mentions the use of aPDT in rabbits after inoculation of the maxillary sinuses with Aspergillus fumigatus [5].

The SinuwaveTM antimicrobial photodynamic therapy was able to eradicate 99.99% of the recoverable fungus as compared to the control rabbits [54].

Even though early animal studies seem promising, a well-designed prospective randomized control trial is required to determine the function of aPDT in the treatment of AFRS.

In a recent retrospective data assessment of their aPDT experience, the authors identified 14 patients with AFRS who underwent aPDT. In nine of the 14 patients (64.2%), there was a significant improvement in the endoscopic scores (MLK) at 6 months [5].

Additionally, they stated that three of the 14 individuals experienced modest adverse events, such as stinging or light bleeding, and that these were only momentary and did not continue for more than three months. This information has not yet been made publicly available.

Intranasal Betadine Rinses

Betadine, a broad-spectrum antimicrobial agent, is effective against a wide range of bacteria, fungi, spores, protozoa, and amoebic cysts [55]. It also has anti-inflammatory properties in vitro that are induced by infections and host reactions [56].

Previous research has been done on the utility of betadine in clinical settings [57, 58].

In a study by Javer et al. individuals with refractory sinusitis who received rinses containing 0.08% povidone-iodine had their MLK and SNOT 22 scores evaluated before and after treatment [5].

They discovered a statistically significant improvement in both the measures. Additionally, the thyroid hormone levels were tracked and found to be within normal ranges in these patients [59].

A different study discovered that betadine rinses caused a 17% reduction in inflammatory mediators [60].

According to certain reports, betadine can have ciliotoxic effects on the nasal mucosa; however, the dosage required to disrupt the cilia is much higher than the concentration required to have an antibacterial effect [61].

There is currently no evidence supporting the efficacy of betadine in patients with AFRS; however, a larger study that includes these individuals could pave the way for its routine application in these patients.

Hydrogen Peroxide Rinses

Given that hydrogen peroxide is mostly composed of two elements; hydrogen and water, it is regarded as the safest natural sanitizer in the world.

It mostly works through oxidation when it comes in contact with organic material.

The creation of hydroxyl ions, which can harm the cell membrane walls, is the main cause of this phenomenon.

The antifungal capabilities of hydrogen peroxide at low levels have been demonstrated in numerous plant-based studies [62].

To eliminate the mucor and kill the supporting dead tissue on which the fungus thrives in humans, hydrogen peroxide has been examined as an adjunct to surgery in the sinuses for invasive fungal sinusitis [63].

There are other instances of the use of hydrogen peroxide to successfully suppress the production of catalase by Candida species [64].

However, there are currently no reports on its use in the treatment of AFRS.

Conclusion

Owing to the chronic nature of allergic fungal rhinosinusitis and its high propensity for flare-ups and recurrence, multiple procedures are frequently required. The most likely method of establishing a long-term disease control for AFRS is a comprehensive management strategy that integrates medical, surgical, and immunological care. However, there are still disagreements regarding the exact combinations. In this review, we have mentioned different modalities in the management of AFS, such as monoclonal antibodies, probiotic Manuka honey, and aPDT among others, some of which are promising but require further research.

Author Contributions

OAM conceived and designed the study, conducted research, provided research materials, collected and organized data, and analyzed and interpreted data. RFS wrote initial and final draft of article, and provided logistic support. All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not for-profit sectors.

Declarations

Conflict of interest

Authors have no conflict of interests and the work was not supported or funded by any drug company.

Ethical Statement

We appreciate the reviewer's insightful suggestion and agree that it would be useful. However, it is a review article so no need for ethical approval.