The use of Platelet rich Plasma in COVID-19 Induced Olfactory Dysfunction: Systematic Review

Abstract

Purpose: Different modalities of treatment have been suggested in the treatment for post COVID-19 olfactory dysfunction (OD). Starting with lifestyle modification, smoking cessation, for example, was shown to improve the symptoms for patients with OD. Intranasal and oral corticosteroids have been described in the literature for the treatment of OD. In this review, we are looking at a novel intervention using platelet-rich plasma injection into the nasal cleft for treatment of post COVID-19 infection olfactory dysfunction. Methods: A literature search was done using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 Guidelines, the databases of PMC, Medline, CINAHL, Wiley online library were searched from their year of inception until February 2023. Search terms were used and included a combination of the following keywords; “platelet-rich plasma”, “platelet rich plasma”, “PRP”, “Anosmia”, “olfactory dysfunction” and ”COVID”. Results: The four studies in this review included a total of 238 adult patients who presented with olfactory dysfunction. The studies were heterogenic in terms of follow up period which was not long enough through all the included studies. Additionally, different protocol of injecting was seen in different studies. Conclusion: Injecting PRP for treatment of COVID-19 induced olfactory dysfunction is a safe technique with what seems like promising initial results with low complication rate. However, there are not enough studies assessing its effectiveness compared to other treatment modalities. Further randomized controlled trials with shared protocol are needed to establish further understanding of its role in treatment of COVID-19 induced OD.

Introduction

Olfactory dysfunction (OD) is one of the most reported symptoms related to COVID-19 infection with more than 40% of patients being affected to different degrees, from decreased or distorted to complete loss of the function [1, 2]. This is believed to occur as a result of the damaging effect of COVID-19 on the olfactory neuroepithelium [3]. The natural course of post COVID-19 OD is for resolution of symptoms by day 9 with more than 95% of patients having their symptoms resolved in less than 4 weeks duration. However, some patients continue to suffer from OD for longer durations. [4] OD has shown devastating effects on the quality of life for affected individuals. In addition to the loss of life enjoyment, the patient will lack the ability to identify hazardous smells and toxic materials. [5] Almost 75% of the patients reported experiencing hazards due to their disease [6]. The effects of OD do not stop here, but it is associated with significant debilitating psychosocial effects including pathological mental health disorders [7].

Different modalities of treatment have been suggested in the treatment for post COVID-19 OD. Starting with lifestyle modification, smoking cessation, for example, was shown to improve the symptoms for patients with OD [8]. The main non-pharmacological, non-surgical treatment for OD consists of olfactory training as the first line of treatment. Furthermore, intranasal and oral corticosteroids have been described in the literature for the treatment of OD [9].

In this review, we are looking at a novel intervention using platelet-rich plasma injection into the nasal cleft for treatment of post COVID-19 infection olfactory dysfunction.

Methods

The protocol was registered with the international prospective register of systematic reviews PROSPERO, ID number CRD42023400048.

Search Strategy

A literature search was done using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 Guidelines, the databases of PMC, Medline, CINAHL, Wiley online library were searched from their year of inception until February 2023. Search terms were used and included a combination of the following keywords; “platelet-rich plasma”, “platelet rich plasma”, “PRP”, “Anosmia”, “olfactory dysfunction” and ”COVID”.

The inclusion criteria were studies which reported on the use of platelet rich plasma in the treatment of post covid-19 infection olfactory dysfunction. Studies that reported the use of PRP to treat anosmia not related to covid were not included.

Data were extracted using a predesigned proforma by two researchers (MA and MB), independently. Any discrepancies were resolved through discussion with a further researcher. Details extracted included demographics of participant groups (including - study design, time of study, number of participants, age/sex of participants), tests used, type of and technique of intervention, and results of intervention.

Risk of bias of Included Studies

Two authors (MA and MB) independently examined the risk of bias of included studies according to the Cochrane Risk of Bias instrument (version 2) for randomized controlled trials [10]. This instrument examines the following domains: randomisation process, deviation from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported result. The authors scored each domain of the instrument and the overall quality of the included studies as low risk, some concerns, or high risk. Disagreements were solved by discussion.

The risk of bias in non-randomized studies – of interventions (ROBINS-I) assessment tool was used for the one nonrandomized trial included in the study. ROBINS-I tool for follow-up studies was used to assess risk of bias in cohort observational studies.

Results

A total of 488 articles were identified from all databases. Duplicate articles were removed; the remaining were screened, and non-relevant articles were excluded by titles and abstracts. Four full articles were included in the quality analysis. (Table 1)

Table 1.

List of the included studies in this review

Author	Year	Journal	Sample Size
Y. Steffens et al.	2022	European Archives of OtoRhinoLaryngology	56
CH Yan et al.	2022	International Forum of Allergy & Rhinology	35
JR Lechien	2022	European Archives of OtoRhinoLaryngology	87
Abo El Naga H.A. et al.	2022	The Egyptian Journal of Otolaryngology	60

The four studies in this review included a total of 238 adult patients who presented with olfactory dysfunction. All patients included in the study had confirmed positive polymerase chain reaction (PCR) COVID tests. The follow up period ranged from 1 month to 3 months. Three studies included patients with symptoms lasting more than 6 months but did not mention an upper limit of duration of symptoms [11–13], and one study included patients who had their symptoms for more than 6 months but less than a year [14],

Two studies mentioned all the participants received olfactory training or topical corticosteroid treatment for at least 12 weeks prior to PRP treatment [12, 14]. One study showed heterogeneity between participants with more than half of them receiving olfactory training and less than half received local or nasal corticosteroid therapy [13]. One study did not mention if the patients received any kind of treatment for OD prior to PRP [11].

In two studies, patients received a single PRP injection into their nasal cleft [11, 13], in the remaining studies the patients received 3 PRP injections on different visits [12, 14].

There was a degree of heterogenicity in the injection technique between different studies, Yan et al. [14] used two separate 1- mL sterile syringes and injected the PRP submucosally at two sites within the olfactory cleft along the superior septum, posterior to the head of the middle turbinate, without mentioning the use of local anaesthetic prior to the procedure, even though in their previous study on the use of PRP in OD they have described the use of local anaesthetic and endoscopic visualization [15]. Steffens et al. [14] followed the protocol described by Yan et al. [15]. Using a 0 degree scope and after applying local anaesthetic, Lechien et al. [13] injected several points of 0.2–0.5 mL were in the middle turbinate and in the nasal septum in regard of the head of the middle turbinate, the same was done to the contralateral nasal fossa. With the aid of a nasal endoscope Abo El Naga et al. [12], injected PRP into the olfactory region approximately every 1 cm2 using a 1-ml syringe and 30-G needle.

Generally, across all studies there were very limited side effects reported of PRP treatment. Three studies reported no adverse effects [11, 12, 14] whilst one reported transient acute epistaxis, parosmia secondary to the local anaesthetic spray and postnasal drip sensation as the main complications [13].

Although olfaction is a relatively subjective measure between individuals, there are several recognised methods that can be used to quantify this. The Sniffin Sticks test is a widely used and validated objective test that measures olfactory dysfunction and quantifies this on a threshold discrimination and identification (TDI) score [16]. This test was used in three of the four studies included in our report [11, 13, 14]. Steffens et al. [11] combined this with a subjective self-assessment Likert Scale score between 0 and 3 to assess for improvement in smell function. Yan et al. [14] combined the objective Sniffing Sticks test with a subjective olfaction assessment via a 0 to 10 point visual analogue scale (VAS). One study reported the outcomes using a 10 points VAS only [12]. Table 2 shows a summary of included studies.

Table 2.

Summary of the included studies

Author	Follow up period	Previous Treatment received	No. of PRP injections	Measure of symptoms	Case Group (PRP)	Control Group	P Value
Y. Steffens et al.	1 month	Not mentioned	1	TDI Likert	TDI: 6.7 point improvement Likert: 1.8 point improvement	TDI: 0.5 improvement Likert: 0.3 improvement	Difference in Likert p < 0.001 TDI case group p < 0.001
CH Yan et al.	3 months	Olfactory training and local treatment for 3 months	3	TDI VAS	TDI: 6.25 point improvement VAS: 3.63 point improvement	TDI: 2.58 improvement VAS: 2.45 improvement	Difference in TDI p = 0.047 Difference in VAS p = 0.167
JR Lechien	2 months	67% had olfactory training for 3 months, while 45% and 42% local or oral treatment.	1	TDI ODQ	TDI: 5.7 point improvement ODQ: 10.3 point improvement	N/A	TDI 0.009 ODQ 0.001
Abo El Naga H.A. et al.	1 month	Olfactory training and local and/or oral treatment for 3 months	3	VAS	VAS: 5.8 point improvement	VAS: 1.84 point improvement	Difference in VAS p = 0.002

Three of the studies showed low concerns when assessed for risk of bias [11, 12, 14], while Lechien et al. [13] showed some concern during the assessment of risk of bias mainly due to the high number of patients lost to follow up.

Discussion

Due to the novelty of Platelet-Rich Plasma (PRP) and its more recent discovery, few studies have been conducted on its efficacy in human subjects. PRP has been found to be effective in several case-control studies in addition to several non-controlled clinical trials. In addition to its use in treating chronic skin and soft tissue ulcerations, platelet-rich plasma use has also been reported in periodontal and oral surgery, maxillofacial surgery, orthopaedic and trauma surgery and cosmetic and plastic surgery. PRP proved to be effective in controlling pain in temporomandibular joint osteoarthritis, rotator cuff tears, tendonitis, and low back pain, with significant differences in both the long and short term [17–20].

PRP demonstrated promise in peripheral nerve regeneration through stimulation of vascular and axonal regeneration via growth factors and by regulation of inflammatory response in the microenvironment. The growth factors released by platelets include vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF) β-1, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF)-I, basic fibroblast growth factor (bFGF) and connective tissue growth factor (CTGF), which contribute significantly to tissue proliferation. A key characteristic of these platelets is that they can release cytokines, chemokines and chemokine receptors and, thus, contribute to the regulation of inflammatory responses and immunological aspects of tissue healing. including prevention of excessive leukocyte recruitment by anti-inflammatory cytokines [20, 21].

This systematic review evaluated studies reporting the effect of PRP on the CVOID-19 related olfactory dysfunction in a total of 238 patients with the studies prospectively evaluating the outcomes. All included articles reported the potential role of PRP in the treatment of olfactory dysfunction.

Steffens et al. [11] reported statistically significant improvement in the study group when compared to the control group where TDI increased by 6.7 (p < 0.001). Abo El Naga et al. [12] found a significant improvement in both case group and the control group in their VAS score, however, the degree of improvement in the case group was significantly higher than the control group. Lechien et al. [13] found their mean TDI scores significantly improved from baseline to 2-month post-injection (p < 0.01). Yan et al. [14] noted significant improvement in the PRP group when compared to the placebo group at 1 month and 3 months follow ups, however, there was no statistical difference in over- all subjective improvement between the PRP and placebo arms. While the duration of OD often predicts poorer prognosis, Steffens et al. [11] found no significant difference in patients with OD for less than 12 months when compared to those with loss of function for more than 12 months. The use of PRP in treating non-COVID related OD, was reported by Yan et al. [15], in a previous study, which showed possible efficacy of the intervention.

The studies were heterogenic in terms of follow up period which was not long enough through all the included studies. Additionally, different protocol of injecting was seen in different studies.

Conclusion

Injecting PRP for treatment of COVID-19 induced olfactory dysfunction is a safe technique with what seems like promising initial results with low complication rate. However, there are not enough studies assessing its effectiveness compared to other treatment modalities. Further randomized controlled trials with shared protocol are needed to establish further understanding of its role in treatment of COVID-19 induced OD.

Limitations

The limitations of the studies used in this systematic review included the heterogeneity of the evaluation outcome assessment methods, as well as the use of non- validated scoring systems by some.

Funding

No funding was received for this article.

Declarations

Compliance with Ethical Standards

The study is compliant with the ethical standard as advised by the journal.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

Ethical Approval was deemed unnecessary due to the nature of the study.

Informed Consent in the manuscript

The involved study in this review obtained consent from the research cohort, no patients identifiers are used in the involved studies.