Management of hair loss after severe acute respiratory syndrome coronavirus 2 infection: Insight into the pathophysiology with implication for better management

Abstract Coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was declared a pandemic by the World Health Organization, and COVID‐19 continues to have a major impact on society. Numerous studies have reported impaired health sequelae after COVID‐19 recovery, one of which is hair loss. Individuals with hair loss experience a substantial mental burden, which potentially hinders their social life. However, few studies have systematically analyzed the details including hair loss. Therefore, we conducted a narrative review using PubMed on the frequency, associated comorbidities, disease characteristics, and treatment of hair loss after SARS‐CoV‐2 infection (HLASCI). Two search strings were used to identify 28 articles. Of note, most of the literature identified on COVID‐19 sequelae reported an emergence/occurrence of hair loss. HLASCI is speculated to be composed of a heterogeneous population, with the onset or exacerbation of telogen effluvium (TE), anagen effluvium, androgenetic alopecia (AGA), and alopecia areata (AA) reported as possible underlying mechanisms. Among these, acute TE is thought to be the primary cause of HLASCI, with COVID‐19 treatment and TE improvement being considered crucial for HLASCI management. An association between COVID‐19 and AA exacerbation has also been implicated with still insufficient evidence. Spontaneous recovery of TE can be expected once infection reduces; however, faster improvement in symptoms is expected to reduce the mental and social burden of patients. An additional search string identified 11 articles about TE treatment which suggested that the use of minoxidil may be beneficial. Topical minoxidil has been widely used for AGA patients, who have been speculated to exhibit poor resistance to SARS‐CoV‐2. Topical minoxidil may provide relief from HLASCI, but future clinical research is warranted to confirm this observation.


| INTRODUC TI ON
A meta-analysis of COVID-19-infected patients showed that 80% of patients developed one or more long-term non-respiratory symptoms with sequelae lasting weeks to months after resolution of the primary symptoms. 1 This condition has been referred to as "Long COVID-19," with patients with this condition being called "Long Haulers." 1 Of note, one study reported hair loss as a sequela in 25% of patients. 1 The reported frequency of hair loss as a sequela in other studies varies from 6% to 28.6%. [1][2][3] Pre-existing alopecia has been reported to be a risk factor for COVID-19. Worsening of autoimmune alopecia such as alopecia areata (AA) as a complication of COVID-19 has also been reported. [4][5][6] Although hair loss after SARS-CoV-2 infection (HLASCI) has attracted global interest as a sequela of COVID-19, its etiopathogenesis and pathophysiology have not been investigated in depth.
Therefore, we conducted a narrative literature review to clarify the characteristics of HLASCI, especially focusing on its pathomechanism, and propose a probable therapeutic option.

| ME THODS
Articles published between January 2020 and September 2021, when the COVID-19 pandemic started, in the PubMed database were included.
We used three search strings (1, 2, and 3) to identify studies reporting the disease state of hair loss with COVID-19 and possible therapies. Telogen effluvium (TE) is a common cause of hair loss, which has been related to severe infection, 7 and the aforementioned literature search suggested that HLASCI mainly comprised acute TE. Next, the relationship between acute TE and therapy was examined by search formulae 2 and 3. To maximize the range of detection, the words, "telogen" and "effluvium," were separately adopted in Search string 2, while, in Search string 3, "telogen effluvium" was adopted as a single term to minimize the noise in the identification of treatments specific to the condition. From the viewpoint of the content and quality of articles, the search formula and inclusion/exclusion criteria for the articles to be reviewed were determined as follows:

| [Inclusion and exclusion criteria]
Systematic reviews, literature reviews, case series reports, original articles, clinical trials, and observational studies were included in the search, and non-English-language articles, letters to the editor, commentaries, editorials, individual case reports, mini or brief reviews, pre-clinical (animal/in vitro) studies, and non-hair loss-related articles were excluded.

| association between covid-19 and hair loss
After full-text review of the 21 articles on HLASCI were obtained.  9 In this cohort, TE as HLASCI seemed to occur earlier than classic acute TE. The onset of TE after COVID-19 reported to be after a median of 2 months (range, 1-3 months) and the median duration 5 months (range, 1-6 months) after infection, while classic acute TE is usually observed 3-4 months after triggering events. 9 The underlying mechanism of HLASCI was postulated to be exposure to a milieu of inflammatory cytokines or direct viral damage to hair follicles. 9 In another study, excessive hair loss was reported to have occurred within 2-3 months after infection. 10 In some patients/cases with TE, hair loss began more than 12 weeks after infection was documented. 8 Exacerbation of pre-existing TE could occur in correlation with the stress of lockdown. 11 Five articles reported AA. [4][5][6][7]12 Similar to the findings for TE, a statistically significant increase in AA was reported in patients with COVID-19. 5,6 Furthermore, not only new onset but also rapid progression and relapse of pre-existing diseases were reported in COVID-19 patients with AA. 4,12 The onset and relapse of AA are speculated to be triggered by a cytokine storm caused by  or the stress associated with being quarantined. 4,12 For other hair loss clinical subtypes of HLASCI, one case each of anagen effluvium (AE), 11,13 scarring alopecia 14 were reported. The case of AE was considered to be a result of anagen hair loss, likely due to profound inflammatory destruction of the hair follicle bulb that occurs abruptly after COVID-19 infection. 13 The incidence of scarring alopecia was reported to be statistically significantly higher during the pandemic period than before the pandemic period. 14 In contrast, a statistically significant decrease in AGA was noted during the pandemic. 15  Probable TE? Forty-five patients were included in a retrospective chart review, which identified seven major types of cutaneous manifestations. One of them is hair loss (probably TE) these patients. 26 This report further underscored that COVID-19 infection is a significant trigger for TE. Figure 1 shows a typical case of HLASCI in which hair loss typical of TE was confirmed approximately 2 months after SARS-CoV-2 infection.

| Theoretical etiopathogenesis/ pathophysiology of HLASCI
The theoretical etiopathogenesis/pathophysiology of HLASCI inferred from the above outcomes is summarized in Figure 2.  individuals, such as quarantine, may exacerbate autoimmune disease due to extreme physiological stress, resulting in exacerbation of AA.

| Management of HLASCI
It is of paramount importance to control the inflammation caused by COVID-19 to manage HLASCI. Control of comorbidities and physiological stress may also be essential in reducing the incidence or magnitude of HLASCI.
Given that TE is assumed to be the main cause of HLASCI, a survey of the strategies for improvement of TE would be advantageous in the management of HLASCI. TE is characterized by an increasing ratio of telogen hairs. Under normal conditions, anagen (growing) hair follicles account for 90%-95% of the total follicles on the scalp, with the remaining 5%-10% of hair follicles in the telogen phase. 27 In TE, the ratio of telogen is reported to increase to more than 25%. 24,27 TE is classified into three groups: acute TE, chronic TE, and chronic diffuse telogen hair loss. 25  An additional survey on TE and treatment using search string 3 identified 11 papers (Table 1). [28][29][30][31][32][33][34][35][36][37][38] Currently, no established treatments or guidelines on TE treatment are available. 23 Various studies on treatment have been conducted. [28][29][30][31][32][33][34][35][36][37][38] The most common treatment was oral minoxidil ( Table 3). 28 can inhibit shortening of the anagen phase induced by androgens in AGA and promote the shift from the telogen to early anagen phase ( Figure 3). Thus, topical minoxidil is expected to be useful for the treatment of TE.
In cases of AGA and HLASCI, hair loss may be more apparent. Use of topical minoxidil would be preferentially supported in such cases.
Minoxidil has also been reported to be efficacious for treatment of AA. 35 Exacerbation of AA has been implicated in the mechanisms of HLASCI, 4,12 and topical minoxidil would be beneficial in this scenario, especially when primary inflammatory change is reduced.
Besides minoxidil, promise of various therapeutic approaches, including biotin 31 or iron 32 supplementation, growth factors vacuolated through iontophoresis, 33 antioxidant and anti-inflammatory shampoo and lotion, 34 vitamin D 3 intake, 35 microneedles, 36 sandalwood, 37 and photobiostimulation combined with microinjection, 38 have been explored to treat TE. Other remedies, which was not retrieved by search string 3, including an oral formulation containing l-cystine, thiamin, calcium d-pantothenate, medicinal yeast, keratin and p-aminobenzoic acid, may also be beneficial to improve TE; 43 however, current evidence levels are relatively low and high-quality, specific, prospectively designed, randomized controlled trials are essential to establish their efficacy.

| FUTURE DIREC TION
In our attempt to dissect the association between hair loss condi- Further study of HLASCI can provide a basis for understanding such conditions.

| CON CLUS ION
Although further study of the pathophysiology underlying HLASCI is necessary, this literature review indicates that the main cause of HLASCI is acute TE. Topical minoxidil, as an adjunct to optimal care of patients with COVID-19 disease, represents a favorable therapeutic option to better manage HLASCI.

ACK N OWLED G M ENTS
The authors thank Drs. Misaki Kinoshita-Ise and Masahiro

CO N FLI C T O F I NTE R E S T
M.O. is a medical advisor for Taisho Pharmaceutical Co., Eli Lilly Japan K.K., Pfizer Japan Inc., and ROHTO Pharmaceutical Co. and receives advisory fees. He also receives research grants for projects not related to this study from Maruho Co., Sun Pharma Japan Ltd., and Shiseido Co. T.F. and K.M. are employees of Taisho Pharmaceutical Co.