COVID-19 and Hair

EDITORIAL

 

Dr Andrea Marliani M.D. 

Firenze

 

 

Introduction

Hair loss after an event such as infections with febrile episodes is well known.

In this period we are seeing a high number of patients with hair loss linked in some way to Covid-19 and the latency period between the infectious episode and hair loss seems shorter than what is commonly observed after other infectious illnesses. This article attempts to examine the causes responsible for hair loss after Covid-19 and to understand if this differs from hair loss after other infectious conditions. It is also trying to understand if infection with the Covid-19 virus has a direct impact on the hair follicle bringing the hair into telogen.

The disease seems to have started in the city of Wuhan, in the Chinese province of Hubei, from there it has spread to most of the world (pandemic). According to the World Health Organization (WHO), the cumulative number of reported cases globally is now over 350 million and the number of deaths, as of January 2022, has exceeded 6 million individuals.

Coronavirus disease SARS-CoV-2 (Covid-19) is the third documented epidemic of an animal coronavirus that has affected humans. This highly diffusive pathogen is called coronavirus due to the two-dimensionally crown-like appearance of the spike glycoproteins on the viral envelope, and is an RNA virus.

Since the start of the pandemic, hair doctors have been approached by numerous patients with COVID-19-related telogen effluvium, most of whom had COVID-19 infection, but many of whom had no medical history of infection.

 

Hair loss as telogen effluvium after bacterial or viral infections is certainly not a new phenomenon and has been reported many times in the past.

After a common infection, not Covid-19, which has caused fever, the effluvium usually begins 3 to 4 months after the triggering infection. Personal experience, on the other hand, tells us that the interval between Covid-19 infection and the onset of effluvium is often shorter than that observed with other febrile conditions, sometimes also starting during infection and more often about 4 weeks later, raising the suspicion that SARS-CoV-2 causes direct injury to the hair follicle. Furthermore, the duration of the Covid-19-related effluvium can be particularly long, passing into subacute and chronic telogen effluvium.

In this editorial we try to understand if the mechanism of COVID-19-related effluvium is similar to what has been observed so far as a response to the stress created by febrile episodes after or during any other infection, or how COVID-19 infection may have instead a direct impact on the hair follicles.

Furthermore, we try to understand if hair loss is due not only to a combination of various factors such as cytokines and drugs used for the treatment (antivirals, antibiotics, steroids, anticoagulants, etc.) but also to the psychological impact and personal restrictions (quarantine and environmental stress) of the pandemic.

 

Pathogenesis of COVID-19 infection

The SARS-CoV-2 virus is spread primarily if not essentially by air through the transmission of respiratory droplets. After the virus has entered the airways, binding to the angiotensin converting enzyme (ACE2) receptor occurs in the bronchi, lungs and other tissues.

The virus first and foremost affects the respiratory tract, but then affects most organs, including the skin. Viral replication first causes direct tissue damage followed, in some patients, by a later and more severe phase.

The late phase is characterized by an immune response with the recruitment of T lymphocytes, monocytes and neutrophils, the release of cytokines such as tumor necrosis factor-α (TNF α), the granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-1β (IL-1 β), interleukin-8 (IL-8), interleukin-12 (IL -12) and interferon-γ (IFN-γ), the so-called “cytokine storm” that causes multi-organ damage.

 

 

Involvement of the skin in SARS-CoV-2 infection and cytokine storm

Skin involvement in COVID-19 was not noticed in the early stages of the pandemic, however was observed later but often as a presenting disorder of the infection. Although the pathophysiology of skin manifestations still eludes us, we can assume that the virus enters the skin tissue through the blood vessels, as the endothelium expresses ACE-2, initiating a skin inflammatory response. So, the circulating cytokines released in response to the viral infection impact not only the keratinocytes of the skin, but also the rapidly multiplying cells of the hair matrix. Cytokines released due to infection / fever prematurely push the follicles into catagen and the hair into telogen.

COVID-19 infection causes a strong antiviral response in the form of cytokine release. These factors affect the rapidly multiplying keratinocytes of the matrix.

The tumor necrosis factor-α, interleukin-6 and interferon-γ are known inhibitors of hair follicle growth in vitro. Interleukin-4 which is increased in the elderly is known to cause apoptosis of keratinocytes.

In a study of COVID-19 survivors in Wuhan, 534 patients were followed up three months after discharge and alopecia was observed in 154 of these. Most of these patients complained of alopecia already immediately after discharge (classic telogen effluvium) and almost a third of these patients had alopecia already during hospitalization.

Any event that suddenly interrupts the mitotic or metabolic activity of the hair follicle is known to cause hair loss in the growth phase (anagen effluvium). This is commonly seen after chemotherapy / radiotherapy, but it could also be due to sudden exposure to pro-inflammatory factors and cytokines. Probably, in these patients, the intensity of the inflammatory response that occurs over a short period of time affects the onset of hair loss and, in these cases, there may not be a latency period between the actual damage to the hair follicles and the onset of hair loss. Underlying nutritional deficiencies can also contribute to or exacerbate post COVID effluvium.

 

Arteritis

The histopathological evaluation of skin lesions during COVID-19 showed an intense perivascular lymphocyte and plasma cell infiltrate with extravasation of red blood cells and intraluminal thrombi. The virus is thought to reach the skin through blood vessels. The resulting inflammatory reaction and subsequent immune response sets in motion a cascade of events that lead to the release of cytokines by CD4 helper T cells and to the recruitment of eosinophils, CD8 cytotoxic T cells, B cells and ultimately natural killer (NK) cells, culminating in lymphocytic thrombophilic arteritis. This microvascular arteritis could play a role in creating local skin tissue hypoxia, thus affecting hair follicles as well.

 

Therapies for the treatment of COVID-19

Patients hospitalized for COVID-19 are treated with a number of medications including antibacterials, antivirals, anticoagulants, corticosteroids, and immunomodulators. We know that anticoagulants, antivirals and even antibiotics can cause transient hair loss.

Anticoagulants in particular can play an important role.

The exact cause of telogen effluvium with the use of anticoagulants is not known. Hypotheses have been advanced such as the focal degeneration of collagen bundles in the vicinity of the vessels of the follicular connective sheath or a direct lesion of the matrix or papilla. At the moment there is no consensus on this hypothesis, but there is on the fact that anticoagulants cause fall hair. The anticoagulants involved are mainly low molecular weight heparins and direct oral anticoagulants such as rivaroxaban, dabigatran and apixaban.

Anticoagulant therapy, therapeutic or prophylactic, is indicated in hospitalized patients with Covid in almost 80% of cases.

 

 

Psychological stress

The literature is full of reports of hair loss associated with psycho-emotional stress.

The COVID-19 pandemic has had a psychological impact on multiple levels. Whether it is the general population, health workers, the vulnerable population or those who have been affected by the infection, everyone has been affected. As part of the non-pharmacological control of the spread of COVID-19, it was recommended interpersonal distancing, the use of masks in public places, strict personal hygiene and lockdown with isolation of positive and suspected COVID-19 patients, quarantine of people exposed, travel restrictions, closure of educational institutions, workplaces and prohibition of mass gatherings.

Although these measures helped control the spread of the disease, they also caused a significant psychological impact with severe psychological distress. During quarantine or isolation or, worse, hospitalization, the patient is separated from family and friends, has uncertainty about the progression and status of the disease, communication is also reduced with health workers, and even boredom significantly affects the psyche of the patient with days that seem never to end. Constant updates, on social media, on the number of new cases and deaths due to the pandemic are also additional stressors for the patient in quarantine or isolation.

A multi-center and multinational study has shown that as the duration of the quarantine increases, the quantum of perceived stress also increases proportionally. Furthermore, the restrictions imposed to prevent the spread of the pandemic have led to social isolation which has triggered feelings of anxiety and depression, and this itself is also a cause of increased hair loss.

Stress can also be caused by hair loss, in which case the hair loss itself acts in a secondary way in aggravating the hair loss.

 

It is important to understand how stress affects the hair follicle. At the biological level, we (as in all living organisms) have an intrinsic system that reacts by adapting and protecting us from exogenous and endogenous (including psychological and social) stressors.

The classic stress response involves the activation of the sympathetic-adrenal-medullary axis (SAM), the hypothalamus-pituitary-adrenal axis (HPA) and the immune system. However, if the stress is severe or persistent or repetitive, the same adaptive response can damage the organism.

The rapid response results in increased secretion of epinephrine and norepinephrine from the adrenal medulla and helps the body prepare for fight or flight action.

The relatively slower response involves activation of the hypothalamic-pituitary-adrenal (HPA) axis with the release of corticotropin-releasing hormone and activation of pituitary CRH receptors leading to the production and release of proopiomelanocortin-derived peptides and adrenal hormones.

Aside from the sympathetic-adrenal-medullary axis and the hypothalamus-pituitary-adrenal axis mentioned above, there is a brain-hair follicle axis that is responsible for the growth-limiting effects of psycho-emotional stress. Experimental animal studies have shown that perceived stress can trigger neuroendocrine immune responses that cause neurogenic inflammation and promote apoptosis in hair follicles. From studies in mice, stress has been hypothesized to activate the neuroendocrine-immune circuits. It is believed that these circuits are present at the self / environment interface such as the skin and that they interact with mast cells activating them in times of psycho-emotional stress. It is known that psychological stress significantly increases the production of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, interferon-γ, mast cell activation. It is known how these cytokines released in response to intense stress drive epithelial and mesenchymal cells to apoptosis causing premature termination of hair growth.

Peters et al, correlating increased cortisol levels and blood cytokine levels to hair loss in healthy individuals exposed to psychological stress, concluded that stress can lead to temporary hair loss. Telogen effluvium itself could be a source of stress and can further amplify hair loss in affected patients.

The literature is full of reports of hair loss associated with psycho-emotional stress. Stress can impact hair loss as a primary or effluvium inducer, or it can contribute to aggravating an existing medical problem.

 

COVID-19 has also been associated with forms of alopecia areata in rapidly progressing patches towards the universal form, and with relapses of alopecia areata. The stress caused by the pandemic and interpersonal distancing measures also appears to have triggered alopecia areata in patients who were antibody (IgG) negative for SARS-CoV-2 but suffered from isolation stress.

 

Another hair loss problem observed during the pandemic is a “perceived only increase” in hair loss or “pseudo loss”. It is quite normal for 80 to 150 hairs to fall out a day, which is not commonly noticed. When interpersonal restrictions were imposed to prevent the spread of COVID-19 and most people were forced home, these same people, already worried, only then noticing hair loss around the house, panicked without having true effluvium. In most of these patients, a trichological examination revealed a negative pull test and normal trichoscopy.

 

Medical management of post-COVID-19 telogen effluvium

The most common presenting disorder is a sudden onset of increased hair loss, seemingly for no reason as it usually begins when one is fully recovered from COVID-19. Often the patient complains of pain in the skin and hair “trichodynia”.

Telogen effluvium is in these cases due to a synchronization of the growth cycles of the hair follicle that occurs when stress factors cause the follicles to leave the anagen phase and enter telogen phase prematurely, resulting in an increase in hair loss after 2 or 3 months.

In the medical history there will be a history of COVID-19 or febrile episodes in the recent past that many times are not accompanied by immediate hair loss.

There may be other predisposing factors such as weight loss or nutritional deficiencies due to dietary restrictions, hypothyroidism etc.

Trichodynia is typically associated with telogen effluvium. However, no organic basis was found for this symptom. Examination of the patient’s scalp may reveal widespread hair thinning especially if the effluvium has been severe and prolonged. It is necessary to lose almost 40% of the hair for there to be a visual appreciation of the hair loss.

An important diagnostic test is pull test. This test, when done correctly, is accurate enough for the diagnosis of telogen effluvium.

Trichoscopy is one of the most important tools for assessing hair loss. the aspects observed in telogen effluvium are typical: reduced density and presence of empty hosts and absence of variability in the diameter of the hair shaft (isotrichia). An important differential diagnosis is diffuse alopecia areata or “unknown”. The differential diagnostic clue is the presence of many yellowdot and pseudo vellus hairs.

Patient reassurance is the key to reducing anxiety associated with hair loss. Most of these patients will need time and empathy from the doctor. There is no specific treatment other than to counteract stressors. It is important to look for and correct any deficiencies that predispose to effluvium such as iron, vitamin and protein deficiencies; check thyroid function and check for the use of any drug such as β-blockers, retinoids, anticoagulants, etc. Minoxidil may not be an option. Topical use of hydrocortisone may be helpful. Reassure the patient. Ensuring a nutritious diet and adequate sleep will be very helpful in helping the patient cope with and resolve hair loss.

 

Conclusion

The connection between cause and effect with respect to COVID-19 infection and hair loss is simple. The most obvious connection is the hair follicle response to the increased biological stress created by systemic infection and subsequent release of cytokines leading to telogen effluvium. In the typical telogen effluvium there is a latency period of 3 to 4 months between the triggering event and the onset of hair loss. In the authors’ experience, patients who recovered from COVID-19 had a much shorter latency period, in some cases up to 4 weeks. Similar observations in some published studies have also suggested a possible direct insult to the hair follicle caused by the SARS-CoV-2 virus.

However, like all other telogen effluviums, almost all patients have a reversal of hair loss over a period of 2 to 3 months. Another unique feature of the effluvium seen after COVID-19 is the significant overlap of psychoemotional stress. Telogen effluvium would be one of the important aspects of the long COVID, which will impact the affected person’s quality of life. With the pandemic still ongoing, doctors caring for COVID-19 patients will also need to be empathetic to this aspect of the disease and prepare patients for effluvium, and also reassure them that it is self-limiting and that regrowth is the norm. In conclusion, a number of factors could be responsible for the severity and onset of hair loss in patients recovering from COVID-19, including the severity and duration of COVID-19 infection, the treatment administered, the underlying nutritional deficiencies, the current state of the patient’s hair, emotions, lability and psychological constitution. As part of the treatment, reassurance and explanation that hair loss is self-limited and would reverse in about 2-3 months is an important stress reliever for patients and helps them cope emotionally with hair loss.

 

 

References

1. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses . The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS- CoV-2. Nat Microbiol. 2020;5(04):536–544.

 

2. Cascella M, Rajnik M, Aleem A.Features, Evaluation, and Treatment of Coronavirus (COVID-19) [Updated 2021 Jul 17] Treasure Island (FL)StatPearls Publishing; 2021. Accessed November 17, 2021 from:https://www.ncbi.nlm.nih.gov/books/NBK554776/ [Google Scholar]

 

3. Parasher A.COVID-19: Current understanding of its pathophysiology, clinical presentation and treatment Postgrad Med J 202197(1147):312–320.

 

4. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports

https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports

 

5. Xiong Q, Xu M, Li J. Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clin Microbiol Infect. 2021;27(01):89–95.

 

6. Mieczkowska K, Deutsch A, Borok J. Telogen effluvium: a sequela of COVID-19. Int J Dermatol. 2021;60(01):122–124.

 

7. Olds H, Liu J, Luk K, Lim H W, Ozog D, Rambhatla P V. Telogen effluvium associated with COVID-19 infection. Dermatol Ther (Heidelb) 2021;34(02):e14761.

 

8. Rizzetto G, Diotallevi F, Campanati A. Telogen effluvium related to post severe Sars-Cov-2 infection: clinical aspects and our management experience. Dermatol Ther (Heidelb) 2021;34(01):e14547.

 

9. Lv S, Wang L, Zou X. A case of acute telogen effluvium after SARS-CoV-2 infection. Clin Cosmet Investig Dermatol. 2021;14:385–387.

 

10. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34(05):e212–e213. [

 

11. Fatemeh S, Bahareh H. COVID-19 and skin manifestations: an overview of case reports/case series and meta-analysis of prevalence studies. JOURNAL Frontiers in Medicine. 2020;7:651.

 

12. Sachdeva M, Gianotti R, Shah M. Cutaneous manifestations of COVID-19: Report of three cases and a review of literature. J Dermatol Sci. 2020;98(02):75 –81.

 

13. Jia J L, Kamceva M, Rao S A, Linos E. Cutaneous manifestations of COVID-19: a preliminary review. J Am Acad Dermatol. 2020;83(02):687–690.

 

14. Genovese G, Moltrasio C, Berti E, Marzano A V. Skin manifestations associated with COVID-19: current knowledge and future perspectives. Dermatology. 2021;237(01):1–12.

 

15. Deshmukh V, Motwani R, Kumar A, Kumari C, Raza K. Histopathological observations in

COVID-19: a systematic review. J Clin Pathol. 2021;74(02):76–83. [

 

16. Trüeb R M, Dutra Rezende H, Gavazzoni Dias M FR. What can the hair tell us about COVID-19? Exp Dermatol. 2021;30(02):288–290.

 

17. Shanshal M. COVID-19 related anagen effluvium. J Dermatolog Treat. 2020:1–2.

doi: 10.1080/09546634.2020.1792400.

 

18. Salamanna F, Maglio M, Landini M P, Fini M. Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2. Front Med (Lausanne) 2020;7:594495.

 

19. Saponaro F, Rutigliano G, Sestito S. ACE2 in the era of SARS-CoV-2: controversies and novel perspectives. Front Mol Biosci. 2020;7:588618.

 

20. Radzikowska U, Ding M, Tan G. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy. 2020;75(11):2829 –2845.

 

21. Hamming I, Timens W, Bulthuis M L, Lely A T, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(02):631–637. [PMC free article] [PubMed] [Google Scholar]

 

22. Rossi A, Magri F, Sernicola A. Telogen effluvium after SARS-CoV-2 infection: a series of cases and possible pathogenetic mechanisms. Skin Appendage Disord. 2021;21:1–5. [

 

23. Tirado S M, Yoon K J. Antibody-dependent enhancement of virus infection and disease. Viral Immunol. 2003;16(01):69–86.

 

24. Ulrich H, Pillat M M, Tárnok A. Dengue fever, COVID-19 (SARS-CoV-2), and antibody-dependent enhancement (ADE): a perspective. Cytometry A. 2020;97(07):662–667.

 

25. Hajela K.Structure and function of Fc receptors Biochem Educ 1991190250–57.

 

26. Wei K C, Huang M S, Tsung-Hsien C. Dengue VIPHHFDPC. Front Cell Infect Microbiol. 2018;8:268.

 

27. Okamoto T, Suzuki T, Kusakabe S. Regulation of apoptosis during flavivirus infection. Viruses. 2017;9(09):243.

 

28. Abrantes T F, Artounian K A, Falsey R.Time of onset and duration of post-COVID-19 acute telogen effluvium J Am Acad Dermatol 20218504975 –976.[published online ahead of print, 2021 Jul 21]

 

29. Gohary Y M, Abdel Fattah D S. Detection of tumor necrosis factor-alpha in nonlesional tissues of alopecia areata patients: a prove for a systemic disease. Int J Trichology. 2017;9(04):154–159.

 

30. Kanwar A J, Narang T. Anagen effluvium. Indian J Dermatol Venereol Leprol.

2013;79(05):604–612.

 

31. Gianotti R, Zerbi P, Dodiuk-Gad R P. Clinical and histopathological study of skin dermatoses in patients affected by COVID-19 infection in the Northern part of Italy. J Dermatol Sci. 2020;98(02):141–143.

 

32. Magro C, Mulvey J J, Berlin D. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13.

 

33. Watras M M, Patel J P, Arya R. Traditional anticoagulants and hair loss: a role for direct oral anticoagulants? A review of the Literature. Drugs Real World Outcomes. 2016;3(01):1–6.

 

34. Vaughn V M, Yost M, Abshire C. Trends in venous thromboembolism anticoagulation in patients hospitalized with COVID-19. JAMA Netw Open. 2021;4(06):e2111788.

 

35. Luo M, Guo L, Yu M, Jiang W, Wang H. The psychological and mental impact of coronavirus disease 2019 (COVID-19) on medical staff and general public – a systematic review and meta-analysis. Psychiatry Res. 2020;291:113190.

 

36. Rajkumar R P. COVID-19 and mental health: a review of the existing literature. Asian J Psychiatr. 2020;52:102066.

 

37. Brooks S K, Webster R K, Smith L E.The psychological impact of quarantine and how to reduce it: rapid review of the evidence Lancet 2020395(10227)912–920.

 

38. Nguyen H, Tran N. Perceived stress of quarantine and isolation during COVID-19 pandemic: a global survey. Frontiers in Psychiatry, Volume. 2021;12:651.

 

39. Botchkarev V A. Stress and the hair follicle: exploring the connections. Am J Pathol. 2003;162(03):709–712.

 

40. Chu B, Marwaha K, Sanvictores T.Physiology, Stress Reaction. [Updated 2021 Jun 8] Treasure Island (FL)StatPearls Publishing; 2021. Jan.

 

41. Peters E MJ, Müller Y, Snaga W. Hair and stress: a pilot study of hair and cytokine balance

            alteration in healthy young women under major exam stress. PLoS One. 2017;12(04):e0175904.

            [

42        Hadshiew I M, Foitzik K, Arck P C, Paus R. Burden of hair loss: stress and the underestimated psychosocial impact of telogen effluvium and androgenetic alopecia. J Invest Dermatol. 2004;123(03):455–457.

 

43        FIvenson D. COVID-19: association with rapidly progressive forms of alopecia areata. Int J Dermatol. 2021;60(01):127.

 

44. Malkud S. Telogen effluvium: a review. J Clin Diagn Res. 2015;9(09):WE01 –WE03.

 

45. Grover C, Khurana A. Telogen effluvium. Indian J Dermatol Venereol Leprol. 2013;79(05):591–603.

 

46. Rebora A. Telogen effluvium: a comprehensive review. Clin Cosmet Investig Dermatol. 2019;12:583–590.

 

47. McDonald K A, Shelley A J, Colantonio S, Beecker J. Hair pull test: evidence-based update and revision of guidelines. J Am Acad Dermatol. 2017;76(03):472–477.

 

48. Jain N, Doshi B, Khopkar U. Trichoscopy in alopecias: diagnosis simplified. Int J Trichology. 2013;5(04):170–178. doi: 10.4103/0974-7753.130385.