Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(3):e2024170 1 The Difference Between SARS-CoV-2 Associated Telogen Effluvium and Telogen Effluvium Due to Other Causes Didem Kazan1,2, Defne Özkoca3, Nazlı Dizen Namdar1 1 Kutahya Health Science University, Evliya Celebi Training and Research Hospital, Dermatology and Venerology Clinic, Kutahya, Turkey 2 Istanbul Arel University, Department of Dermatology and Venerology, Istanbul, Turkey 3 Zonguldak Atatürk State Hospital, Dermatology and Venerology Clinic, Zonguldak, Turkey Key Words: telogen efflivium, dermoscopy, trichoscopy, SARS-CoV-2 Citation: Kazan D, Özkoca D, Dizen Namdar N. The Difference Between SARS-CoV-2 Associated Telogen Effluvium and Telogen Effluvium Due to Other Causes. Dermatol Pract Concept. 2024;14(3):e2024170. DOI: https://doi.org/10.5826/dpc.1403a170 Accepted: March 13, 2024; Published: July 2024 Copyright: ©2024 Kazan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Didem Kazan, Kutahya Health Science University, Evliya Celebi Training and Research Hospital, Dermatology and Venerology Clinic,Kütahya; Istanbul Arel University, Department of Dermatology and Venerology, Istanbul, Turkey. Bussiness tel: +902742236053, E-mail: didem.senses_343@hotmail.com Introduction: Telogen effluvium (TE) is a common type of non-cicatricial alopecia, and it is reported frequently in patients with SARS-CoV-2 infection. Objectives: Herein, we aimed to examine the demographic, dermoscopic, and laboratory features of the patients with SARS-CoV-2 associated TE (CATE) and compare them with TE due to other causes (TEDOC) according to these features. Methods: In this retrospective case-control study we evaluated the patients who were diagnosed with TE and were above 18 years of age between April and June 2022. The patients were divided into two groups based on their medical history and SARS-CoV-2 PCR positivity. The first group included pa- tients with CATE and positive SARS-CoV-2 PCR test results in the last 3 months. The second group consisted of patients with TEDOC. Patients gender, age, disease duration, additional systemic disease, dermoscopic findings, and laboratory results were recorded. Results: A total of 92 patients, 86 (93.5%) females, and 6 (6.5%) males, were included in the study. CATE was detected in 52 (56.5%) patients whereas 40 (44.5%) patients had TEDOC. The mean time between the onset of SARS-CoV-2 infection and hair loss complaint was calculated as 64.8 + 25.6 days, and this time was significantly shorter than patients with TEDOC (P = 0.003). The dermoscopic eval- uation showed that empty follicular openings and yellow dots were statistically higher in patients with CATE, whereas short regrowing hair were markedly higher in patients with TEDOC (P = 0.001, P = 0.001, and P = 0.001, respectively) Conclusions: CATE is characterized by excessive hair-shedding that begins sooner after infection than classic TE. Dermoscopic findings can assist clinicians in diagnosis. ABSTRACT 2 Original Article| Dermatol Pract Concept. 2024;14(3):e2024170 Introduction Telogen effluvium (TE) is a type of diffuse non-cicatricial alo- pecia that develops as a result of a disturbance in the growth cycle of the hair follicle. There are five functional types of TE, which are classified according to alterations in specific phases of the follicular cycle: immediate or delayed anagen release, short anagen syndrome, and rapid or delayed telogen release. This results in intense hair shedding, which can be acute or chronic. Acute TE usually resolves within 3-6 months, while chronic TE persists for more than 6 months. TE is often trig- gered by underlying emotional stress, febrile illness, the post- partum period, weight loss, systemic disease, systemic drug use, or surgery [1]. Numerous studies reported many patients with TE af- ter SARS-CoV-2 infection and as well as after receiving its vaccines [2-4]. The development of TE has been linked to the release of proinflammatory cytokines due to systemic in- flammation, the occlusion of the vascular system of the hair follicle, and direct infection of the hair follicle by the virus [5-7]. Emotional and psychological stress, fever, weight loss, nutritional deficiency, and systemic medications may also in- crease the prevalence and severity of TE during SARS-CoV-2 infection [8]. Objectives In this study, we planned to examine the demographic, dermoscopic, and laboratory features of the patients with SARS-CoV-2 -associated TE (CATE) and compare them with TE due to other causes (TEDOC) according to these features. Methods This study is a descriptive, retrospective and case-control study. It was conducted in a tertiary dermatology center after approval from the ethics committee according to the Decla- ration of Helsinki (Approval date: August 2023, approval number:2023/09-31). Study Population The study included patients who visited our dermatology clinic between April and June 2022 due to excessive hair loss, had a positive hair-pulling test, were diagnosed with TE based on the clinic and dermoscopic features, and were over 18 years old. The patients reported that their hair loss started after contracting SARS-CoV-2 infection and had SARS-CoV-2 PCR positivity in the last 3 months in our hospital record- ing system were categorized as CATE, on the other hand, patients who did not link their hair loss to SARS-CoV-2 infection and had no records of SARS-CoV-2 positivity in the last three months were classified as TE due to other causes (TEDOC). All patients provided informed consent forms be- fore participating in the study. Data Collection Patients gender, age, disease duration, accompanying sys- temic disease, dermoscopic findings, and laboratory results were recorded. All dermoscopic examinations were per- formed using a hand-held dermoscop (Plusmed) and data were collected from hospital records. Statistical Analysis Statistical analysis was done with the IBM SPSS 20.0 (IBM Corp.) package program. Numerical variables were given as mean ± standard deviation or median (25th-75th percentile). Categorical variables were given as frequency (percentage). Relationships between categorical variables were evaluated by chi-square analysis. Two samples Student t-test was used to compare mean values of normally distributed quantitative variables. In the testing of two-sided hypotheses, P < 0.05 was considered sufficient for statistical significance. Results A total of 92 patients, 86 (93.5%) females, and 6 (6.5%) males, were included in the study. Previous SARS-CoV-2 infec- tion before hair shedding was detected in 52 (56.5%) patients whereas 40 (44.5%) patients had TEDOC. Female dominance was detected in both groups, however, there was no statisti- cally significant difference between the groups (P = 0.197). The mean age of the patients with CATE was 30.3 + 10.7 years. The mean duration of the disease was 102.5 + 35.2 days. As a result of that, acute TE was found to be higher in patients with CATE (P = 0.001). In terms of the mean age of the patients and the mean duration of the disease, there was no significant difference between the groups (P = 0.888, P = 0.077, respec- tively). However, the mean time between the onset of trigger and hair loss complaint was calculated as 64.8 + 25.6 days, and this time was markedly shorter than patients with TEDOC (P = 0.003). Evaluation of the additional systemic diseases revealed that 2 (3.8%) patients had hypertension in patients with CATE, whereas 4 (10%) patients had Hashimoto thyroid- itis, 3 (7.5%) patients had diabetes mellitus, and 1 (2.5%) patient had chronic hepatitis due to hepatitis B virus in pa- tients with TEDOC, and there was no statistically significant difference between the groups (P = 0.073). Reduced hair density was detected in all patients with CATE and/or TEDOC. After evaluating in terms of the dif- ference in dermoscopic examination, empty follicular open- ings and yellow dots were significantly higher in patients with CATE (respectively P = 0.001 and P = 0.001), whereas Original Article | Dermatol Pract Concept. 2024;14(3):e2024170 3 short regrowing hair were higher in patients with TEDOC (P = 0.001). Iron deficiency was the most common laboratory finding in 54 (58.6%) of total patients. Among all CATE patients with accompanying anemia, vitamin B12 deficiency and 25-OH-vitamin D deficiency, these deficiencies were present before SARS-CoV-2 infection and were not related to hair loss. Iron deficiency and hypothyroidism were found statis- tically higher in patients with TEDOC (P = 0.005, P = 0.03, respectively) Conclusions In this study, we retrospectively evaluated 92 patients with TE between April and June 2022. Among 92 patients, 52 (56.5%) had CATE and 40 (44.5%) had TEDOC. The mean time between the onset of trigger and hair loss complaint was statistically shorter in patients with CATE than patients with TEDOC. We found empty follicular openings and yel- low dots significantly higher in patients with CATE, whereas short regrowing hair markedly higher in patients with TEDOC. Iron deficiency and hypothyroidism were also higher in patients with TEDOC. TE was reported as the most common hair disease in patients with SARS-CoV-2 infection in many studies in the literature [5-7]. The main pathogenesis of CATE was still not fully understood, however, several factors were implicated. Recent studies reported that proinflammatory cytokines such as interleukin 1β, interleukin 6, tumor necrosis factor α, type 1 and type 2 interferon, and metalloproteinases 1 and 3 affect matrix cells of the follicle [7-9]. Metalloproteinases 1 and 3, and interleukin 1β inhibit hair follicle growth, and interleukin 6 induces the catagen phase [10,11]. In addition, this systemic cytokine storm may mediate microvascular inflammation and the activation of the coagulation cas- cade and decrease the concentration of anticoagulant pro- teins. This process may end with capillary thrombosis and dermal fibrosis [12-14]. Another hypothesized mechanism was Fcγ-mediated virus entry into the host cells because of non-neutralizing virus-specific antibodies (NAb) [15]. Therefore, CATE develops because of the early-onset telo- gen phase, namely, dystrophic anagen effluvium. Thus, pa- tients with CATE have a shorter time of onset, typically 1–2 months instead of 3 months compared with TEDOC [16]. In our study, we found shorter time between the onset of trigger and hair loss complaint in patients with CATE than in patients with TEDOC. Common dermoscopic findings of the patients with TE are reduced hair density, one emerging hair on the follicle, etc [17]. Unfortunately, these findings were not specific and could be seen in CATE and/or TEDOC.[18] However, Lv et al reported a case with CATE had scalp capillary ectasia without any inflammatory scalp disease because of medium to small vessel dilatation due to the inflammatory stimulus of SARS-CoV-2. [19]. They also declared that this dermoscopic finding was regressed at 3rd month of control. Saber et al. suggested scalp capillary ectasia as a trichoscopic sign and a diagnostic clue for patients with CATE [20]. We did not observe this dermoscopic finding in our patients with CATE because our patients applied to the hospital when the mean disease duration was 102.5 + 35.2 days. However, empty fol- licular openings and yellow dots were statistically higher in patients with CATE, whereas short regrowing hair were sig- nificantly higher in patients with TEDOC. This result could be explained by the fact that CATE patients were more in acute TE, while TEDOC patients were more in chronic TE. Because of having more stressful events such as deliv- ery, abortion, lactation, etc, TE is more commonly seen in Table 1. Demografic features of the patients Demografic features of the patients SARS-CoV-2 associated TE N = 52 (%) TE due to other causes N = 40 (%) P value Gender Female Male 46 (88.5%) 6 (11.5%) 37(92.5%) 3 (7.5%) 0.197 Mean age of the patients (+ SD) (year) 30.3 + 10.7 27.9 + 10.7 0.888 Mean duration of disease (+ SD) (day) 102.5 + 35.2 249.7 + 109.3 0.077 Mean time between the onset of trigger and hair loss com- plaint (day) 64.8 + 25.6 133.5 + 5.8 0.003 Acute TE Chronic TE 48 (92.3%) 4 (7.7%) 19 (47.5%) 21 (52.5%) 0.001 Accompanying systemic disease Present Absent 3 (5.8%) 49 (94.2%) 7 (17.5%) 33 (82.5%) 0.073 SD = standard deviation; TE = Telogen effluvium. 4 Original Article| Dermatol Pract Concept. 2024;14(3):e2024170 CATE is characterized by excessive hair loss, positive hair pull test, not having anisotrichosis in dermoscopic examina- tion and not having underlying other common TE causes. However, lots of patients could have systemic comorbidities and SARS-CoV-2 infection at the same time. They could also have CATE after infection. At this situation, the exact time of the onset of the complaint was taken as basis. If the complaints started after SARS-CoV-2 infection immediately, it is catego- rized as CATE [23]. In our study, 24 (46.2%) patients had iron deficiency, 14 (26.9%) patients had vitamin B12 deficiency, and 10 (19.2%) patients had 25-OH-vitamin D deficiency in CATE group. However, statistical analysis showed that TE- DOC patients had significantly more iron and vitamin B12 de- ficiency. Therefore, we should think that patients prone to the development of TE could facilitate the development of CATE. females. In addition, females are prone to be more affected emotionally by hair shedding, and having longer hair makes them think of having more hair loss. Therefore, they are more likely to seek medical attention [21]. Numerous stud- ies in the literature also reported female dominance in pa- tients with CATE [2,5-8]. We also found female dominance in both groups in our study. However, the exact mechanism under this situation was still not understood. Estrogens and progesterone are known to be immunomodulatory, anti-inflammatory, and work protectively at hair follicles. The reduction of estrogen and progesterone levels at blood due to systemic inflammation could cause hair loss in female patients with SARS-CoV-2 [22]. However, we need further studies to enlighten the relationship between hair loss and SARS-CoV-2. Table 2. Dermoscopic features of the patients Dermoscopic findings SARS-CoV-2 associated TE N = 52 (%) TE due to other causes N = 40 (%) P value Empty follicular opening Present Absent 40 (76.9%) 12 (23.1%) 4 (10%) 36 (90%) 0.001 Yellow dots Present Absent 29 (55.8%) 23 (44.2%) 3 (7.5%) 37 (92.5%) 0.001 Short regrowing hair Present Absent 10 (10.2%) 42 (80.8%) 30 (75%) 10 (25%) 0.001 One emerging hair shaft on the follicle Present Absent 8 (15.4%) 44 (84.6%) 8 (20%) 32 (80%) 0.563 TE = Telogen effluvium. Table 3. Laboratory findings of the patients Laboratory findings SARS-CoV-2 associated TE N = 52 (%) TE due to other causes N = 40 (%) P value Iron deficiency Present Absent 24 (46.2%) 28 (53.8%) 30 (75%) 10 (25%) 0.005 Hypothyroditis Present Absent 0 52 (100%) 4 (10%) 36 (90%) 0.033 Vitamin B12 deficiency Present Absent 14 (26.9%) 38 (73.1%) 11 (27.5%) 29 (72.5%) 0.951 25-OH-vitamin D deficiency Present Absent 10 (19.2%) 42 (80.8%) 8 (20%) 32 (80%) 0.927 Folic acid deficiency Present Absent 0 52(100%) 2 (5%) 38 (95%) 0.186 TE = Telogen effluvium. Original Article | Dermatol Pract Concept. 2024;14(3):e2024170 5 10. Xiong Y, Harmon CS. Interleukin-1beta is differentially ex- pressed by human dermal papilla cells in response to PKC acti- vation and is a potent inhibitor of human hair follicle growth in organ culture. J Interferon Cytokine Res. 1997;17(3):151-157. DOI: 10.1089/jir.1997.17.151. PMID: 9085940. 11. Mandt N, Geilen CC, Wrobel A, et al. Interleukin-4 induces apoptosis in cultured human follicular keratinocytes, but not in dermal papilla cells. Eur J Dermatol. 2002;12(5):432-438. PMID: 12370129. 12. Rosei CA, Gaggero A, Famà F, et al. Skin capillary alter- ations in patients with acute SarsCoV2 infection. J Hypertens. 2022;40(12):2385–93. DOI: 10.1097/HJH.0000000000003271. Epub 2022 Aug 18. PMID: 35983856; PMCID: PMC9640263. 13. Michelini S, Caro G, Di Fraia M, et al. Telogen effluvium in SARS-CoV-2 infection: histological aspects. J Eur Acad Dermatol Venereol. 2023; 8:1–3. DOI: 10.1111/jdv.19015. Epub ahead of print. PMID: 36883793. 14. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. 2020;8(6):e46-e47. DOI:10.1016/S2213-2600(20)30216-2. Epub 2020 Apr 27. PMID: 32353251; PMCID: PMC7185942. 15. Rossi A, Magri F, Sernicola A, et al. Telogen effluvium after SARS-CoV-2 infection: a series of cases and possible Pathoge- netic mechanisms. 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