The Association between COVID-19 Infection and Gabrin Sign: A Case-Control Study

Dear Editor,

The COVID-19 pandemic has claimed countless lives, including that of Dr. Frank Gabrin, who battled bilateral testicular cancer and androgenetic alopecia before succumbing to the virus. In his memory, Wambier et al. conducted a study highlighting a novel symptom of COVID-19: the Gabrin sign.[1]

Recent research has shown that the SARS-CoV-2 virus primarily infects type II pneumocytes through binding with their angiotensin converting enzyme (ACE)-2 receptors, which is facilitated by the proteolytic priming of viral spike proteins by TMPRSS2. Studies of SARS-CoV-1 have suggested that inhibiting serine proteases can decrease the likelihood of virus attachment to ACE-2 receptors. Furthermore, TMPRSS2 gene transcription is regulated by androgenic promoters.[2]

Studies show that COVID-19 patients have a higher incidence of androgenetic alopecia (AGA), making it critical to investigate AGA in both male and female patients as a potential risk factor.[3,4]

The aim of this prospective case-control study was to explore the potential correlation between COVID-19 severity and androgenic alopecia in hospitalized male and female patients.

We conducted this case-control study at our tertiary care centre between March 2021 and August 2021, with institutional ethical committee approval (F/SPMC/IERB/0904) and informed consent from participants. Hospitalized males and females with COVID-19 infection requiring oxygen support were included, and the virus was detected using real-time reverse transcription-polymerase chain reaction (RT-qPCR) and COVID-19 rapid antigen test (RAT).

Cases included subjects with androgenic alopecia. This group was further divided into ‘positive Gabrin sign’ including Hamilton–Norwood scale (HNS) graded from 3 to 7 for men and Ludwig scale (LS) grade from 2 to 3 for women; and ‘negative Gabrin sign’ including HNS 1-2 and LS-1.

Controls were recruited for this case-control study by selecting individuals without androgenic alopecia who had been diagnosed with lab-proven COVID-19 from the same ward as the cases. Controls were also matched to cases on important variables that may affect the risk of COVID-19 severity, such as age, gender, ethnicity, and comorbidities. Matching controls to cases helped to reduce the effects of confounding variables that may have impacted the study results.

In our study, patients were categorized into three groups according to type of oxygen assistance required, namely those who needed simple oxygen masks (non-severe), those who required high-flow devices such as continuous positive airway pressure or high-flow nasal cannulas (severe), and those who needed mechanical ventilation (critical). The outcomes were: survivor and non-survivor.

To further assess the effect of androgens on infection’s severity, for males, we noted the presence or absence of any prostate disease or history of consuming antiandrogens, while for females, we recorded the history of hormone replacement therapy and signs of hyperandrogenism, such as polycystic ovarian disease and virilization.

The sample size calculation assumed a prevalence of 50% and an odds ratio of 1.7 according to previous studies, a power of 80%, and a significance level of 5%.[5,6] The resultant sample size was 540 subjects (270 with androgenic alopecia and 270 controls without androgenic alopecia).

A total of 270 cases of AGA with confirmed COVID-19 infection, and 270 COVID-19 positive controls without AGA were admitted to ICU and evaluated in this study.

The male-to-female ratio was 4.2:1 (218 males and 52 females) in cases and 4.2:1 (219 males and 51 females) in controls. As far as cases were concerned, 183 (67.8%) had positive Gabrin sign and 87 (32.2%) had negative Gabrin sign. There was a higher incidence of severe and critical COVID-19 infection in cases than in controls (P value <0.001) and in Gabrin sign positive cases than Gabrin sign negative cases (P value <0.001) [Table 1].

Table 1.

Distribution of cases and controls according to severity

	Non-severe	Severe	Critical	P*
Cases	140	72	58	<0.001
Controls	229	25	16
Sub group analysis in cases	Non-severe	Severe	Critical
Gabrin sign positive	82	49	52	<0.001
Gabrin sign negative	58	23	6
	Survivors	Non-survivors	Total
Cases	239	31	270	0.001
Controls	259	11	270
	Survivors	Non-survivors	Total
Gabrin sign positive	157	26	183	0.036
Gabrin sign negative	84	5	87

*Chi-square test

The mortality in cases was 11.4% (n = 31) and 4.2% (n = 11) (P value-0.001). Results showed that Gabrin sign positive cases had a 14.2% mortality rate, while Gabrin negative had a 5.7% mortality rate (P value 0.036) [Table 1].

We also observed that 13 (4.8%) controls had the prostate disease (all cases had benign prostatic hyperplasia), 0.4% cases and 7.1% controls were on hormone replacement therapy, while 5.6% cases and 0.7% controls had signs of hyperandrogenism (including virilization and polycystic ovarian disease) [Table 2].

Table 2.

Presence of androgen-related events in cases and controls

	Cases (n=270)	Controls (n=270)
Prostate disease	0 (0%)	13 (4.8%)
Hormone replacement therapy	1 (0.4%)	19 (7.1%)
Signs of hyperandrogenism 13%	15 (5.6%)	2 (0.7%)

Our study has revealed a noteworthy correlation between the severity of COVID-19 and the degree of androgenic alopecia, supporting the results of previous investigations, including the one conducted by Wambier et al.[1]

In our study, we also found that controls had a higher incidence of conditions associated with downregulated androgens, such as prostate disease and hormone replacement therapy, compared to cases. On the other hand, conditions associated with hyperandrogenism, such as polycystic ovarian disease and virilization, were more common in cases.

These findings suggest that androgen receptor expression and sensitivity may play a role in the development and severity of COVID-19. Interestingly, previous work by Moravvej et al. and Subramanian et al. have also shown a similar correlation between hyperandrogenic manifestations and more severe symptoms of COVID-19 in females, supporting the potential role of androgen in COVID-19.[2,7] These findings also highlight the importance of antiandrogen therapy as a potential treatment option for COVID-19.

In conclusion, our research provides additional evidence to support the relationship between androgen receptor expression and COVID-19 severity. The significant association between Gabrin sign and higher mortality emphasizes the need to recognize androgen activity as a potential risk factor in COVID-19 treatment.

The present study was subject to several notable limitations, including a restricted sample size, a lack of multivariate analysis, and the adoption of a single-centric design. Nevertheless, the positive results suggest that further research could shed more light on the potential role of androgen sensitivity in the severity of COVID-19. Future studies could include a more comprehensive assessment of co-morbidities, drugs used, duration of disease, and other important factors that may contribute to COVID-19 severity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.