The COVID-19 pandemic had severe repercussions on global health; currently, this infection is known for its ability to harm any organ or system in the body (1). As with other viruses (2), the symptoms it causes can become chronic (3). Indeed, due to the success of vaccination efforts, it is estimated that 70% of COVID-19 infections will have a greater long-term impact than during the acute phase of the infection (4). The persistence of symptoms following a COVID-19 infection is known as post-COVID-19 syndrome (5). This condition is characterized by the presence of symptoms for at least 2 months following the initial infection (6,7). The emergence of this syndrome does not depend on the duration of the primary infection (8), but rather on factors, such as age and the number of symptoms during the acute infection (9). The overall prevalence of post-COVID-19 syndrome has been calculated at 41.79%, although significant variations exist across different populations (10). Due to the ability of the virus to cross mucosal barriers (11), post-COVID-19 syndrome can manifest in the cells and structures of the skin (12). Potential lesions associated with COVID-19 have been classified into six groups, listed in order of prevalence: Acral (51%), vesicular (15%), urticarial (9%), morbilliform (9%), petechial (3%), livedo reticularis (1%) and other types (15%) (13). The mechanisms related to these lesions include the excessive production of inflammatory cytokines and stress hormones with subsequent damage to the production of proteoglycans in the extracellular matrix (14), as well as dysregulations in the humoral response of CD8+ T-lymphocytes (15) and residual effects of post-traumatic stress (16). However, the dermatological lesions observed in post-COVID-19 syndrome may differ from those observed during the acute phase of infection. Given that there is no specific treatment for dermatological lesions caused by post-COVID-19 syndrome, the treatment of choice depends on the symptomatology, thus rendering it essential to describe the type and nature of the lesions presented (17). For this reason, in the present study, a systematic review of the dermatological lesions and symptoms presented during post-COVID-19 syndrome was conducted to detail the clinical spectrum of this condition and guide the therapeutic needs of those affected.

Using the PICO strategy, a systematic search was conducted in the repositories of PubMed, Embase, Scopus and Google Scholar, utilizing the following key words: ‘Long-Covid Syndrome and skin manifestations’ OR ‘POST-COVID syndrome and cutaneous manifestations’ OR ‘Post COVID and Skin’. Only original multicentric articles, such as prospective cohort studies, retrospective cohort studies, case series and case reports published between January, 2020 and January, 2024, written in English or Spanish, involving patients diagnosed with post-COVID-19 syndrome and documenting clinical skin manifestations or cutaneous appendages, were included. Studies, such as systematic reviews, meta-analyses, expert consensus, pre-experimental studies and in vitro studies were excluded, as well as studies with unavailable content or imprecise information about symptoms and follow-up. Initially, a total of 271 candidate articles were found, which were reviewed in parallel by two reviewers through the reading of their abstracts and titles. Following the consensus of the reviewers, the results of this analysis were organized in a database, summarizing the characteristics of each record. A total of 119 studies were discarded due to unrelated information to the interests of the present systematic review, another 96 for belonging to other types of studies, one article was excluded for being in a language other than Spanish or English, and 12 studies were excluded for duplications, resulting in 44 eligible articles (Fig. 1).

In the 44 selected articles, data corresponding to the research question were collected, along with information regarding the number of participants, presented dermatological symptoms and follow-up period, among other relevant findings. Of the included articles, a total of 21 studies were prospective cohort studies, while four studies were retrospective cohort studies. Of note, one study was ambispective, and another was a case-control type study. Additionally, nine studies were cross-sectional, one study was a case series, and seven studies were case reports. A list of the included studies is presented in Table I.

Taken together, the analyzed studies compiled findings from 626,128 patients screened for dermatological symptoms secondary to post-COVID-19 syndrome. In the majority of the records, the findings occurred in a population that was previously healthy. In five studies, the target population was notable for the presence of chronical pathologies, psychiatric comorbidities, or a history of autoimmunity. Furthermore, one study focused on describing dermatological symptoms due to post-COVID-19 syndrome in the pediatric population. The average follow-up period and the onset of symptoms within the analyzed were ~7 months, with a minimum follow-up of 6 weeks following the diagnosis of COVID-19 and up to a maximum of 12 months post-diagnosis. The most prevalent dermatological symptoms in the population are detailed in specific sections below. Additionally, Fig. 2 provides a graphical representation of examples of these conditions.

The present systematic review detailed the findings from studies focusing on post-COVID-19 syndrome and the dermatological conditions it causes. The literature review indicated a relatively limited number of records of dermatological alterations resulting from this syndrome. This scarcity may be due to the fact that such dermatological manifestations are not as apparent until the initial impact of the health emergency is mitigated (66). On the one hand, while the majority of studies reported only mild and non-specific skin lesions, other studies revealed two main findings: Firstly, an increase in cutaneous symptoms associated with hyperinflammation and immune dysregulations, and secondly, a significant prevalence of hair loss and alopecia in the affected population.

As regards the first finding, the included studies reported multiple cases of subjects whose pathology was associated with hyperinflammation and the development of autoimmunity, including the reactivation of autoimmune and viral diseases in a silent state, as well as infections by opportunistic pathogens in previously healthy individuals. Post-COVID-19 syndrome is characterized by the development of residual inflammation due to direct viral toxicity, as well as alterations in the regulatory function of T-lymphocytes (67). Studies focusing on this aspect have determined that after recovering from the acute phase of COVID-19, the virus can cause T-lymphocytes to exhibit autologous epitopes on their antigen identification cell receptors, thus creating an autoimmune environment, particularly in the female body (68).

Moreover, the excessive secretion of IL-6, D-dimer and lymphopenia produced during the primary COVID-19 infection increases the likelihood of developing post-COVID-19 syndrome (69). This is consistent with the findings that have been reported in previous research (70) and in the present systematic review, where females and subjects with severe COVID-19 infection presented more intense dermatological symptoms compared to the remainder of the population. In line with this finding, previous research has confirmed that some patients develop autoantibodies following COVID-19 infection, regardless of whether they have a history of autoimmunity or not (71). A proposed mechanism indicates the viral capacity to generate molecular mimicry with normal body structures (71). Thus, it is possible that the generation of antibodies against skin layers contributes to the development of skin lesions as indicated by some studies analyzed in this review (56,57).

As regards hair loss and alopecia, these conditions were initially reported during the peak of the pandemic in Spain (72), and described as expected findings during the acute phase and convalescence of patients infected with COVID-19(73). At that time, these conditions were considered mild and reversible, as with other viral and bacterial infections, resulting from the alteration of hair growth cycles following exposure to persistent inflammation affecting the metabolism of keratinocytes and the dermal papilla (74).

However, in the case of post-COVID-19 syndrome, it has been reported that the onset of alopecia occurs more rapidly and lasts longer compared to other pathogens, suggesting direct damage to the hair follicle. This is due to the fact that ACE2 receptors, used by COVID-19 for viral entry, are present in both mesenchymal cells of the hair follicle and its basal layers (75). Additionally, it has been theorized that certain components of the hair follicle increase immunological reactivity against COVID-19, consequently leading to an increase in antigen-antibody interactions in this area, resulting in the degradation of the follicle root structures (76). Furthermore, it is considered that this localized toxicity generates intense oxidative stress, leading to the premature onset of the catagen phase of the hair follicle and hair apoptosis, as well as a reduction in anticoagulant proteins in the perifollicular vessels, which in turn facilitates the formation of microthrombi that reduce blood flow to the hair root, causing it to thin and become fragile (77).

Although hair loss is considered a benign symptom without real systemic repercussions, its impact on body aesthetics is crucial for the individual, particularly considering that, compared with other dermatopathies, the availability of treatments for this condition is limited (78). This renders hair loss one of the most critical dermatological effects of post-COVID-19 syndrome, given the high prevalence rate of this condition. Thus, the timely approach to this condition in subjects with risk factors, such as women and severe COVID-19 should be considered a priority in dermatological health matters.

Although the findings from the present systematic review are notable due to their clinical implications in dermatological practice, it is important to highlight the inherent limitations of the present study. Since the studies analyzed predominantly rely on reports provided by affected patients, there is a notable risk of human bias. The integration of technological tools, such as neural networks for the analysis of dermatological lesions in post-COVID-19 syndrome, may allow for more accurate data on the impact of this condition on dermatological health, as has been observed with other conditions (79,80). Therefore, the associations generated through these analytical tools could contribute to future studies identifying both the risk factors for symptom onset and the pathogenic pathways responsible for the lesions in post-COVID-19 syndrome.

In conclusion, the present systematic review found that the dermatological manifestations of post-COVID-19 syndrome are primarily hair loss and skin lesions associated with persistent inflammation and the development of autoimmunity, with the severity of the initial clinical presentation and female sex being risk factors for severity. Additionally, given that dermatological lesions in post-COVID-19 syndrome may present in a delayed manner, their diagnosis should always be considered in patients experiencing symptoms that cannot be explained by other dermatological conditions. Furthermore, due to the limited therapeutic success for some symptoms, such as hair loss, further studies are required to focus on comparing specific therapeutic interventions for these conditions.