Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 1 Infections in Hospitalized Patients with Psoriasis in a Skin Referral Hospital Nafise Zaredar1, Hamidreza Mahmoudi1,2, Tahereh Soori1,3, Amir Teimourpour1, Kamran Balighi1,2, Ali Salehi Farid1,2, Maryam Daneshpazhooh1,2 1 Department of Dermatology, Tehran University of Medical Sciences, Tehran, Iran 2 Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran Key words: psoriasis, infection, biologic treatment, anti-TNFa, methotrexate Citation: Zaredar N, Mhamoudi H, Soori T, et al. Infections In Hospitalized Patients With Psoriasis In A Skin Referral Hospital. Dermatol Pract Concept. 2023;13(1):e2023027. DOI: https://doi.org/10.5826/dpc.1301a27 Accepted: July 15, 2022; Published: January 2023 Copyright: ©2023 Zaredar 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: Maryam Daneshpazhooh, Razi Hospital, Vahdate-Eslami Sq, Tehran 11996 Iran; ORCID 0000-0003-1020-8895 Phone number and fax: +98-21-55618989; Email: maryamdanesh.pj@gmail.com Introduction: Psoriasis and its treatments may predispose patients to various infections. This is considered one of the most significant complications in patients with psoriasis. Objectives: In the present study, we aimed to determine the prevalence of infection in hospitalized psoriasis patients and its relationship with systemic and biologic treatments. Methods: All hospitalized patients with psoriasis from 2018 to 2020 in Razi Hospital in Tehran, Iran, were studied and cases of infection were recorded. Results: Overall, 516 patients were studied and 25 types of infection in 111 patients were found. The most common types of infection were pharyngitis and cellulitis, followed by oral candida, urinary tract infections, common cold, fever of unknown origin, and pneumonia. Female sex and pustular psoriasis were significantly associated with infection in psoriatic patients. Those patients who received prednis- olone had a higher risk of infection, and those under treatment with methotrexate or infliximab had a lower risk of infection. Conclusion: Overall, 21.5% of psoriasis patients in our study had at least one episode of infection. This demonstrates that the prevalence of infection in these patients is not low. Using systemic steroids was associated with a higher risk of infection, while using methotrexate or infliximab was concomitant with a lower risk of infection. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 Introduction Psoriasis is a common, chronic, inflammatory cutaneous dis- ease, causing morbidity and mortality in severe cases. The approximate prevalence rate is 0.14-5.32% of the general population. [1, 2] The characteristic of psoriasis is sustained inflammation which causes uncontrolled proliferation of keratinocytes and dysfunctional differentiation that activates through TNF-α, IL-17, and IFN-γ. The psoriatic plaque’s histology shows acanthosis, which covers inflammatory infiltrates consisting of dermal den- dritic cells, macrophages, T cells, and neutrophils as well as neovascularization [3]. Infections are among the most concerning complications of psoriasis per se and its treatments. Two types of conven- tional and biological treatments are used to treat this disease. Biologic treatments are mostly used in more severe psoriasis patients; however, infections are the most crucial side effect of these drugs. Recent studies have found conflicting results regarding the prevalence of infection in this disease and its relationship with various systemic treatments. This study evaluated the prevalence of infection in psoriasis hospital- ized patients in a skin referral hospital and its relationship with variables such as biologic treatments in hospitalized patients with psoriasis. Methods In this retrospective cross-sectional study, all hospitalized pso- riasis patients from 2018 to 2020 in Razi Hospital in Tehran, Iran were examined for any documented infection. Demo- graphic data, psoriasis subtypes, the existence of arthropathy, and present treatments (methotrexate, prednisolone, cyclo- sporine, acitretin, phototherapy, topical treatment, and bio- logical treatment) were extracted. Furthermore, the wound, blood, and urine culture results were recorded. All hospital records over the course of the study were reviewed and cases of diagnosed psoriasis were included in the study. Cases of comorbid psoriasis with other skin disease were excluded. These data were analyzed with SPSS software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Ver- sion 25.0. Armonk, NY: IBM Corp). Associations between infections and other variables were examined using the Chi- Square test. The frequency has been calculated for quantita- tive data, mean and standard deviation, for qualitative data. The significance level was considered a P-value < 0.05. Con- fidence interval (CI) is the range of values between which you expect your estimate to be if you repeat your test, at a certain level of confidence. An odds ratio (OR) is a measure of how an exposure re- lates to a result. The OR represents the probability that a re- sult will occur as a result of a particular exposure compared to the probability that the result will occur in the absence of that exposure. Results Among 516 patients, 172 (33%) women and 344 (67%) men, with a mean age of 43.85 +/- 15.95 (range: 8 to 89). The mean age of men was greater than women (44.97 +/- 15.40 vs 41.62 +/- 16.83) (P- value: 0.024). 380 (73.6%), 106 (20.5%), 25 (4.8%), 4 (0.8%) and 1(0.2%) were plaque-type, pustular, erythrodermic, inverse and guttate, respectively. Furthermore, from 248 available data, 144 (58.06%) patients had arthropathy. Meanwhile, 111 (21.5%) patients had at least one episode of infection; overall, 166 cases were detected. Considering the low number of patients with inverse and guttate psoriasis, only plaque-type, pustular and erythroder- mic psoriasis were analyzed. The most common types of infection were pharyngitis, cellulitis followed by oral candidiasis, urinary tract infec- tions (UTI), common cold, fever of unknown origin (FUO), and pneumonia (Table 1). There was a significant correlation between age and oral candidiasis, UTI, and herpes simplex virus (HSV) infection (P-values: 0.023, 0.012, 0.001, respectively), while no signif- icant relationship was found between age and other types of infections (P-value<0.05 for all). Infections were 2 times more frequent in women (30.2%) than men (17.2%) (OR: 2.09, 95%CI: 1.36-3.21, P-value: 0.001). Additionally, oral candidiasis, flexural candidiasis, and erythrasma were significantly more common in women (P-values: 0.011, 0.044, 0.001, respectively). Regarding psoriasis subtypes, there was a significant relation between plaque-type and pustular psoriasis with in- fection (P-values: <0.001, OR: 0.282; P-value <0.001, OR: 3.845, respectively). In other words, patients with pustular and plaque-type psoriasis had a 3.8 and 2.8 times higher risk of infection in comparison with other subtypes, respectively. Furthermore, cellulitis, pharyngitis, FUO, oral candidiasis, UTI, vaginal candidiasis, and bacterial blepharitis were sig- nificantly more common in the pustular subtype (Table 2). Concerning the relationship between medications and infection, patients treated with prednisolone (OR: 2.93, 95%CI: 1.82-4.73, P-value< 0.001) had a higher risk of infection. From a total of 99 cases on prednisolone, 38 (38.4%) had at least one episode of infection, while the in- fection was seen in 73 (17.5%) out of 417 cases who were not receiving prednisolone (P-value: <0.001, OR: 2.93). On the other hand, those under treatment of methotrexate (OR: 2.1, 95%CI: 0.29-0.76, P-value: 0.002) or infliximab (OR: 5.12, 95%CI: 0.10-0.35, P-value< 0.001) had a lower risk of infection (Table 3). Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 3 In patients on prednisolone, the risk of cellulitis, pharyn- gitis, common cold, FUO, UTI, and blepharitis was higher. Additionally, cyclosporine was associated with a higher risk of FUO and patients receiving methotrexate had a lower chance of pharyngitis (Table 4). Regarding the anti-TNFα group, infliximab was associ- ated with a lower risk of cellulitis (OR:0.04, P-value: 0.001) (Table 4), while adalimumab and etanercept were not linked to any type of infection (all p-values>0.05). It is worth noting that although no case of active tuberculosis was recognized, Table 1. Types of infections and frequency of each occurrence in psoriatic patients. Type of infection Number of infections Total/Person Total/Infection1 2 3 Cellulitis 20 1 - 21 22 (13.25%) Pharyngitis 26 - 1 27 29 (17.47%) Common cold 11 - - 11 11 (6.62%) Pneumonia 7 - - 7 7 (4.21%) Paronychia 3 - - 3 3 (1.8%) FUO 5 - 1 6 8 (4.82%) Oral Candida 17 1 - 18 19 (11.44%) Conjunctivitis 5 1 - 6 7 (4.21%) UTI 12 1 1 14 17 (10.24%) HBV 3 - - 3 3 (1.8%) HCV 4 - - 4 4 (2.41%) HIV 3 - - 3 3 (1.8%) HSV 3 - - 3 3 (1.8%) Erythrasma 6 - - 6 6 (3.61%) Gastroenteritis 4 - - 4 4 (2.41%) Otitis externa 2 - - 2 2 (1.2%) Tuberculosis 1 - - 1 1 (0.6%) Epididymitis 1 - - 1 1 (0.6%) Axillary abscess 1 - - 1 1 (0.6%) Septic arthritis 2 - - 2 2 (1.2%) Impetigo 1 - - 1 1 (0.6%) Flexural candidiasis 7 - - 7 7 (4.21%) Folliculitis 1 - - 1 1 (0.6%) Vaginal Candidiasis 2 - - 2 2 (1.2%) Blepharitis 2 - - 2 2 (1.2%) Total 166 FUO: fever of unknown origin, UTI: urinary tract infection, HBV: hepatitis B virus, HCV: hepatitis C virus, HIV: human immunodeficiency virus, HSV: herpes simplex virus Table 2. The relationship between psoriasis subtypes and the most prevalent infection types. Plaque type Non- plaque type P-value Pustular type Non- pustular type P-value Cellulitis 8 (2.1%) 13 (9.6%) 0.000 11 (10.4%) 10 (2.4%) 0.001 Pharyngitis 15 (3.9%) 12 (8.8%) 0.028 11 (10.4%) 16 (3.9%) 0.008 FUO 1 (0.3%) 5 (3.7%) 0.006 4 (3.8%) 2 (0.5%) 0.018 Oral Candidiasis 7 (1.8%) 11 (8.1%) 0.002 9 (8.5%) 9 (2.2%) 0.004 UTI 7 (1.8%) 7 (5.1%) 0.061 6 (5.7%) 8 (2%) 0.047 HSV 0 (0%) 3 (2.2%) 0.018 2 (1.9%) 1 (0.2%) 0.109 Vaginal Candidiasis 0 (0%) 2 (1.5%) 0.069 2 (1.9%) 0 (0%) 0.042 Blepharitis 0 (0%) 2 (1.5%) 0.069 2 (1.9%) 0 (0%) 0.042 4 Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 detected micro-organisms in blood cultures. In urine cul- tures, E-coli (18.51%) followed by Pseudomonas (11.11%), and in wound cultures, Staph epidermidis (29.76%) fol- lowed by Staphylococcus aureus (28.57%) were the most common pathogens. 63 (12.2%) patients received isoniazid due to positive PPD and use of immunosuppressive therapy. Culture results were available in 82 cases; 45 (54.8%) were negative. Staphylococcus epidermidis (36.36%) fol- lowed by Enterobacter (9.09%) were the most commonly Table 3. The relationship between infections and current treatments. Infection Total P-value OR 95%CINo Yes Methotrexate No Count 237 83 320 0.002 0.47 0.29-0.76 % 74.10% 25.90% 100.00% Yes Count 168 28 196 % 85.70% 14.30% 100.00% Prednisolone No Count 344 73 417 0.000 2.93 1.82-4.73 % 82.50% 17.50% 100.00% Yes Count 61 38 99 % 61.60% 38.40% 100.00% Cyclosporine No Count 386 103 489 0.29 1.57 0.67-3.7 % 78.90% 21.10% 100.00% Yes Count 19 8 27 % 70.40% 29.60% 100.00% Acitretin No Count 249 54 303 0.075 1.68 0.81-1.57 % 82.20% 17.80% 100.00% Yes Count 186 27 213 % 87.32% 12.68% 100.00% Phototherapy No Count 375 100 475 0.38 1.37 0.66-2.84 % 78.90% 21.10% 100.00% Yes Count 30 11 41 % 73.20% 26.80% 100.00% Topical No Count 92 22 114 0.51 1.18 0.7-2 % 80.70% 19.30% 100.00% Yes Count 313 89 402 % 77.90% 22.10% 100.00% Infliximab No Count 241 98 339 0.000 0.19 0.10-0.35 % 71.10% 28.90% 100.00% Yes Count 164 13 177 % 92.70% 7.30% 100.00% Adalimumab No Count 401 110 511 1 0.91 0.1-8.23 % 78.50% 21.50% 100.00% Yes Count 4 1 5 % 80.00% 20.00% 100.00% Etanercept No Count 401 110 511 1 0.91 0.1-8.23 % 78.50% 21.50% 100.00% Yes Count 4 1 5 % 80.00% 20.00% 100.00% Total Count 405 111 516 % 78.50% 21.50% 100.00% Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 5 disease-based registry (PSOLAR) reported that the most common types of serious infections were pneumonia and cel- lulitis. [9] Likewise, in the present study, the most common infections were respiratory tract infections followed by skin infections and UTIs. In terms of the psoriasis subtypes, 50% of inverse, 42.5% of pustular, 24% of erythrodermic, and 15.3% of plaque-type psoriasis had a history of infection. In the pres- ent study, the chance of infection in patients with pustu- lar psoriasis was 3.8 times higher than with other types; however, because of the low frequency of inverse psoriasis, the high frequency of infections in this group cannot be inferred. Patients with psoriasis may be more susceptible to infec- tions due to both the disease per se and the immunosuppres- sive medications. Previous studies have shown conflicting results about the correlation between different treatments and the risk of infection. The essential difference between the biologic and conventional treatments, using combina- tion therapies, could be considered possible reasons for this discrepancy. In our study, cyclosporine was significantly associated with FUO, although the overall risk of infection was not higher in contrast to Sejio et al., who reported a higher risk of overall and serious infections. [10] Likewise, pred- nisolone was associated with 2.93 times more frequent infections. Furthermore, we did not find any relationship between acitretin and infections, while Seijo et al. reported a lower risk of infection with acitretin. [10] These controver- sial results could be due to the predominant use of acitretin as a combination therapy with other drugs in the present study. Another controversial finding of our study was the lower risk of infection among patients treated with metho- trexate, which is not in concordance with its immunosup- pressive nature. These controversies also exist in the prevalence of infec- tions in psoriasis patients using biologic drugs. Hsu et al. stated that biologic treatments might increase the risk of Discussion In the present study, we found that 21.5% of hospitalized psoriasis patients had at least one episode of infection; a to- tal of 25 types were recorded in 111 patients. Men outnum- bered women in this study, which may reflect more severe disease needing hospitalization in men. However, psoriatic women were more prone to infections. In our study, the most common types of infection were pharyngitis (n=29), cellulitis (n=22), oral candidiasis (n=19), UTI (n=17), common cold (n=11), FUO (n=8) and pneumo- nia (n=7). There was a significant correlation between age and oral candidiasis, UTI, and HSV. Previous studies have shown a higher prevalence of oral and cutaneous candida colonization and infection in psoriasis. [4, 5] Similarly, in the present study, oral candidiasis was the third most com- mon infection, especially seen in the elderly; this may be partly attributed to dentures. Meanwhile, the older age of prevalence of UTI could be due to more common genitouri- nary problems in the elderly and lack of personal hygiene in this group. We did not have precise details regarding the reason for the patients’ hospitalization, although it was primarily due to the psoriasis flare-up and not the infections per se. The most serious infections that led to hospitalization in this study were probably cellulitis followed by UTI. In a Prospective Cohort Study from the British Associ- ation of Dermatologists Biologic and Immunomodulators Register, the most common types of infection in psoriatic patients were lower respiratory tract infections, followed by skin and soft tissue infections, and urinary tract infec- tions. [6] While in a cohort study in the United Kingdom, upper and lower respiratory tract infections were the most prevalent. [7] In addition, a population-based cohort in the Netherlands showed that respiratory tract, abdominal, and skin infections occurred most frequently in patients with psoriasis. [8] Another study in a multicenter, longitudinal, Table 4. The relationship between treatments and the most prevalent infection types. Methotrexate Prednisolone Cyclosporine Infliximab P-value OR P-value OR P-value OR P-value OR Cellulitis 0.172 0.497 0.042 2.73 0.302 1.97 0.001* 0.04 Pharyngitis 0.032* 0.355 0.016 2.64 0.645 1.48 0.346 0.65 Common cold 0.755 1.37 0.009 5.31 1 0.75 0.108 0.18 FUO 0.088 0.12 0.001 22.12 0.035 9.7 0.669 0.38 UTI 0.703 1.23 0.034 3.29 0.533 1.408 0.154 0.31 Blepharitis 0.528 0.32 0.037 21.41 0.102 18.77 1 1.92 *Negative correlation 6 Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 References 1. Al Salman M, Ghiasi M, Farid AS, Taraz M, Azizpour A, Mahmoudi H. Oral simvastatin combined with narrowband UVB for the treatment of psoriasis: A randomized controlled trial. 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Davila-Seijo P, Dauden E, Descalzo MA, Carretero G, Carrascosa JM, Vanaclocha F, et al. Infections in Moderate to Severe Psori- asis Patients Treated with Biological Drugs Compared to Classic Systemic Drugs: Findings from the BIOBADADERM Registry. The Journal of investigative dermatology. 2017;137(2):313-21. 11. Hsu DY GK, Silverberg JI. Serious infections in hospitalized patients with psoriasis in the United States. Journal of the American Academy of Dermatology. 2016;75(2):287-96. 12. Carneiro C, Bloom R, Ibler E, Majewski S, Sable KA, Guido NJ, et al. Rate of serious infection in patients who are prescribed systemic biologic or nonbiologic agents for psoriasis: A large, single center, retrospective, observational cohort study. 2017;30(5):e12529. 13. Yiu ZZ, Exton LS, Jabbar-Lopez Z, Mustapa MFM, Samarasekera EJ, Burden AD, et al. Risk of serious infections in patients with psoriasis on biologic therapies: a systematic review and meta-analysis. 2016;136(8):1584-91. 14. Garcia-Doval I, Cohen AD, Cazzaniga S, Feldhamer I, Addis A, Carretero G, et al. Risk of serious infections, cutaneous bacte- rial infections, and granulomatous infections in patients with psoriasis treated with anti–tumor necrosis factor agents versus infection by controlling the inflammatory process and decreasing the disease severity or increasing this risk by suppressing the immune system. [11] In the present study, patients being treated with TNF-a inhibitors did not have any increase in infection risk, and even a lower risk of cellulitis was detected among patients using infliximab. Carneiro et al. [12] and Wakkee et al. [8] did not report any increase in infection risk in patients using biologic treatments compared with conventional drugs. Likewise, according to the Yiu et al. [13] and Garcia-Doval [14] studies, no increased risk of serious infections was found in patients on anti-TNF treatments. On the other hand, Yiu et al. have shown that infliximab was associated with a two-fold increased risk of serious infections compared with non-biologic treatments and a 3-fold increased risk compared with methotrexate. [15] Additionally, in a cohort study, Kalb et al. showed that serious infections were more likely to occur with adalimumab and infliximab than with non-biologic and non-methotrexate treatments. [9] Like- wise, in three other studies, the authors found a higher risk of infection in biologic treatment compared with conven- tional treatments. In recent studies, Systemic-immune inflammation index (SII) (neutrophil X platelet/lymphocyte) as a new complete blood cell index has been used in the prediction of disease progression and was associated with psoriasis activation and severity. Significantly higher SII values were present in higher PASI scores and indicated increased inflammatory response and poor prognosis. SII can also be an additional indicator of disease activation in autoimmune diseases such as Behçet’s disease. [16, 17] Limitation This retrospective survey was restricted solely to inpatient psoriatic cases admitted in the dermatology ward of a skin referral hospital. Therefore, information about patients treated in outpatient clinics and those hospitalized in general hospitals was unavailable. This study was conducted before the COVID-19 outbreak; therefore, it lacks data regarding the relationship between the risk of COVID-19 infection and the variables mentioned above. Conclusion Overall, 21.5% of psoriasis patients in the present study had at least one episode of infection. We observed an increased risk of infection in patients receiving prednisolone, while there was no increase in infection risk in patients treated with biologic drugs and even a relatively reduced risk in MTX-treated patients. Original Article | Dermatol Pract Concept. 2023;13(1):e2023027 7 16. Dincer Rota D, Tanacan E. The utility of systemic-immune in- flammation index for predicting the disease activation in pa- tients with psoriasis. International Journal of Clinical Practice. 2021;75(6):e14101. 17. Tanacan E, Dincer D, Erdogan FG, Gurler A. A cutoff value for the Systemic Immune-Inflammation Index in determining activ- ity of Behçet disease. Clinical and experimental dermatology. 2021;46(2):286-91. classic therapies: Prospective meta-analysis of Psonet registries. 2017;76(2):299-308. e16. 15. Yiu ZZN, Ashcroft DM, Evans I, McElhone K, Lunt M, Smith CH, et al. Infliximab is associated with an increased risk of seri- ous infection in patients with psoriasis in the U.K. and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR). The British journal of dermatology. 2019;180(2):329-37.