Cecal appendicitis as a rare manifestation of paracoccidioidomycosis: a case report and systematic review of the literature

Cecal appendicitis as a rare manifestation of paracoccidioidomycosis: a case report and systematic review of the literature | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Cecal appendicitis as a rare manifestation of paracoccidioidomycosis: a case report and systematic review of the literature Isadora de Lima Xavier Andrade, Bruna Abdul Ahad Saad, Alexandre Albuquerque Bertucci, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6147795/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Paracoccidioidomycosis (PCM) is a systemic mycosis endemic to Latin America, with the acute/subacute form predominantly affecting children and young adults. Cases of cecal appendicitis caused by Paracoccidioides spp. have rarely been reported. This study aimed to describe the clinical manifestations and evolution of a case of cecal appendicitis due to PCM and to conduct a systematic literature review. A case report and systematic review were conducted using Embase, Web of Science, LILACS, MEDLINE, LIEPCS, PubMed, SciELO, and Gray Literature databases. We present the case of a 20-year-old male with generalized lymphadenopathy who was diagnosed with PCM and treated with oral trimethoprim-sulfamethoxazole. After the initial improvement, the patient returned with clinical deterioration. The treatment was changed to liposomal amphotericin B. Six days later, the patient developed an acute abdomen and underwent exploratory laparotomy with appendectomy. Histopathological examination confirmed acute granulomatous appendicitis due to PCM, and the patient showed postoperative clinical improvement. Of the 11 identified articles included in the systematic review, most case reports with a low risk of bias were found in South American countries. Five patients had confirmed appendicitis due to PCM through biopsy, while others had confirmed PCM at another site. Two patients were initially misdiagnosed with Crohn's. Most studies have reported favorable outcomes. Appendicitis caused by PCM is rare, even in endemic countries. It has a benign course when properly treated with both clinical and surgical management. This should be considered in the differential diagnosis of acute abdomen with lymphadenopathy in endemic regions. Paracoccidioidomycosis Paracoccidioides brasiliensis appendicitis appendectomy acute abdomen Figures Figure 1 Figure 2 Figure 3 Introduction Paracoccidioidomycosis (PCM) is a systemic mycosis endemic to Brazil, accounting for more than 80% of reported cases of the disease [1]. PCM is also found in almost all Latin American countries [2]. The etiological agents belong to the genus Paracoccidioides , with the main representatives being the P. brasiliensis complex (including P. brasiliensis sensu stricto, P. americana , P. restrepiensis , and P. venezuelensis ) and P. lutzii [3]. These fungi are found in nature and human infections occur through the inhalation of infectious propagules and spores. The main risk factor is soil exposure, usually during the first two decades of life, which is the period during which infection is acquired. However, clinical manifestations of the disease often appear several years later [4]. PCM manifests in two main clinical forms: the chronic form, which accounts for most cases, and the acute/subacute form (ASF). The chronic form is characterized by symptoms that persist for more than six months and predominantly affects the lungs, upper airways, and digestive tract. ASF is more common in children, adolescents, and young adults and mainly involves the organs of the mononuclear phagocytic system, including the lymph nodes, bone marrow, liver, and spleen [5]. Involvement of the cecal appendix in PCM, which is part of the gut-associated lymphoid tissue (GALT), has rarely been described in the literature, and its diagnosis can be challenging. Therefore, the present study aimed to describe the clinical, diagnostic, and therapeutic manifestations of appendicitis caused by Paracoccidioides spp. through a case report and systematic literature review. Methods The CARE guidelines [6] were used in this case report. The patient provided informed consent for publication of the cases, and the project was approved by the Institutional Review Board of the Universidade Federal de Mato Grosso do Sul, Brazil (protocol number 2.102.875). Written informed consent for publication was obtained from the patient. 1 Case Report Data Collection: Data related to the patients’ age, sex, clinical and epidemiological characteristics, laboratory and imaging results, and culture results of the biological materials were collected from the patients’ medical records. 2 Systematic Review A systematic review was conducted, as recommended by the AMSTAR 2 tool (A MeaSuremen Tool to Assess systematic Reviews) [7]. The description was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [8]. The systematic review protocol was registered under number CRD42024508229 on PROSPERO (International Prospective Register of Systematic Reviews): https://www.crd.york.ac.uk/prospero/ . 2.1 Search Strategies and Eligibility Criteria The research question in the protocol was as follows: What is the clinical course of patients with cecal appendix involvement by Paracoccidioides spp.? Patients with a confirmed diagnosis of cecal appendicitis caused by Paracoccidioides spp., with an assessment of clinical manifestations, treatment, and outcomes, were included. EPPI Reviewer 6 software (version 6.15) was used ( https://eppi.ioe.ac.uk/cms/Default.aspx?tabid=2914 ). Two reviewers (ILXA and BAAS) screened titles, abstracts, and descriptors to identify articles for analysis. A third reviewer (CEVC) screened all excluded abstracts and any conflicts were resolved. Searches were conducted in August 2023, and the search strategy was updated until July 2024. The Embase, Web of Science, LILACS, MEDLINE, LIEPCS, PubMed, and SciELO databases were used. Searches for unpublished studies were conducted in Open Grey ( http://www.opengrey.eu/ ), the CAPES Thesis and Dissertation Bank, the Brazilian Digital Library of Theses and Dissertations (BDTD), Open Access Theses and Dissertations (OATD), MedNar, and WorldWidescience.org. The complete search strategy is shown in Supplementary Information (Appendix 1). To construct search strategies for each database, descriptors from MeSH (Medical Subject Headings) and other related terms, including EMTREE terms, were selected. The search strategy consisted of the following terms: (((appendicitis[MeSH Terms]) OR (appendices, omental[MeSH Terms])) OR (small intestine[MeSH Terms])) AND ((((paracoccidioides brasilienses[MeSH Terms])) OR (paracoccidioidomycoses[MeSH Terms]))) and “paracocc*” and “apendic*.” Articles that were irrelevant to the theme or were duplicates were excluded. Articles meeting the inclusion criteria were read in full and the data obtained from each study were recorded by the EPPI Reviewer. Only articles that met the inclusion criteria for clinical cases of PCM involving the cecal appendix were selected for data extraction. We conducted several tests to make the search strategy as sensitive as possible; however, only a few articles were found. For this reason, some articles included for full reading and some included cases of appendicitis caused by PCM were found through a manual search, mainly by reviewing the references of the included studies as well as through our outpatient clinic's PCM research database. After reading the full texts, articles that did not meet the inclusion criteria were excluded and the reasons for exclusion were recorded. The search results are reported in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2020) flowchart and an evidence map. Articles included for full reading that could not be accessed after several attempts were excluded. The authors of these articles were contacted via email or the ResearchGate platform ( https://www.researchgate.net/ ), and only one author responded to our inquiry. Some articles could not be found because they were old. 2.2 Data Extraction Data were extracted by two reviewers (IXLA and BAAS), and the accuracy and completeness were verified by a third reviewer (CEVC). A table was used to characterize the articles based on the following information: study type, age, sex, clinical presentation, diagnostic method, pharmacological treatment, and outcomes. 2.3 Risk of Bias Assessment The risk of bias assessment was carried out by one reviewer (CEVC) using the guidelines recommended by the Joanna Briggs Institute (JBI) [9]. Full verification of all judgments was performed by a second reviewer (BAAS). The JBI critical appraisal checklist for textual evidence includes the following options: N (no), N/A (not applicable), U (unclear), and Y (yes). The risk of bias was interpreted based on the proportion of items met: low risk of bias (most critical items were met), moderate risk of bias (some important items were not met), and high risk of bias (many critical items were not met). 2.4 Evidence map To characterize the volume, characteristics, outcomes, and quality of the available studies, we developed an evidence map to visually summarize the main information found in the systematic review. We used EPPI Reviewer 6 software (version 6.15) ( https://eppi.ioe.ac.uk/cms/Default.aspx?tabid=2914 ). Results 3 Case Presentation A 20-year-old male patient, born and residing in Campo Grande, MS, working for an urban waste selective collection company, presented with a history of a nine-kilogram weight loss and generalized lymphadenopathy for three months, initially affecting the cervical region and later involving the bilateral axillary and inguinal regions. One week before admission, he developed febrile peaks of 38°C, fatigue, odynophagia, and hyporexia. The patient denied any comorbidities, medication use, previous hospitalizations or surgeries, or history of allergies. On physical examination, lymphadenopathy was observed bilaterally in the preauricular, retroauricular, right occipital, superficial and deep cervical, tonsillar, subclavicular, submental, axillary, and inguinal lymph node chains, with sizes ranging from one to two centimeters (cm), painful, and fixed. Larger lymph nodes were found in the left superficial cervical, left subclavicular, submental, left retroauricular, and right superficial cervical chains, varying between three and seven cm, and were painful and fixed. Laboratory tests revealed normocytic and normochromic anemia, leukocytosis with a left shift, elevated C-reactive protein (CRP), and hypoalbuminemia (see Supplement 1, Table 1 ). The antibody test for anti- Paracoccidioides using double immunodiffusion in agar gel was positive, with a titer of 1:64. Computed tomography (CT) of the cervical region revealed enlarged lymph nodes in all the cervical, supraclavicular, and axillary lymph node chains, several of which exhibited liquefied necrotic centers (Fig. 1 ). Treatment with trimethoprim-sulfamethoxazole (TMP-SMX) was initiated orally at a dose of 800/160 mg every 8 h, and the patient was discharged with clinical improvement after four days of treatment. Itraconazole was not initiated because of intestinal involvement and erratic absorption. After 11 days, the patient returned to the outpatient clinic with poor adherence to pharmacological treatment, fever, and persistent diffuse lymphadenopathy. An attempt was made to use intravenous fluconazole; however, the patient did not tolerate it and was maintained on TMP-SMX, taking two tablets orally (PO) every 8 h. The patient returned to the outpatient clinic after three weeks and presented with significant abdominal pain and increased cervical lymphadenopathy. Liposomal amphotericin B (L-AmB) was administered at a dose of 150 mg/day in a day hospital setting. Six days after starting L-AmB, the patient experienced worsening abdominal pain, particularly in the right inguinal region, with a negative Blumberg sign but positive Dunphy and Rovsing signs. An ultrasound of the entire abdomen revealed a fluid collection with thin septations in the posterior cul-de-sac, measuring 8.6 x 5.3 cm, and an elongated image with imprecise contours in the right iliac fossa, measuring 8.0 x 2.6 cm, suggestive of acute cecal appendicitis (ACA). The patient underwent appendectomy. Histopathological examination of the cecal appendix showed an intense granulomatous inflammatory process in the wall of the appendix with multinucleated giant cells and numerous fungal structures compatible with Paracoccidioides spp., highlighted by Grocott–Gomori staining (Fig. 2 ). The patient was discharged from the hospital with progressive clinical improvement and continued treatment with TMP- SMX. The patient remains under outpatient follow-up. The timeline of the reported case is described in Supplementary Information, Fig. 1 . 4 Systematic Literature Review Using this search strategy, 91 articles based on case reports were identified. The articles were written in Portuguese, English and Spanish, with the publication years ranging from 1913 to 2023. Twelve articles were excluded because of duplication, and 77 articles were eligible for title and abstract reading. Thirty-seven articles were eligible for full-text review. Twenty-eight articles were excluded after reading their full texts. The results of the search strategy are shown in Fig. 3 . Eleven articles [5, 10–19] met the inclusion criteria for clinical cases of PCM affecting the cecal appendix, and the characteristics of the studies are described in Table 1 . We also included the data from our case reports (Table 1 ). A meta-analysis was not conducted due to the small number of included articles. Table 1 Characterization of included studies with cecal appendicitis caused by paracoccidioidomycosis Reference Country Study type Age (years) Sex Comorbidities Clinical presentation Diagnostic method Pharmacological treatment Outcome Viana, 1913* 10 Brazil Case report No report * No report * No report * No report * No report * No report * Autopsy study Cesar, Carini, Lauand, Lia, 1962** 11 Brazil Case report No report ** No report ** No report ** No report** No report ** No report ** No report ** Barbosa, Daher, Oliveira, 1968 12 Brazil Case report – Case series 26 M No report Sudden abdominal pain with nausea, vomiting, and sweating Histopathology of ACA due to PCM No report No report Bittencourt et al., 1988 13 Brazil Case report 4 M No report Fever, dry cough, weight loss, dyspnea, and enlarged cervical lymph nodes. Presence of hepatosplenomegaly and abdominal mass Postmortem necrotic appendicitis and positive skin test with paracoccidioidin, and histopathology of the cervical lymph node with a culture positive for P. brasiliensis Did not receive pharmacological treatment Death Navas et al., 1994 Venezuela Case report 20 No report *** No report *** No report*** No report *** TMP- SMX Satisfactory response to treatment. *** Muñoz Urribarri et al., 2006 15 Peru Case report 5 M Previously healthy Fever, vomiting, abdominal distension, and abdominal pain Histopathology of ACA due to PCM Itraconazole 10 mg/kg/day PO Clinical improvement and outpatient follow-up Gava et al., 2015 16 Brazil Case report - Letters to the editor 20 M Crohn's disease as a misdiagnosis and use of immunosuppressants Hematochezia, enterorrhagia, and weight loss; papular Histopathology of oral lesion and abdominal CT with description of ACA. Appendectomy not performed. L-AmB IV Satisfactory clinical response. Surgery was not performed. Da Cruz et al., 2021 5 Brazil Case report 32 F Previously healthy Acute abdominal pain in the right iliac fossa, and abdominal distension Histopathology of ileum, colon, and pericolic lymph nodes. Abdominal CT showing signs of ACA D-AmB 50 mg/day IV for 28 days Clinical improvement and outpatient follow-up Luna-Vilchez et al., 2022 17 Peru Case report 10 M Previously healthy Fever, generalized lymphadenopathy, weight loss, diarrhea, pain in the right iliac fossa Histopathology of ACA due to PCM L-AmB 3mg/kg/day IV for 14 days Clinical improvement and outpatient follow-up Sales et al., 2022 **** 18 Brazil Case report – Poster at a conference 33 M Previously healthy Periumbilical and lower abdomen pain associated with nausea, hyporexia, and weight loss Histopathology of ACA due to PCM No report of the antifungal used Clinical improvement and outpatient follow-up Marinho Falcão et al., 2023 19 Brazil Case report 42 M Crohn's disease as a misdiagnosis and use of corticosteroids odynophagia, weight loss, disseminated skin lesions, diffuse lymphadenopathy and significant abdominal pain Histopathology of ACA due to PCM Itraconazole 400 mg/day PO for 24 months Clinical cure Andrade et al., 2024 ***** Brazil This case report 20 M Previously healthy Weight loss, disseminated lymphadenopathy, abdominal pain Histopathology of ACA due to PCM TMP- SMX 800/160 mg PO every 8 hours. Followed by L-AmB 3 mg/kg/day for 10 days, and then resuming TMP- SMX PO for outpatient treatment Clinical improvement and outpatient follow-up ACA, acute cecal appendicitis; PO, oral route; IV, intravenous; M, male; F, female. PCM, paracoccidioidomycosis; TMP− SMX, trimethoprim−sulfamethoxazole; CT, computed tomography; L−AmB, liposomal amphotericin B; D−AmB, deoxycholate amphotericin B; *Thesis description not found, but cited by Barbosa, Daher, Oliveira, 1968 as an autopsy study as the first report of cecal appendicitis; **Article not found, cited by Andrade, 1983 as a case report of cecal appendicitis due to PCM; ***Article not found and data extracted from the abstract; ****Data extracted from a conference poster. *****Data from this case report . Of the 11 articles included as cases of cecal appendicitis due to PCM, six were found through a manual search, as listed in Supplementary Information, Table 2. The studies that met the criteria for the systematic review were all case reports, including one described in a thesis from 1913 [10], one study presented as a letter to the editor [16], and one presented as conference posters [18]. Eight reports were from Brazil [5, 10–13, 16, 18, 19], two from Peru [15, 17], and one from Venezuela [14], covering the period from 1913 to 2023. In two studies [10, 11], access to case reports was not possible; they were only referenced in the included studies. Seven patients were male, one was female, and three were of unspecified sex. Their ages ranged from four to 42 years. The main symptoms were abdominal pain, weight loss, fever, and presence of lymph nodes. Six patients were previously healthy [5, 15–19] but two were treated for Crohn’s disease prior to the diagnosis of PCM and had used immunosuppressants [16] and corticosteroids [19], which intensified the progression of PCM. One patient who died had a presumptive diagnosis of non-Hodgkin lymphoma due to an abdominal mass and did not present with abdominal pain [13]. Five cases were confirmed through histopathology of the appendix, identifying the agent Paracoccidioides spp. [12, 15, 17–19]. Other studies confirmed PCM histopathologically at other sites [5, 13, 16]. Two cases were diagnosed using abdominal CT [5, 16]. In two cases, the diagnosis was made postmortem [10, 13]. In the cases described in the systematic review, three patients were treated with AmB, with two receiving L-AmB [16, 17] and one receiving D-AmB [5]. Two patients were treated only with itraconazole from the diagnosis [15, 19] and two patients received itraconazole after induction therapy with D-AmB [5] and L-AmB [17]. One patient was treated with TMP- SMX [14]. One study did not report outpatient treatment following the use of L-AmB [16] and four studies did not report any pharmacological treatment instituted [10–12, 18]. Seven patients showed clinical improvement after treatment [5, 14–19]. One patient showed clinical improvement with pharmacological treatment alone and did not require surgery [16]. One patient died without receiving treatment [13]. Four articles did not report the clinical outcome [10–12, 14]. In the risk of bias assessment (JBI) for the cases included in the systematic review, five articles were rated as having a low risk of bias [5, 12, 15, 17, 19]; two reports were rated as having a moderate risk of bias [12, 16] and four articles were rated as having a high risk of bias [10, 11, 14, 18] due to not being accessible for full-text reading (see Suplementary Information, Table 3). We did not exclude articles with a high risk of bias owing to the small number of reported cases. In Supplementary Information (Fig. 2 ), we present an evidence map to characterize the volume, characteristics, outcomes, and quality of the available studies. Discussion This study reports a rare form of ACA caused by P. brasiliensis in a case with acute/subacute PCM (AS-PCM) following an exploratory laparotomy of the acute abdomen during the initial phase of treatment. AS-PCM accounts for a minority of reported cases in the literature (5–10%) and primarily affects children and young adults [4] consistent with our patient's presentation, who exhibited classic signs and symptoms at onset, such as fever, weight loss, anorexia, and generalized lymphadenopathy. Although the patient was not directly involved in rural activities, a significant epidemiological factor in PCM [20], he worked at a waste collection company and was occasionally exposed to inhaled soil particles while passing through unpaved streets, which may have been a route of infection for the fungus. In Campo Grande, the patients’ place of origin, PCM cases were monitored at the Systemic Mycoses Outpatient Clinic of Maria Aparecida Pedrossian University Hospital. A study conducted at this reference service found that AS-PCM was more frequent among patients in their second and third decades of life, with an average age of 22.2 years and a male-to-female ratio of 3:1. The main clinical manifestations include involvement of the mononuclear phagocyte system, primarily lymphadenopathy (95.4%), hepatomegaly (40%), and splenomegaly (23.1%) [21]. Another study published in 2014 showed that in Mato Grosso do Sul, the prevalence of the ASF during in 2000–2009 decade decreased compared to the two previous decades, probably due to an intense campaign against child labor in agriculture in the country [22]. Our patient presented with typical feature of appendicitis, including right lower quadrant pain and a positive Dunphy and Rovsing signs. Laboratory findings revealed leukocytosis with left shift and elevated CRP levels. Preoperatively distinguishing between bacterial ACA and appendicitis caused by PCM is challenging and is often achieved only through histopathological examination of the resected appendix. Although appendectomy is a common and often necessary intervention for appendicitis related to PCM, follow-up with appropriate antifungal treatments is crucial to prevent recurrence or complications. The systematic review identified only 11 documented cases of cecal appendicitis caused by Paracoccidioides spp. [5, 10–19], indicating that this is a rare disease restricted to South American countries. Most of the described cases had favorable outcomes following diagnosis and treatment. One case was untreated, and the diagnosis was made only late, resulting in the patient’s death [13]. The first report of cecal appendicitis by PCM described in 1914 [10] was diagnosed during an autopsy; however, we did not have access to the article. In addition, we believe that many cases are either undiagnosed or unreported. This also reflects the difficulty in identifying cases using our search strategy, necessitating the use of grey literature and references from the included studies. In our review, we observed reports of older cases [10, 11, 12], where in two instances [10, 11], we did not have access to the full text of the articles. One case was described in letters to the editor [16], one in a conference poster [18], and one for which we only had access to the abstract [14]. With characteristics similar to those of our case report, studies on cecal appendicitis have involved young patients between the ages of 4 and 42 years, the vast majority of whom were male and previously healthy. The main symptoms include abdominal pain, fever, weight loss, and lymphadenopathy, highlighting the presence of a systemic disease. On the initial abdominal CT scan, the patient presented with adenopathy in the inguinal chains and thickened and hyperechoic mesenteric fat with an inflammatory appearance suggestive of diffuse enteropathy. There are numerous reports in the literature of PCM mimicking Crohn's disease or ulcerative colitis, as in the case described in 1979, due to its tendency to affect intestinal lymph nodes and cause enteropathy [23]. Furthermore, this diagnostic confusion led to inadequate treatment and consequently greater immunosuppression in the two cases reported in our review, resulting in clinical progression and surgical complications [16, 19]. We opted not to initiate pharmacological treatment with itraconazole due to intestinal involvement, as absorption of this medication would likely be impaired in this case [24]. The patient was discharged on TMP-SMX 800/160 mg every 8 h, as indicated in the latest PCM consensus, which includes this as one of the treatment options [20]. In our systematic review, we observed no preference for treatment; however, in general, conventional or lipid formulations of amphotericin B may have been initially chosen in three studies [5, 16, 17] due to the severity of the cases and difficulty with oral absorption. However, other patients were treated with oral drugs such as TMP-SMX [14], or itraconazole [15, 19]. What we observed that the most important factor was immediate initiation of treatment. The only patient who did not receive treatment progressed to death [13]. With the worsening of the clinical picture and significant abdominal pain, the possibility of a paradoxical reaction was raised, which can be explained by clinical deterioration during appropriate treatment of the infectious agent. Given the patient’s irregular medication use, the primary hypothesis was disease progression in the acute/subacute phase; however, we did not dismiss the possibility of appendicitis due to a paradoxical reaction, as an exacerbation of the immune response may have occurred after the treatment began [25]. A common characteristic of the cases in the systematic review, including the one presented in this study, was that five of the reported cases had a diagnosis confirmed by histopathological examination of the appendix, with cases subsequently leading to appendectomy. One report highlighted the need for early diagnosis, including inflammation of the appendix caused by PCM, as in this case [16], the patient received only pharmacological treatment and did not require surgical intervention. Appendicitis likely developed because of the involvement of the intestinal lymph nodes by the fungus, leading to an ileocecal mass that caused obstruction and subsequent suppuration of the appendix [16]. Overall, despite treatment initiation, the reported lethality for all forms of PCM was between 6.1% and 7.6% [21, 26]. In our case, the evolution was satisfactory and comparable to most cases involving cecal appendicitis reported in our review. In a study of 46 clinical cases of intestinal PCM, 12.8% of patients died [5]. In our systematic review, one patient did not present with abdominal pain suggestive of appendicitis and was initially managed as a suspected case of non-Hodgkin lymphoma, with clinical deterioration. The diagnosis of PCM with necrosis of the appendix was confirmed only after death [13]. Furthermore, the first reported case of cecal appendicitis caused by PCM was described in an autopsy study [10]. The main limitations of this study, which can also be observed in the evidence map (Supplementary Information, Fig. 2 ), are: 1. limited number of reported cases in the literature, primarily from South America; 2. very old studies; 3. difficulty contacting authors for article retrieval: 4. many articles were excluded because of a lack of access; 5. data were not available for some studies with a moderate and high risk of bias. The literature does not describe the diagnostic challenges in differentiating cecal appendicitis caused by PCM from other infectious or inflammatory etiologies or clinical studies addressing the best therapeutic management in such cases. Additionally, the absence of compulsory notification for the disease in Brazil hampers our ability to identify the true impact and complications of these two clinical presentations. Satisfactorily, our patient was discharged and is currently under outpatient follow-up. Conclusion Cecal appendicitis due to PCM is a rare presentation of the ASF of PCM. It affects young individuals and can be difficult to diagnose even in endemic regions of Latin America. With accurate diagnosis and appropriate treatment, including surgical intervention, outcomes can be satisfactory. Particularly in endemic areas, gastrointestinal involvement leading to cecal appendicitis due to invasive fungal disease should be considered as it may be confused with other inflammatory bowel diseases and treated with immunosuppressive therapies that can trigger dissemination and potentially unfavorable outcomes. Abbreviations ACA, acute cecal appendicitis; CT, computed tomography; PCM, paracoccidioidomycosis; ASF, acute/subacute form; AS-PCM, acute/subacute PCM; TMP-SMX, trimethoprim-sulfamethoxazole; AmB, amphotericin; L-AmB, liposomal amphotericin B; D-AmB, amphotericin; DM, direct mycology; US, ultrasound; CRP, C-reactive protein; PO, oral administration. Declarations Funding 1. Universidade Federal de Mato Grosso do Sul (grant number: code 001); 2. Conselho Nacional de Desenvolvimento Científico e Tecnológico (Grant number: 312910/2020-7); 3. Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado do Mato Grosso do Sul (Grant number: 06/2021). Competing interests The authors declare that they have no competing interests. Author Contributions Isadora de Lima Xavier Andrade, Cláudia Elizabeth Volpe-Chaves, Anamaria Mello Miranda Paniago contributed to the study conception and design. Material preparation, data collection and analysis were performed by Isadora de Lima Xavier Andrade, Bruna Abdul Ahad Saad, Alexandre Albuquerque Bertucci, Marcel Arakaki Asato, João Paulo Gregório Machado, Maína de Oliveira Nunes, Eliana da Costa Alvarenga de Brito, James Venturini, Sandra Maria do Valle Leone de Oliveira, Cláudia Elizabeth Volpe-Chaves, Anamaria Mello Miranda Paniago. The first draft of the manuscript was written by Isadora de Lima Xavier Andrade, Bruna Abdul Ahad Saad, Cláudia Elizabeth Volpe-Chaves, Anamaria Mello Miranda Paniago and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics approval and consent to participate The project was approved by the Institutional Review Board of the Federal University of Mato Grosso do Sul, Brazil (protocol number 2.102.875), and the patient provided informed consent for the publication of the case. The systematic review protocol was registered under number CRD42024508229 on PROSPERO (International Prospective Register of Systematic Reviews): https://www.crd.york.ac.uk/prospero/. Acknowledgements: We thank the teams of the Unidade de Doenças Infecciosas e Parasitárias, Hospital dia Esterina Corsini e Hospital Universitário Maria Aparecida Pedrossian/EBSERH. We also thank the Universidade Federal de Mato Grosso do Sul (UFMS). 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Forma linfático-abdominal da blastomicose Sul-americana. Rev. Inst. Med. trop. São Paulo. 1968;10(1):16-21. Bittencourt AL, de Andrade JAF, Cendon Filha SP. Paracoccidioidomycosis in a four-year-old boy. Mycopathologia, 1993;93:55–9. Navas T, Castillo R, García W, Mora A, Zambrano G, Sambrano F, et al. Abdomen agudo quirurgico: presentación infrecuente en una paracoccidioidosis sistemica. Med. interna (Caracas). 1994;10(1):25-9. Muñoz-Urribarri AB, Chaparro Dammert E, Ferrufino Llach JC, Vasquez Flores Luciola, et al. Apendicitis por Paracoccidioides brasiliensis . Revista Medica Herediana, 2006;17(1):58-60. Gava P, de Melo AS, Marchiori E, Costa MH, Pereira E, Rangel RD. Intestinal and appendiceal paracoccidioidomycosis. Radiol Bras. 2015;48(2):126-7. Luna-Vilchez M, Chiara-Chilet C, Maquera-Afaray J, Portillo-Alvarez D, López JW. Paracoccidioidomicosis sistémica con compromiso del apéndice cecal en un niño: reporte de caso. Revista Peruana de Medicina Experimental y Salud Publica. 2022;38:660-3. Sales LFNC, Martins FP, Castro ALD, Gomes VMS, Assunção PB, Matos GBC. Apendicite associada à infecção por Paracoccidioides brasiliensis : um relato de caso [poster]. XXI Semana do Aparelho Digestivo. 2022; Brazil. Marinho-Falcão EM, da Costa Medeiros M, Freitas A, de Almeida Soares JC, Fernandes Pimentel MI, Quintella LP, et al. Acute paracoccidioidomycosis worsened by immunosuppressive therapy due to a misdiagnosis of Crohn’s disease. PLoS Negl Trop Dis. 2023;17(1):e0011023. Shikanai-yasuda MA, Mendes RP, Colombo AL, Telles FDQ, Kono A, Paniago AMM, et al. II Consenso Brasileiro em Paracoccidioidomicose-2017. Epidemiologia e Serviços de Saúde. 2018;27:e0500001. Paniago AMM, Aguiar JIA, Aguiar ES, da Cunha RV, Pereira GR, Londero AT, et al. Paracoccidioidomicose: estudo clínico e epidemiológico de 422 casos observados no Estado do Mato Grosso do Sul. Rev Soc Bras Med Trop. 2003;36:455-9. Fabris LR, Andrade Ú, Ferreira Dos Santos A, Marques AP, Oliveira SM, Mendes RP, et al. Decreasing prevalence of the acute/subacute clinical form of paracoccidioidomycosis in Mato Grosso do Sul State, Brazil. Rev Inst Med Trop Sao Paulo. 2014;56(2):121-5. Penna FJ. Blastomycosis of the colon resembling clinically ulcerative colitis. Gut. 1979;20(10):896-9. Yasuda MA. Pharmacological management of paracoccidioidomycosis. Expert Opin Pharmacother. 2005;6(3):385-97. Gryschek RCB, Pereira RM, Kono A, Patzina RA, Tresoldi AT, Shikanai-Yasuda MA, et al. Paradoxical reaction to treatment in 2 patients with severe acute paracoccidioidomycosis: a previously unreported complication and its management with corticosteroids.Clinical Infectious Diseases. 2010;50:e56-e58. Vieira GD, Alves TC, Lima SM, Camargo LM, Souza CM. Paracoccidioidomycosis in a western Brazilian Amazon State: clinical-epidemiologic profile and spatial distribution of the disease. Rev Soc Bras Med Trop. 2014;47:63-8. Additional Declarations The authors declare no competing interests. Supplementary Files SUPPLEMENTARYMATERIALMYCO.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Paniago","email":"","orcid":"https://orcid.org/0000-0002-8925-7712","institution":"Universidade Federal de Mato Grosso do Sul","correspondingAuthor":false,"prefix":"","firstName":"Anamaria","middleName":"Mello Miranda","lastName":"Paniago","suffix":""}],"badges":[],"createdAt":"2025-03-03 15:56:25","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6147795/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6147795/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78424651,"identity":"c2fc6a22-398b-433a-be11-c586aad9e265","added_by":"auto","created_at":"2025-03-13 06:16:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":164543,"visible":true,"origin":"","legend":"\u003cp\u003eCervical region tomography highlighting a necrotic lymph node (red arrow)\u003c/p\u003e\n\u003cp\u003eAbdominal CT scan showed no abnormalities in the liver, spleen, kidneys, aorta, inferior vena cava, bladder, or prostate. The pancreas was normally positioned but was located near the densified mesenteric fat, which limited the evaluation of its contours. There were adenopathies in the inguinal chains with lymph nodes measuring up to 0.42 cm in the short axis, thickened and hyperechoic mesenteric fat, and adjacent intestinal loops exhibiting inflammatory features suggestive of diffuse enteropathy. Histological examination of the inguinal lymph nodes revealed chronic granulomatous lymphadenitis with numerous refringent, rounded structures of varying sizes within the histiocytes. Direct mycological examination revealed structures suggestive of \u003cem\u003eParacoccidioides\u003c/em\u003e spp. (+++), which were confirmed by culture.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6147795/v1/23e9f33bdb8fc731326a1cc4.png"},{"id":78424024,"identity":"9a740be9-af66-473e-9e3a-27c2bbd0eecc","added_by":"auto","created_at":"2025-03-13 06:08:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":922214,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological examination of cecal appendicitis caused by paracoccidioidomycosis\u003c/p\u003e\n\u003cp\u003e(a) Histopathological examination showing an intense granulomatous inflammatory process in the cecal appendix wall (40x); (b) Fungal structures and inflammatory infiltrate with multinucleated giant cells (400x, arrows indicating the fungal structures); (c) Grocott–Gomori special staining showing numerous structures compatible with Paracoccidioides sp. (400x)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6147795/v1/0367fa5859cb9b0d8d3e5f9b.png"},{"id":78426178,"identity":"32fe8ed7-1160-47ac-9898-469b558d4f21","added_by":"auto","created_at":"2025-03-13 06:24:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":111780,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of study selection\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6147795/v1/b7ef415ca96721b88b1d774e.png"},{"id":78426472,"identity":"e127ba6a-ebe4-49b7-861d-b5b5bce1cb8d","added_by":"auto","created_at":"2025-03-13 06:32:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2004947,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6147795/v1/47344223-b991-4104-8b58-bd792f810e84.pdf"},{"id":78424023,"identity":"15a09a74-acaf-476e-b720-f69d2959c180","added_by":"auto","created_at":"2025-03-13 06:08:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":644767,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYMATERIALMYCO.docx","url":"https://assets-eu.researchsquare.com/files/rs-6147795/v1/df5e355983c186a20fe8fde4.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eCecal appendicitis as a rare manifestation of paracoccidioidomycosis: a case report and systematic review of the literature\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParacoccidioidomycosis (PCM) is a systemic mycosis endemic to Brazil, accounting for more than 80% of reported cases of the disease [1]. PCM is also found in almost all Latin American countries [2]. The etiological agents belong to the genus \u003cem\u003eParacoccidioides\u003c/em\u003e, with the main representatives being the \u003cem\u003eP. brasiliensis\u003c/em\u003e complex (including \u003cem\u003eP. brasiliensis\u003c/em\u003e sensu stricto, \u003cem\u003eP. americana\u003c/em\u003e, \u003cem\u003eP. restrepiensis\u003c/em\u003e, and \u003cem\u003eP. venezuelensis\u003c/em\u003e) and \u003cem\u003eP.\u003c/em\u003e lutzii [3].\u003c/p\u003e \u003cp\u003eThese fungi are found in nature and human infections occur through the inhalation of infectious propagules and spores. The main risk factor is soil exposure, usually during the first two decades of life, which is the period during which infection is acquired. However, clinical manifestations of the disease often appear several years later [4].\u003c/p\u003e \u003cp\u003ePCM manifests in two main clinical forms: the chronic form, which accounts for most cases, and the acute/subacute form (ASF). The chronic form is characterized by symptoms that persist for more than six months and predominantly affects the lungs, upper airways, and digestive tract. ASF is more common in children, adolescents, and young adults and mainly involves the organs of the mononuclear phagocytic system, including the lymph nodes, bone marrow, liver, and spleen [5].\u003c/p\u003e \u003cp\u003eInvolvement of the cecal appendix in PCM, which is part of the gut-associated lymphoid tissue (GALT), has rarely been described in the literature, and its diagnosis can be challenging. Therefore, the present study aimed to describe the clinical, diagnostic, and therapeutic manifestations of appendicitis caused by \u003cem\u003eParacoccidioides\u003c/em\u003e spp. through a case report and systematic literature review.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe CARE guidelines [6] were used in this case report. The patient provided informed consent for publication of the cases, and the project was approved by the Institutional Review Board of the Universidade Federal de Mato Grosso do Sul, Brazil (protocol number 2.102.875). Written informed consent for publication was obtained from the patient.\u003c/p\u003e \u003cp\u003e1 Case Report\u003c/p\u003e \u003cp\u003eData Collection: Data related to the patients\u0026rsquo; age, sex, clinical and epidemiological characteristics, laboratory and imaging results, and culture results of the biological materials were collected from the patients\u0026rsquo; medical records.\u003c/p\u003e \u003cp\u003e2 Systematic Review\u003c/p\u003e \u003cp\u003eA systematic review was conducted, as recommended by the AMSTAR 2 tool (A MeaSuremen Tool to Assess systematic Reviews) [7]. The description was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [8]. The systematic review protocol was registered under number CRD42024508229 on PROSPERO (International Prospective Register of Systematic Reviews): \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/prospero/\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/prospero/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e2.1 Search Strategies and Eligibility Criteria\u003c/p\u003e \u003cp\u003eThe research question in the protocol was as follows: What is the clinical course of patients with cecal appendix involvement by \u003cem\u003eParacoccidioides\u003c/em\u003e spp.? Patients with a confirmed diagnosis of cecal appendicitis caused by \u003cem\u003eParacoccidioides\u003c/em\u003e spp., with an assessment of clinical manifestations, treatment, and outcomes, were included.\u003c/p\u003e \u003cp\u003eEPPI Reviewer 6 software (version 6.15) was used (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://eppi.ioe.ac.uk/cms/Default.aspx?tabid=2914\u003c/span\u003e\u003cspan address=\"https://eppi.ioe.ac.uk/cms/Default.aspx?tabid=2914\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTwo reviewers (ILXA and BAAS) screened titles, abstracts, and descriptors to identify articles for analysis. A third reviewer (CEVC) screened all excluded abstracts and any conflicts were resolved.\u003c/p\u003e \u003cp\u003eSearches were conducted in August 2023, and the search strategy was updated until July 2024. The Embase, Web of Science, LILACS, MEDLINE, LIEPCS, PubMed, and SciELO databases were used. Searches for unpublished studies were conducted in Open Grey (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.opengrey.eu/\u003c/span\u003e\u003cspan address=\"http://www.opengrey.eu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), the CAPES Thesis and Dissertation Bank, the Brazilian Digital Library of Theses and Dissertations (BDTD), Open Access Theses and Dissertations (OATD), MedNar, and WorldWidescience.org. The complete search strategy is shown in Supplementary Information (Appendix 1).\u003c/p\u003e \u003cp\u003eTo construct search strategies for each database, descriptors from MeSH (Medical Subject Headings) and other related terms, including EMTREE terms, were selected. The search strategy consisted of the following terms: (((appendicitis[MeSH Terms]) OR (appendices, omental[MeSH Terms])) OR (small intestine[MeSH Terms])) AND ((((paracoccidioides brasilienses[MeSH Terms])) OR (paracoccidioidomycoses[MeSH Terms]))) and \u0026ldquo;paracocc*\u0026rdquo; and \u0026ldquo;apendic*.\u0026rdquo;\u003c/p\u003e \u003cp\u003eArticles that were irrelevant to the theme or were duplicates were excluded. Articles meeting the inclusion criteria were read in full and the data obtained from each study were recorded by the EPPI Reviewer. Only articles that met the inclusion criteria for clinical cases of PCM involving the cecal appendix were selected for data extraction.\u003c/p\u003e \u003cp\u003eWe conducted several tests to make the search strategy as sensitive as possible; however, only a few articles were found. For this reason, some articles included for full reading and some included cases of appendicitis caused by PCM were found through a manual search, mainly by reviewing the references of the included studies as well as through our outpatient clinic's PCM research database. After reading the full texts, articles that did not meet the inclusion criteria were excluded and the reasons for exclusion were recorded.\u003c/p\u003e \u003cp\u003eThe search results are reported in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2020) flowchart and an evidence map. Articles included for full reading that could not be accessed after several attempts were excluded. The authors of these articles were contacted via email or the ResearchGate platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.researchgate.net/\u003c/span\u003e\u003cspan address=\"https://www.researchgate.net/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and only one author responded to our inquiry. Some articles could not be found because they were old.\u003c/p\u003e \u003cp\u003e2.2 Data Extraction\u003c/p\u003e \u003cp\u003eData were extracted by two reviewers (IXLA and BAAS), and the accuracy and completeness were verified by a third reviewer (CEVC). A table was used to characterize the articles based on the following information: study type, age, sex, clinical presentation, diagnostic method, pharmacological treatment, and outcomes.\u003c/p\u003e \u003cp\u003e2.3 Risk of Bias Assessment\u003c/p\u003e \u003cp\u003eThe risk of bias assessment was carried out by one reviewer (CEVC) using the guidelines recommended by the Joanna Briggs Institute (JBI) [9]. Full verification of all judgments was performed by a second reviewer (BAAS). The JBI critical appraisal checklist for textual evidence includes the following options: N (no), N/A (not applicable), U (unclear), and Y (yes). The risk of bias was interpreted based on the proportion of items met: low risk of bias (most critical items were met), moderate risk of bias (some important items were not met), and high risk of bias (many critical items were not met).\u003c/p\u003e \u003cp\u003e2.4 Evidence map\u003c/p\u003e \u003cp\u003eTo characterize the volume, characteristics, outcomes, and quality of the available studies, we developed an evidence map to visually summarize the main information found in the systematic review. We used EPPI Reviewer 6 software (version 6.15) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://eppi.ioe.ac.uk/cms/Default.aspx?tabid=2914\u003c/span\u003e\u003cspan address=\"https://eppi.ioe.ac.uk/cms/Default.aspx?tabid=2914\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e3 Case Presentation\u003c/p\u003e \u003cp\u003eA 20-year-old male patient, born and residing in Campo Grande, MS, working for an urban waste selective collection company, presented with a history of a nine-kilogram weight loss and generalized lymphadenopathy for three months, initially affecting the cervical region and later involving the bilateral axillary and inguinal regions. One week before admission, he developed febrile peaks of 38\u0026deg;C, fatigue, odynophagia, and hyporexia. The patient denied any comorbidities, medication use, previous hospitalizations or surgeries, or history of allergies.\u003c/p\u003e \u003cp\u003eOn physical examination, lymphadenopathy was observed bilaterally in the preauricular, retroauricular, right occipital, superficial and deep cervical, tonsillar, subclavicular, submental, axillary, and inguinal lymph node chains, with sizes ranging from one to two centimeters (cm), painful, and fixed. Larger lymph nodes were found in the left superficial cervical, left subclavicular, submental, left retroauricular, and right superficial cervical chains, varying between three and seven cm, and were painful and fixed. Laboratory tests revealed normocytic and normochromic anemia, leukocytosis with a left shift, elevated C-reactive protein (CRP), and hypoalbuminemia (see Supplement 1, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe antibody test for anti-\u003cem\u003eParacoccidioides\u003c/em\u003e using double immunodiffusion in agar gel was positive, with a titer of 1:64. Computed tomography (CT) of the cervical region revealed enlarged lymph nodes in all the cervical, supraclavicular, and axillary lymph node chains, several of which exhibited liquefied necrotic centers (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTreatment with trimethoprim-sulfamethoxazole (TMP-SMX) was initiated orally at a dose of 800/160 mg every 8 h, and the patient was discharged with clinical improvement after four days of treatment. Itraconazole was not initiated because of intestinal involvement and erratic absorption. After 11 days, the patient returned to the outpatient clinic with poor adherence to pharmacological treatment, fever, and persistent diffuse lymphadenopathy. An attempt was made to use intravenous fluconazole; however, the patient did not tolerate it and was maintained on TMP-SMX, taking two tablets orally (PO) every 8 h.\u003c/p\u003e \u003cp\u003eThe patient returned to the outpatient clinic after three weeks and presented with significant abdominal pain and increased cervical lymphadenopathy. Liposomal amphotericin B (L-AmB) was administered at a dose of 150 mg/day in a day hospital setting. Six days after starting L-AmB, the patient experienced worsening abdominal pain, particularly in the right inguinal region, with a negative Blumberg sign but positive Dunphy and Rovsing signs. An ultrasound of the entire abdomen revealed a fluid collection with thin septations in the posterior cul-de-sac, measuring 8.6 x 5.3 cm, and an elongated image with imprecise contours in the right iliac fossa, measuring 8.0 x 2.6 cm, suggestive of acute cecal appendicitis (ACA). The patient underwent appendectomy.\u003c/p\u003e \u003cp\u003eHistopathological examination of the cecal appendix showed an intense granulomatous inflammatory process in the wall of the appendix with multinucleated giant cells and numerous fungal structures compatible with \u003cem\u003eParacoccidioides\u003c/em\u003e spp., highlighted by Grocott\u0026ndash;Gomori staining (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe patient was discharged from the hospital with progressive clinical improvement and continued treatment with TMP- SMX. The patient remains under outpatient follow-up.\u003c/p\u003e \u003cp\u003eThe timeline of the reported case is described in Supplementary Information, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e4 Systematic Literature Review\u003c/p\u003e \u003cp\u003eUsing this search strategy, 91 articles based on case reports were identified. The articles were written in Portuguese, English and Spanish, with the publication years ranging from 1913 to 2023. Twelve articles were excluded because of duplication, and 77 articles were eligible for title and abstract reading.\u003c/p\u003e \u003cp\u003eThirty-seven articles were eligible for full-text review. Twenty-eight articles were excluded after reading their full texts. The results of the search strategy are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eEleven articles [5, 10\u0026ndash;19] met the inclusion criteria for clinical cases of PCM affecting the cecal appendix, and the characteristics of the studies are described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We also included the data from our case reports (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A meta-analysis was not conducted due to the small number of included articles.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacterization of included studies with cecal appendicitis caused by paracoccidioidomycosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eClinical presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDiagnostic method\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePharmacological treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViana, 1913*\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo report *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo report *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo report *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo report *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo report *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo report *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAutopsy study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesar, Carini, Lauand, Lia, 1962**\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo report **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo report **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo report **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo report**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo report **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo report **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo report **\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBarbosa, Daher, Oliveira, 1968\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report \u0026ndash; Case series\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSudden abdominal pain with nausea, vomiting, and sweating\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ACA due to PCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBittencourt et al., 1988\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFever, dry cough, weight loss, dyspnea, and enlarged cervical lymph nodes. Presence of hepatosplenomegaly and abdominal mass\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePostmortem necrotic appendicitis and positive skin test with paracoccidioidin, and histopathology of the cervical lymph node with a culture positive for \u003cem\u003eP. brasiliensis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDid not receive pharmacological treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNavas et al., 1994\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVenezuela\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo report ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo report ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo report***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo report ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTMP- SMX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSatisfactory response to treatment. ***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMu\u0026ntilde;oz Urribarri et al., 2006\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeru\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePreviously healthy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFever, vomiting, abdominal distension, and abdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ACA due to PCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eItraconazole 10 mg/kg/day PO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical improvement and outpatient follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGava et al., 2015\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report - Letters to the editor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCrohn's disease as a misdiagnosis and use of immunosuppressants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHematochezia, enterorrhagia, and weight loss; papular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of oral lesion and abdominal CT with description of ACA. Appendectomy not performed.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL-AmB IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSatisfactory clinical response. Surgery was not performed.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDa Cruz et al., 2021\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePreviously healthy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAcute abdominal pain in the right iliac fossa, and abdominal distension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ileum, colon, and pericolic lymph nodes. Abdominal CT showing signs of ACA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eD-AmB\u003c/p\u003e \u003cp\u003e50 mg/day IV for 28 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical improvement and outpatient follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuna-Vilchez et al., 2022 \u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeru\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePreviously healthy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFever, generalized lymphadenopathy, weight loss, diarrhea, pain in the right iliac fossa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ACA due to PCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL-AmB\u003c/p\u003e \u003cp\u003e3mg/kg/day IV for 14 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical improvement and outpatient follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSales et al., 2022 ****\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report \u0026ndash; Poster at a conference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePreviously healthy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePeriumbilical and lower abdomen pain associated with nausea, hyporexia, and weight loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ACA due to PCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo report of the antifungal used\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical improvement and outpatient follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarinho Falc\u0026atilde;o et al., 2023\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCrohn's disease as a misdiagnosis and use of corticosteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eodynophagia, weight loss, disseminated skin lesions, diffuse lymphadenopathy and significant abdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ACA due to PCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eItraconazole 400 mg/day PO for 24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical cure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAndrade et al., 2024\u003c/p\u003e \u003cp\u003e*****\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThis case report\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePreviously healthy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWeight loss, disseminated lymphadenopathy, abdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHistopathology of ACA due to PCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTMP- SMX 800/160 mg PO every 8 hours. Followed by L-AmB 3 mg/kg/day for 10 days, and then resuming TMP- SMX PO for outpatient treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical improvement and outpatient follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003eACA, acute cecal appendicitis; PO, oral route; IV, intravenous; M, male; F, female. PCM, paracoccidioidomycosis; TMP\u0026minus; SMX, trimethoprim\u0026minus;sulfamethoxazole; CT, computed tomography; L\u0026minus;AmB, liposomal amphotericin B; D\u0026minus;AmB, deoxycholate amphotericin B; *Thesis description not found, but cited by Barbosa, Daher, Oliveira, 1968 as an autopsy study as the first report of cecal appendicitis; **Article not found, cited by Andrade, 1983 as a case report of cecal appendicitis due to PCM; ***Article not found and data extracted from the abstract; ****Data extracted from a conference poster. *****Data from this case report\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOf the 11 articles included as cases of cecal appendicitis due to PCM, six were found through a manual search, as listed in Supplementary Information, Table\u0026nbsp;2.\u003c/p\u003e \u003cp\u003eThe studies that met the criteria for the systematic review were all case reports, including one described in a thesis from 1913 [10], one study presented as a letter to the editor [16], and one presented as conference posters [18]. Eight reports were from Brazil [5, 10\u0026ndash;13, 16, 18, 19], two from Peru [15, 17], and one from Venezuela [14], covering the period from 1913 to 2023. In two studies [10, 11], access to case reports was not possible; they were only referenced in the included studies. Seven patients were male, one was female, and three were of unspecified sex. Their ages ranged from four to 42 years.\u003c/p\u003e \u003cp\u003eThe main symptoms were abdominal pain, weight loss, fever, and presence of lymph nodes. Six patients were previously healthy [5, 15\u0026ndash;19] but two were treated for Crohn\u0026rsquo;s disease prior to the diagnosis of PCM and had used immunosuppressants [16] and corticosteroids [19], which intensified the progression of PCM. One patient who died had a presumptive diagnosis of non-Hodgkin lymphoma due to an abdominal mass and did not present with abdominal pain [13].\u003c/p\u003e \u003cp\u003eFive cases were confirmed through histopathology of the appendix, identifying the agent \u003cem\u003eParacoccidioides\u003c/em\u003e spp. [12, 15, 17\u0026ndash;19]. Other studies confirmed PCM histopathologically at other sites [5, 13, 16]. Two cases were diagnosed using abdominal CT [5, 16]. In two cases, the diagnosis was made postmortem [10, 13].\u003c/p\u003e \u003cp\u003eIn the cases described in the systematic review, three patients were treated with AmB, with two receiving L-AmB [16, 17] and one receiving D-AmB [5]. Two patients were treated only with itraconazole from the diagnosis [15, 19] and two patients received itraconazole after induction therapy with D-AmB [5] and L-AmB [17]. One patient was treated with TMP- SMX [14]. One study did not report outpatient treatment following the use of L-AmB [16] and four studies did not report any pharmacological treatment instituted [10\u0026ndash;12, 18].\u003c/p\u003e \u003cp\u003eSeven patients showed clinical improvement after treatment [5, 14\u0026ndash;19]. One patient showed clinical improvement with pharmacological treatment alone and did not require surgery [16]. One patient died without receiving treatment [13]. Four articles did not report the clinical outcome [10\u0026ndash;12, 14].\u003c/p\u003e \u003cp\u003eIn the risk of bias assessment (JBI) for the cases included in the systematic review, five articles were rated as having a low risk of bias [5, 12, 15, 17, 19]; two reports were rated as having a moderate risk of bias [12, 16] and four articles were rated as having a high risk of bias [10, 11, 14, 18] due to not being accessible for full-text reading (see Suplementary Information, Table\u0026nbsp;3). We did not exclude articles with a high risk of bias owing to the small number of reported cases.\u003c/p\u003e \u003cp\u003eIn Supplementary Information (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), we present an evidence map to characterize the volume, characteristics, outcomes, and quality of the available studies.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study reports a rare form of ACA caused by \u003cem\u003eP. brasiliensis\u003c/em\u003e in a case with acute/subacute PCM (AS-PCM) following an exploratory laparotomy of the acute abdomen during the initial phase of treatment.\u003c/p\u003e \u003cp\u003eAS-PCM accounts for a minority of reported cases in the literature (5\u0026ndash;10%) and primarily affects children and young adults [4] consistent with our patient's presentation, who exhibited classic signs and symptoms at onset, such as fever, weight loss, anorexia, and generalized lymphadenopathy.\u003c/p\u003e \u003cp\u003eAlthough the patient was not directly involved in rural activities, a significant epidemiological factor in PCM [20], he worked at a waste collection company and was occasionally exposed to inhaled soil particles while passing through unpaved streets, which may have been a route of infection for the fungus.\u003c/p\u003e \u003cp\u003eIn Campo Grande, the patients\u0026rsquo; place of origin, PCM cases were monitored at the Systemic Mycoses Outpatient Clinic of Maria Aparecida Pedrossian University Hospital. A study conducted at this reference service found that AS-PCM was more frequent among patients in their second and third decades of life, with an average age of 22.2 years and a male-to-female ratio of 3:1. The main clinical manifestations include involvement of the mononuclear phagocyte system, primarily lymphadenopathy (95.4%), hepatomegaly (40%), and splenomegaly (23.1%) [21]. Another study published in 2014 showed that in Mato Grosso do Sul, the prevalence of the ASF during in 2000\u0026ndash;2009 decade decreased compared to the two previous decades, probably due to an intense campaign against child labor in agriculture in the country [22].\u003c/p\u003e \u003cp\u003eOur patient presented with typical feature of appendicitis, including right lower quadrant pain and a positive Dunphy and Rovsing signs. Laboratory findings revealed leukocytosis with left shift and elevated CRP levels. Preoperatively distinguishing between bacterial ACA and appendicitis caused by PCM is challenging and is often achieved only through histopathological examination of the resected appendix. Although appendectomy is a common and often necessary intervention for appendicitis related to PCM, follow-up with appropriate antifungal treatments is crucial to prevent recurrence or complications.\u003c/p\u003e \u003cp\u003eThe systematic review identified only 11 documented cases of cecal appendicitis caused by \u003cem\u003eParacoccidioides\u003c/em\u003e spp. [5, 10\u0026ndash;19], indicating that this is a rare disease restricted to South American countries. Most of the described cases had favorable outcomes following diagnosis and treatment. One case was untreated, and the diagnosis was made only late, resulting in the patient\u0026rsquo;s death [13]. The first report of cecal appendicitis by PCM described in 1914 [10] was diagnosed during an autopsy; however, we did not have access to the article. In addition, we believe that many cases are either undiagnosed or unreported. This also reflects the difficulty in identifying cases using our search strategy, necessitating the use of grey literature and references from the included studies.\u003c/p\u003e \u003cp\u003eIn our review, we observed reports of older cases [10, 11, 12], where in two instances [10, 11], we did not have access to the full text of the articles. One case was described in letters to the editor [16], one in a conference poster [18], and one for which we only had access to the abstract [14].\u003c/p\u003e \u003cp\u003eWith characteristics similar to those of our case report, studies on cecal appendicitis have involved young patients between the ages of 4 and 42 years, the vast majority of whom were male and previously healthy. The main symptoms include abdominal pain, fever, weight loss, and lymphadenopathy, highlighting the presence of a systemic disease.\u003c/p\u003e \u003cp\u003eOn the initial abdominal CT scan, the patient presented with adenopathy in the inguinal chains and thickened and hyperechoic mesenteric fat with an inflammatory appearance suggestive of diffuse enteropathy. There are numerous reports in the literature of PCM mimicking Crohn's disease or ulcerative colitis, as in the case described in 1979, due to its tendency to affect intestinal lymph nodes and cause enteropathy [23]. Furthermore, this diagnostic confusion led to inadequate treatment and consequently greater immunosuppression in the two cases reported in our review, resulting in clinical progression and surgical complications [16, 19].\u003c/p\u003e \u003cp\u003eWe opted not to initiate pharmacological treatment with itraconazole due to intestinal involvement, as absorption of this medication would likely be impaired in this case [24]. The patient was discharged on TMP-SMX 800/160 mg every 8 h, as indicated in the latest PCM consensus, which includes this as one of the treatment options [20]. In our systematic review, we observed no preference for treatment; however, in general, conventional or lipid formulations of amphotericin B may have been initially chosen in three studies [5, 16, 17] due to the severity of the cases and difficulty with oral absorption. However, other patients were treated with oral drugs such as TMP-SMX [14], or itraconazole [15, 19]. What we observed that the most important factor was immediate initiation of treatment. The only patient who did not receive treatment progressed to death [13].\u003c/p\u003e \u003cp\u003eWith the worsening of the clinical picture and significant abdominal pain, the possibility of a paradoxical reaction was raised, which can be explained by clinical deterioration during appropriate treatment of the infectious agent. Given the patient\u0026rsquo;s irregular medication use, the primary hypothesis was disease progression in the acute/subacute phase; however, we did not dismiss the possibility of appendicitis due to a paradoxical reaction, as an exacerbation of the immune response may have occurred after the treatment began [25].\u003c/p\u003e \u003cp\u003eA common characteristic of the cases in the systematic review, including the one presented in this study, was that five of the reported cases had a diagnosis confirmed by histopathological examination of the appendix, with cases subsequently leading to appendectomy. One report highlighted the need for early diagnosis, including inflammation of the appendix caused by PCM, as in this case [16], the patient received only pharmacological treatment and did not require surgical intervention. Appendicitis likely developed because of the involvement of the intestinal lymph nodes by the fungus, leading to an ileocecal mass that caused obstruction and subsequent suppuration of the appendix [16].\u003c/p\u003e \u003cp\u003eOverall, despite treatment initiation, the reported lethality for all forms of PCM was between 6.1% and 7.6% [21, 26]. In our case, the evolution was satisfactory and comparable to most cases involving cecal appendicitis reported in our review. In a study of 46 clinical cases of intestinal PCM, 12.8% of patients died [5]. In our systematic review, one patient did not present with abdominal pain suggestive of appendicitis and was initially managed as a suspected case of non-Hodgkin lymphoma, with clinical deterioration. The diagnosis of PCM with necrosis of the appendix was confirmed only after death [13]. Furthermore, the first reported case of cecal appendicitis caused by PCM was described in an autopsy study [10].\u003c/p\u003e \u003cp\u003eThe main limitations of this study, which can also be observed in the evidence map (Supplementary Information, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), are: 1. limited number of reported cases in the literature, primarily from South America; 2. very old studies; 3. difficulty contacting authors for article retrieval: 4. many articles were excluded because of a lack of access; 5. data were not available for some studies with a moderate and high risk of bias. The literature does not describe the diagnostic challenges in differentiating cecal appendicitis caused by PCM from other infectious or inflammatory etiologies or clinical studies addressing the best therapeutic management in such cases. Additionally, the absence of compulsory notification for the disease in Brazil hampers our ability to identify the true impact and complications of these two clinical presentations.\u003c/p\u003e \u003cp\u003eSatisfactorily, our patient was discharged and is currently under outpatient follow-up.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCecal appendicitis due to PCM is a rare presentation of the ASF of PCM. It affects young individuals and can be difficult to diagnose even in endemic regions of Latin America. With accurate diagnosis and appropriate treatment, including surgical intervention, outcomes can be satisfactory. Particularly in endemic areas, gastrointestinal involvement leading to cecal appendicitis due to invasive fungal disease should be considered as it may be confused with other inflammatory bowel diseases and treated with immunosuppressive therapies that can trigger dissemination and potentially unfavorable outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACA, acute cecal appendicitis; CT, computed tomography; PCM, paracoccidioidomycosis; ASF, acute/subacute form; AS-PCM, acute/subacute PCM; TMP-SMX, trimethoprim-sulfamethoxazole; AmB, amphotericin; L-AmB, liposomal amphotericin B; D-AmB, amphotericin; DM, direct mycology; US, ultrasound; CRP, C-reactive protein; PO, oral administration.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Universidade Federal de Mato Grosso do Sul (grant number: code 001); 2. Conselho Nacional de Desenvolvimento Cient\u0026iacute;fico e Tecnol\u0026oacute;gico (Grant number: 312910/2020-7); 3. Funda\u0026ccedil;\u0026atilde;o de Apoio ao Desenvolvimento do Ensino, Ci\u0026ecirc;ncia e Tecnologia do Estado do Mato Grosso do Sul (Grant number: 06/2021).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIsadora de Lima Xavier Andrade, Cl\u0026aacute;udia Elizabeth Volpe-Chaves, Anamaria Mello Miranda Paniago contributed to the study conception and design. Material preparation, data collection and analysis were performed by Isadora de Lima Xavier Andrade, Bruna Abdul Ahad Saad, Alexandre Albuquerque Bertucci, Marcel Arakaki Asato, Jo\u0026atilde;o Paulo Greg\u0026oacute;rio Machado, Ma\u0026iacute;na de Oliveira Nunes, Eliana da Costa Alvarenga de Brito, James Venturini, Sandra Maria do Valle Leone de Oliveira, Cl\u0026aacute;udia Elizabeth Volpe-Chaves, Anamaria Mello Miranda Paniago. The first draft of the manuscript was written by Isadora de Lima Xavier Andrade, Bruna Abdul Ahad Saad, Cl\u0026aacute;udia Elizabeth Volpe-Chaves, Anamaria Mello Miranda Paniago and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe project was approved by the Institutional Review Board of the Federal University of Mato Grosso do Sul, Brazil (protocol number 2.102.875), and the patient provided informed consent for the publication of the case. The systematic review protocol was registered under number CRD42024508229 on PROSPERO (International Prospective Register of Systematic Reviews): https://www.crd.york.ac.uk/prospero/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe thank the teams of the Unidade de Doen\u0026ccedil;as Infecciosas e Parasit\u0026aacute;rias, Hospital dia Esterina Corsini e Hospital Universit\u0026aacute;rio Maria Aparecida Pedrossian/EBSERH. We also thank the Universidade Federal de Mato Grosso do Sul (UFMS).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGiacomazzi J, Baethgen L, Carneiro LC, Millington MA, Denning DW, Colombo AL, et al. In Association with the LIFE Program. The burden of serious human fungal infections in Brazil. Mycoses. 2016;59(3):145-50.\u003c/li\u003e\n\u003cli\u003eRoberto TN, de Carvalho JA, Beale MA, Hagen F, Fisher MC, Hahn C, et al. Exploring genetic diversity, population structure, and phylogeography in \u003cem\u003eParacoccidioides\u003c/em\u003e species using AFLP markers. Stud Mycol. 2021;100:100131.\u003c/li\u003e\n\u003cli\u003eTurissini DA, Gomez OM, Teixeira MM, McEwen JG, Matute DR. Species boundaries in the human pathogen \u003cem\u003eParacoccidioides\u003c/em\u003e. Fungal Genet Biol. 2017;106:9\u0026ndash;25.\u003c/li\u003e\n\u003cli\u003eMendes RP, Cavalcante RS, Marques SA, Marques MEA, Venturini J, Sylvestre TF, et al. Paracoccidioidomycosis: Current Perspectives from Brazil. Open Microbiol J. 2017;11:224-82.\u003c/li\u003e\n\u003cli\u003eDa Cruz ER, Dal Forno A, Pacheco SA, Bigarella LG, Ballotin VR, Salgado K, et al. Intestinal Paracoccidioidomycosis: Case report and systematic review. The Brazilian Journal of Infectious Diseases. 2021;25(4):101605.\u003c/li\u003e\n\u003cli\u003eCase Report Guidelines CARE [internet]. Checklist of information to include when writing a case report. Available from: https://www.care-statement.org/checklist. Accessed 18 Jun 2024. \u003c/li\u003e\n\u003cli\u003eAMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. \u003c/li\u003e\n\u003cli\u003eAromataris E, Lockwood C, Porritt K, Pilla B, Jordan Z, editors. JBI Manual for Evidence Synthesis. JBI; 2024. Available from: https://synthesismanual.jbi.global. Accessed 18 Jun 2024\u003c/li\u003e\n\u003cli\u003eVianna GO. Doen\u0026ccedil;a de Posada-Wernicke nas les\u0026otilde;es apendiculares. Arq Bras Med. 1914;4:336.\u003c/li\u003e\n\u003cli\u003eCesar HC, Carini A, Lauand F, Lia N. Abdome agudo de etiologia blastomic\u0026oacute;tica. Hospital (Rio de Janeiro). 1962;61:625-37.\u003c/li\u003e\n\u003cli\u003eBarbosa W, Daher R, Oliveira AR. Forma linf\u0026aacute;tico-abdominal da blastomicose Sul-americana. Rev. Inst. Med. trop. S\u0026atilde;o Paulo. 1968;10(1):16-21.\u003c/li\u003e\n\u003cli\u003eBittencourt AL, de Andrade JAF, Cendon Filha SP. Paracoccidioidomycosis in a four-year-old boy. 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Expert Opin Pharmacother. 2005;6(3):385-97.\u003c/li\u003e\n\u003cli\u003eGryschek RCB, Pereira RM, Kono A, Patzina RA, Tresoldi AT, Shikanai-Yasuda MA, et al. Paradoxical reaction to treatment in 2 patients with severe acute paracoccidioidomycosis: a previously unreported complication and its management with corticosteroids.Clinical Infectious Diseases. 2010;50:e56-e58.\u003c/li\u003e\n\u003cli\u003eVieira GD, Alves TC, Lima SM, Camargo LM, Souza CM. Paracoccidioidomycosis in a western Brazilian Amazon State: clinical-epidemiologic profile and spatial distribution of the disease. Rev Soc Bras Med Trop. 2014;47:63-8.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"4275771a-71ed-4d13-924d-1b7e8e8776ff","identifier":"10.13039/501100016182","name":"Universidade Federal de Mato Grosso do Sul","awardNumber":"grant number: code 001","order_by":0},{"identity":"16f58876-b640-4a30-9705-39983f7b5058","identifier":"10.13039/501100003593","name":"Conselho Nacional de Desenvolvimento Científico e Tecnológico","awardNumber":"Grant number: 312910/2020-7","order_by":1},{"identity":"198e6486-4303-4952-9d66-dc1829691010","identifier":"10.13039/501100005672","name":"Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul","awardNumber":"Grant number: 06/2021","order_by":2}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Universidade Federal de Mato Grosso do Sul","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Paracoccidioidomycosis, Paracoccidioides brasiliensis, appendicitis, appendectomy, acute abdomen","lastPublishedDoi":"10.21203/rs.3.rs-6147795/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6147795/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eParacoccidioidomycosis (PCM) is a systemic mycosis endemic to Latin America, with the acute/subacute form predominantly affecting children and young adults. Cases of cecal appendicitis caused by \u003cem\u003eParacoccidioides\u003c/em\u003e spp. have rarely been reported. This study aimed to describe the clinical manifestations and evolution of a case of cecal appendicitis due to PCM and to conduct a systematic literature review. A case report and systematic review were conducted using Embase, Web of Science, LILACS, MEDLINE, LIEPCS, PubMed, SciELO, and Gray Literature databases. We present the case of a 20-year-old male with generalized lymphadenopathy who was diagnosed with PCM and treated with oral trimethoprim-sulfamethoxazole. After the initial improvement, the patient returned with clinical deterioration. The treatment was changed to liposomal amphotericin B. Six days later, the patient developed an acute abdomen and underwent exploratory laparotomy with appendectomy. Histopathological examination confirmed acute granulomatous appendicitis due to PCM, and the patient showed postoperative clinical improvement. Of the 11 identified articles included in the systematic review, most case reports with a low risk of bias were found in South American countries. Five patients had confirmed appendicitis due to PCM through biopsy, while others had confirmed PCM at another site. Two patients were initially misdiagnosed with Crohn's. Most studies have reported favorable outcomes. Appendicitis caused by PCM is rare, even in endemic countries. It has a benign course when properly treated with both clinical and surgical management. This should be considered in the differential diagnosis of acute abdomen with lymphadenopathy in endemic regions.\u003c/p\u003e","manuscriptTitle":"Cecal appendicitis as a rare manifestation of paracoccidioidomycosis: a case report and systematic review of the literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-13 06:08:28","doi":"10.21203/rs.3.rs-6147795/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b83c6a48-9cea-4410-a49c-78a9eed5ab01","owner":[],"postedDate":"March 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-13T06:08:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-13 06:08:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6147795","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6147795","identity":"rs-6147795","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}