Although ICI therapy has changed the landscape of cancer treatment, irAEs continue to pose a significant challenge to its use. Case reports have suggested that immune-mediated appendicitis is one such adverse event. However, it is still poorly understood, and whether this condition is pathologically or histologically different from conventional appendicitis is unclear (Mangas et al., 2020; Papageorgiou et al., 2021). Additionally, whether it is a separate entity from ICI colitis or lies on a spectrum of disease remains unclear. In this study, we addressed this knowledge gap by describing the characteristics and disease course of post-ICI therapy appendicitis and its associated complications.
Researchers have extensively studied ICI-mediated colitis over the past 5 years. It often presents with diarrhea, abdominal pain, rectal bleeding, and fever (Abu-Sbeih & Wang, 2020; Wang, Abu-Sbeih, Mao, Ali, Ali, et al., 2018; Wang, Abu-Sbeih, Mao, Ali, Qiao, et al., 2018). Whereas some of these symptoms also occur with post-ICI therapy appendicitis as described herein, diarrhea, a predominant symptom of colitis, did not occur in our cohort. The absence of this symptom may help differentiate ICI colitis from post-ICI therapy appendicitis clinically. Radiological patterns of appendicitis can be pathognomonic for the disease, markedly distinct from the appendiceal wall thickening commonly described in colitis cases. Moreover, the mainstay of medical management of conventional appendicitis is antibiotics, which drastically differs from the immunosuppressive therapy used for ICI colitis. In fact, antibiotic therapy has had a negative impact on the course of ICI-mediated colitis and the long-term survival of patients with ICI colitis (Abu-Sbeih et al., 2019). In our cohort, no patients received steroids or immunosuppressive agents. Also within our cohort, post-ICI therapy appendicitis appeared to typically occur in isolation following ICI therapy, although authors have reported the co-existence of appendicitis and colitis (Papageorgiou et al., 2021). Despite their similar clinical presentations and adjacent anatomical locations, we suspect that these two conditions are different entities, and further investigation to distinguish between them and guide appropriate treatment is warranted.
Conventional acute appendicitis is one of the most common general surgery emergencies worldwide, with an estimated lifetime risk of 7–8% (Körner et al., 1997; Omari et al., 2014; Stewart et al., 2014). The peak incidence is usually in the second or third decade of life. However, the patients with post-ICI therapy appendicitis in our cohort had a median age of 59 years, with a range of 55–60 years. This trend of advanced age at onset was also seen in previous post-ICI therapy appendicitis case reports (Mangas et al., 2020; Patel et al., 2021). One explanation for this discrepancy may be the advanced age of cancer patients receiving ICIs. This difference aside, post-ICI therapy appendicitis in this study had presenting symptoms similar to those of conventional appendicitis, consisting of abdominal pain, fever, nausea, and vomiting. Radiological findings of appendiceal dilation, appendiceal wall thickening, periappendiceal inflammation, and fat stranding were common to both types of appendicitis. Moreover, pathological analysis of gross surgical specimens obtained in our study commonly revealed comparable findings between post-ICI therapy appendicitis and conventional appendicitis: acute appendicitis with transmural inflammation and serositis. Of note, the rate of complications associated with appendicitis (perforation or abscess) was about 20% in our cohort, similar to that for conventional appendicitis (Omari et al., 2014). However, post-ICI therapy appendicitis may foreshadow future irAEs as seen in four of our patients who resumed ICI therapy. This is not a risk in patients with conventional appendicitis.
The management of both conventional appendicitis and post-ICI therapy appendicitis is broadly classified as surgical or nonsurgical treatment. Historically, conventional appendicitis has been managed using appendectomy in the general population. Recently, nonoperative management has become a feasible alternative for uncomplicated appendicitis; in complicated cases, appendectomy within 24 hours of presentation is recommended (Di Saverio et al., 2020; Teng et al., 2021). With this in mind, cancer patients are typically considered poor surgical candidates due to the clinical complexity of their underlying cancer as well as other comorbid conditions. Limited studies have shown that both nonsurgical management and early appendectomy are suitable strategies for cancer patients (Park et al., 2021; Santos et al., 2016). Within our cohort of post-ICI therapy appendicitis patients, nonsurgical management with antibiotics or IR drainage was employed more often than was surgical intervention. We observed no significant differences in outcome of surgical and nonsurgical management within our cohort. However, the significance of this finding could certainly be limited due to the small sample size.
As the most applied medical treatment of appendicitis, broad-spectrum antibiotics are usually used for coverage for gram-positive, gram-negative, and anaerobic organisms. A meta-analysis by Talan et al (Talan et al., 2019) described the conservative management of uncomplicated conventional appendicitis with antibiotics. In that study, the researchers found that most treatments included an initial parenteral regimen of a second or third-generation cephalosporin plus metronidazole, amoxicillin-clavulanate, piperacillin-tazobactam, or a carbapenem. This was followed by administration of an oral regimen of a fluoroquinolone, an advanced-generation cephalosporin plus metronidazole, or amoxicillin-clavulanate upon hospital discharge. Of note, whereas GI infections are typically caused by gram-negative organisms and anaerobes, gram-positive organisms may also be present, albeit to a lesser extent, necessitating broad-spectrum coverage (Leigh et al., 1974; Merlin et al., 2010; Rautio et al., 2000; Song et al., 2018). The antibiotic regimens used in our study were unique to each patient. This can be attributed to each patient’s distinctive circumstances in terms of their immunocompromise, comorbidities, and severity of presenting illness. Nonetheless, all patients received some combination of antibiotics that are routinely used to treat conventional appendicitis, with occasional addition of less frequently used antibiotics like vancomycin and aztreonam or antifungals such as caspofungin (Di Saverio et al., 2020; Teng et al., 2021).
Treatment of uncomplicated conventional appendicitis can last anywhere from 4 to 15 days, with the most common duration being 7–10 days (Becker et al., 2018; Di Saverio et al., 2020; Talan et al., 2019). Following an appendectomy, current guidelines recommend 1–2 weeks of postoperative antibiotic therapy, whereas a few studies have suggested that 3 days is sufficient (de Wijkerslooth et al., 2019; Mazuski et al., 2017; van den Boom et al., 2020; van Rossem et al., 2014). Given the complicated medical history of the patients in our study, the durations of antibiotic therapy exhibited great variation, ranging from 5 days to 6 weeks. Longer treatment durations were utilized when surgical appendectomy was not achievable. Overall, the management of conventional appendicitis and that of post-ICI therapy appendicitis have some striking similarities. However, given the complexity of patients presenting post-ICI therapy appendicitis, a more individualized approach to treatment than that of conventional appendicitis may be necessary regarding the decision to operate, antibiotic selection, and treatment duration. This is especially true considering the additional concerns faced by patients receiving ICIs. For instance, studies have shown that the use of antibiotics, especially those with anaerobic activity, after ICI therapy is associated with an increased risk of severe ICI colitis, likely through disruption of the gut microbiome (Abu-Sbeih et al., 2019). Although the fundamental treatment remains the same for both types of appendicitis, more factors must be considered with the immune-related form of the disease. As such, the optimal treatment strategy for post-ICI therapy appendicitis requires further investigation.
Recently, investigators have used next-generation sequencing to examine the appendiceal microbiome in pediatric patients with appendicitis. Findings of this analysis revealed an increased abundance of fusobacteria and certain other oral cavity flora.(Jackson et al., 2014; Zhong et al., 2014) Additionally, studies have demonstrated that the intraluminal microbial composition differed significantly depending on the degree of inflammation in pediatric patients with acute appendicitis (Schülin et al., 2017). Another study demonstrated differences in the composition of the intestinal microbiota of appendicitis patients and healthy individuals; specifically, the diversity of the phyla Firmicutes, Actinobacteria, Fusobacteria, and Verrucomicrobia were lower in the patients with appendicitis (Peeters et al., 2019). Microbiome analysis of patients with post-ICI therapy appendicitis has yet to be performed, but based on our current knowledge of the microbiome in patients with conventional appendicitis, certain microbiological signatures may be discovered. Furthermore, microbiota analysis has greatly increased our understanding of ICI-mediated colitis and could be another way of differentiating post-ICI therapy appendicitis from conventional appendicitis or ICI-mediated colitis (Abu-Sbeih et al., 2019; Dubin et al., 2016; Wang, Wiesnoski, et al., 2018). The distinction of post-ICI therapy appendicitis from ICI-mediated colitis is a particular concern, as therapies for ICI-mediated colitis, including fecal microbiota transplantation, have had documented success (Wang, Wiesnoski, et al., 2018). If these two entities lie on a spectrum, then effective treatments of ICI-mediated colitis would also be beneficial for post-ICI therapy appendicitis.
To the best of our knowledge, our sample is one of the largest of post-ICI therapy appendicitis cases to date. Nonetheless, our study had certain limitations that reduce its applicability. First, this is a retrospective, single-center, small-scale study. Therefore, selection bias and all limitations inherent in this study design are present. Second, given the overlap of nonspecific GI symptoms of appendicitis and other GI diseases, the frequent use of antibiotics in cancer patients, some cases may have been missed, leading to underestimation of the real incidence of post-ICI therapy appendicitis. Third, the complexity of cancer patients and their comorbidities limited the surgical options for select patients and may have confounded their outcomes. Fourth, the rarity of post-ICI therapy appendicitis makes drawing conclusions from the data difficult; at best, only inferences can be made, and even then, making any generalizations would be difficult considering the variations in the cases.
Appendicitis directly attributed to ICI therapy is rare. Compared with conventional appendicitis, it manifests at an older age but with similar clinical presentations and comparable complication rates. The management strategies for post-ICI therapy appendicitis overlap those for conventional appendicitis, with appendectomy being the mainstay of treatment, although it is often limited by the complexity of cancer patients. The appropriateness of continuing ICI therapy after an episode of appendicitis has yet to be delineated. Further studies are needed to bring awareness to this clinical entity and advance understanding of its management.