The study showed that the majority of patients receiving nivolumab therapy (55.8%) presented to the ED. These visits were with many different complaints, and the patients received various diagnoses. In 21 (8%) visits, irAE was diagnosed. While 14 (67%) of the irAE diagnoses were made directly in the ED, 6 (28%) were made in the oncology outpatient clinic (recommended for control by the ED physician), and one (5%) was made during hospitalization. This shows us that the diagnosis of irAE is complex and can not always be easily made in the ED. Still, with the collaboration of ED physicians and oncologists, more patients can be diagnosed and treated successfully.
The chief complaints for ED visits are shortness of breath, pain, upper respiratory tract symptoms, fever, and cough in our study. This situation is similar to the literature; our patient population, where non-small cell lung cancer is predominant, generally applied with complaints related to the underlying cancer and received malignancy-related diagnoses [8]. ED visit rates and numbers in our study are higher than in previous studies [7, 13]. However, when we examine the studies containing fewer visits, they are based on data from the pre-pandemic period [7, 13–15]. It is known that the COVID-19 pandemic increases visits in patients using ICIs. It also makes diagnosis difficult due to similar symptomatology in these patients [16]. For these reasons, the rate and number of visits are high in our cohort, mainly consisting of patients followed in the post-pandemic period. When we look at the annual number of visits, it was seen that patients in the post-pandemic period (2.95 applications/year) presented more than patients in the pre-pandemic period (2.02 applications/year), but this difference was not statistically significant. The low number of patients who followed the pre-pandemic period may have been insufficient to show this difference statistically. Similar to the literature, our study found that patients with comorbidities were more likely to present to the ED [4]. In subgroup analyses, patients with hypertension and chronic obstructive pulmonary disease were more likely to present to the ED.
Despite the high number of visits, irAEs were diagnosed less frequently than other studies [13, 17]. The most important reason for this is the difficulty of diagnosing irAE in ED. Regarding diagnostic challenges: First, most irAEs are mild and classified as grades 1 and 2. For example, immune-related cutaneous side effects account for more than 50% of all side effects but are rarely severe, and most do not even require discontinuation of the ICI [17]. This often vague symptomatology and mild course make it challenging to identify irAEs in the ED [6].
Secondly, patients with mild complaints are likelier to present to the OC than the ED. Even if they apply to the ED, they may be referred to OC for further examination after the first intervention for mild and non-life-threatening complaints, and they may not be diagnosed. In our study six patients were diagnosed with irAE in the OC, and five had grade 1–2 irAEs. The last patient (Table 4 No: 11) was presented to the ED with shortness of breath, cough, and fever. He was diagnosed with a possible COVID-19 infection during his evaluation in the ED. Since his general condition was stable, he was discharged with a following of COVID-19 PCR test results, and an OC visit was recommended. When the patient visited the OC four days after this visit, it was observed that his general condition had worsened, and his saturation was low (82% on room air). His chest computed tomography revealed bilateral widespread inflammation (right hilar, right lower lobe superior and left upper lobe anterior segment) and an appearance in favor of pneumonitis (Fig. 1). His COVID-19 PCR test resulted as negative. The patient's general condition worsened, and he died in the intensive care unit on the 8th day of hospitalization. It is known that COVID-19 can mimic irAE with similar symptoms and vice versa. [16]. As in this case, more likely and more common diagnoses overshadow irAE and make diagnosis difficult. Among the patients diagnosed with irAE in our study, five patients diagnosed in OC recovered completely. However, four of the 14 patients diagnosed in the ED developed a chronic disease (heart failure, kidney failure, hypothyroidism, oxygen need), and two died. It is thought that ED outcomes are worse because patients diagnosed with irAE in the ED are at a more advanced stage [13].
Finally, other possible causes must be excluded to diagnose irAE, but this is often not possible in the ED. According to a meta-analysis evaluating 9234 ICI-using patients, ICI-related anemia occurs at a rate of 9.8% [15]. Generally, anemia is not a rare condition in cancer patients. Many reasons include bone marrow suppression due to chemotherapy, tumor progression, chronic disease, and nutritional disorders [14]. Since these causes are more likely than irAE, these causes should be considered and evaluated first in the ED. According to guidelines, 80% of patients diagnosed with ICI-related anemia are diagnosed in advanced stages (grade 3–4). The mortality rate in these patients reaches around 15% due to delayed diagnosis and organ failure due to severe anemia [14]. In our study, no patient was diagnosed with ICI-related anemia. Therefore, awareness and suspicion should be high for this condition, which is seen at a high rate in patients with vague complaints and also has serious mortality. Multidisciplinary management with oncology departments is essential to diagnose these patients and prevent harmful consequences [7, 13]. On the other hand, since patients with more severe complaints are primarily investigated for more lethal diagnoses, and underlying irAEs may have been unrecognized. Infective pathologies were detected in 32% of the patients in our study. This rate is higher than the normal cancer population [4]. It is not possible to understand whether irAE contributes to or accompanies the infective process in these patients with the available data. In our study, one patient was diagnosed with adrenal insufficiency (Table 4; No:1). This patient was hospitalized with a diagnosis of stroke and accompanying urinary tract infection. The patient had intermittent hypoglycemia attacks during hospitalization, so while being investigated he was diagnosed with adrenal insufficiency. The patient's hemodynamics were stable, sepsis was not considered, and there was no adrenal metastasis, suggesting that adrenal insufficiency was caused by nivolumab. The presence of multiple confounding factors accompanying patients is another reason that makes the diagnosis of irAE difficult.
In our study, no parameter was found that could predict the development of irAE in patients receiving nivolumab therapy. This may be caused by our relatively low number of irAE cases. Therefore, if a patient receiving nivolumab therapy presents to ED with vague symptomatology, there should be a high clinical index of suspicion of irAE. Also, while taking a history of cancer patients, they should be asked whether they use ICIs (many patients may describe themselves as receiving chemotherapy while on ICI). A detailed investigation should be performed in cases where they are unsure. For patients using ICI, we can say that their immune systems are under fire, and anything could be triggered [18]. Therefore, when evaluating these patients, ED physicians should be aware of irAEs and expand their work-up by including special tests that are not frequently used in the ED (such as endocrine panels, comprehensive liver function tests and/or acute phase reactants) [18]. A multidisciplinary approach should be made with oncologists for these patients, and even if one-to-one communication is not established in the ED, close-term follow-up examinations should be organized.
Limitations
Although oncology patients generally visit to the hospitals where they are followed when they get ill, they may present to other hospitals in emergencies. We may not have been able to access this data. Therefore, ED visits and irAEs may be underdetected. Additionaly, considering the complexity of cancer patients in the ED, irAEs may have been missed in a retrospective study. For example, blood sugar dysregulation is a known side effect of nivolumab [19]. In a hyperglycemic patient without known diabetes, it is easy to attribute this situation to nivolumab. In contrast, it is difficult to say that nivolumab is the cause of disruption of regulation in a person already diagnosed with diabetes. In this case, nivolumab may or may not have contributed to this situation through immune effects. Thus, large-scale prospective case-control studies are needed.