Adrenal crisis mainly manifested as recurrent syncope secondary to Tislelizumab:a case report and literature review

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Case Report

Adrenal crisis mainly manifested as recurrent syncope secondary to Tislelizumab:a case report and literature review

https://doi.org/10.21203/rs.3.rs-3234717/v1

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As immune checkpoint inhibitors (ICIs), Tislelizumab is an anti-programmed cell death protein 1 (PD-1) drug. With the extensive application of ICIs, there is an ever-increasing proportion of immune-related adverse events (irAEs) in clinic, some of which may even be life-threatening. Herein we present a patient of Tislelizumab-induced adrenal crisis. The main clinical manifestation is recurrent syncope accompanied by high-grade fever. Timely identification and hormone replacement therapy helped the patient get through the crisis well. Finally,the patient discontinued Tislelizumab and switch to ADC therapy.We reported this case to improve our understanding of this situation, identify this kind of disease and prevent adrenal crisis in time. Eventually, limiting toxicities to reduce the interruption of immunotherapy. Since irAEs are multisystem damage with more non-specific symptoms, except for oncologists, general practitioners who endorse the need for taking a holistic approach to the patient should play a vital role in the management of cancer treatment.

Tislelizumab

immune-related adverse events (irAEs)

adrenal crisis

immune checkpoint inhibitors (ICIs)

recurrent syncope

Nowadays, the treatment of multiple malignancies has been revolutionized by immune checkpoint inhibitors (ICIs), prolonged patients’ long-term survival and produced durable remisssions. ICIs are monoclonal antibodies, which target two key signaling pathways related to T cell activation and exhaustion by binding and inhibiting cytotoxic T lymphocyte antigen (CTLA)-4 or programmed death (PD) -1 and its ligand PD-L1 (1, 2). However, ICIs may also demolish the maintenance of immunological tolerance to self-antigens (3), leading to immune-related adverse events (irAEs) in different organ systems, especially autoimmune-like manifestations targeting endocrine glands (4). These toxic effects are a major cause of onset, often lead to the treatment discontinuation and can have debilitating long-term consequences (1). Endocrine dysfunction is one of the most commonly reported irAEs in ICIs clinical trials, including hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal hypofunction (PAI) and type 1 diabetes (5).

Little is known about severe adrenal insufficiency (AI) related to ICIs, with an incidence rate of ≤ 1% (6, 7, 8, 9). AI usually manifests as grade 1–2 irAEs, while adrenal crisis (AC) manifested as grade 3–4 irAEs is rare. The presentation of AI is usually nonspecific. The main clinical symptoms including fatigue, anorexia and nausea, etc., which may be misdiagnosed as complications of malignant tumor. When AI is not recognized, misdiagnosis or delayed diagnosis may lead to life-threatening AC (10, 11). A history of previous AC is a susceptible factor for patients with AI to experience AC again (10). Severe symptoms of adrenal crisis may lead to a decline in confidence and discontinuation of immunotherapy. Therefore, it is of great clinical significance to identify and treat AI in time.

This case report describes a middle-aged man with non-invasive urothelial carcinoma who occurred AC characterized by recurrent syncopal episodes after treatment with PD-1 inhibitor, Tislelizumab.

A 58-year-old male patient was admitted to our Department due to recurring syncopal episodes for more than 3 months. He was also suffering from high fever, confused, fatigue, anorexia, nausea and vomiting. The patient's family once monitored his blood pressure after syncope with a systolic blood pressure of 50-60mmHg and the blood glucose level of 4.6mmol/L. Prior to referral he consulted the Department of Cardiology and Neurology for several times and underwent the relevant examinations. They are suspicious of the possibility of cardiological and neurological diseases, but no specific etiology was identified and the symptomatic treatment was less effective. Besides physical symptoms, the patient was under great mental pressure at the time of admission.

Three years ago, he was diagnosed with urothelial carcinoma and underwent minimally invasive surgery. The tumor recurred 6 months after resection and on May 20^th, 2022, he underwent complete transurethral resection of bladder tumor (TURBT). Histological diagnosis: low-grade non-invasive papillary urothelial carcinoma, low grade. Cancer tumor staging showed no metastasis or local invasion and the last contrast-enhanced multislice computed tomography (CT) was normal. The patient received treatment with Tislelizumab (about 8 cycles). The first 4^th cycles of immunotherapy from May 25th,2022 to July 27^th, 2022 with infusion of Tislelizumab(200 mg, injection d1 3weeks) without specific discomfort. However, On August 17^th, 2022, he began to develop a rash. Then on October 5th, anorexia and occasional fever occurred. On October 26^th, he found himself was losing weight. Finally on November 6^th,2022, after the injection he presented to the emergency room because of syncope. Smoking history for more than 30 years. Previous endocrine disorders were unclear.

On admission, his body temperature (BT) was 35.5°C, blood pressure (BP) was 117/77 mmHg. His physical examination reveals breath sounds increased and a positive Murphy's sign. Combined with the results of previous laboratory examinations and clinical manifestations, we first consider the possibility of Adams-Stokes syndrome attack, viral myocarditis, transient ischemic attack (TIA) attack, pulmonary embolism, sepsis, vasovagal syncope, insulinoma, PD-1 related adverse reactions and so on.

Laboratory data revealed a high level of high-sensitivity C-reactive protein. We further performed contrast-enhanced multislice CT which shows interstitial infiltrates and exaggerated lung markings. The level of serum sodium was normal. Other abnormal data were showed in Table1. Diurnal rhythm changes of serum ACTH and cortisol suggested extremely low cortisol and ACTH and inconsistent diurnal rhythm(Table 2), considering that the patient had hypoadrenalism. In view of the low level of ACTH and no abnormalities were seen on adrenal CT, the diagnosis of central hypoadrenalism was confirmed. Given the history of immunotherapy, we considered the possibility of immune-related hypophysitis (irH). Consequently, we comprehensively evaluated the endocrine system of patients as irH could involve the hypothalamic pituitary thyroid axis, gonadal axis involvement in addition to the cumulative hypothalamic pituitary adrenal axis (HPA). Thyroid function tests revealed that although thyroglobulin was slightly elevated, FT3, FT4, TSH were normal, thyroid peroxidase and thyrotropin receptor antibodies were negative, suggesting normal pituitary thyroid function; The results of sex hormone test showed that luteinizing hormone and progesterone were mildly elevated and the remaining indexes were within normal limits, suggesting normal pituitary gonadal function. To this point the patient's etiology could be clarified as irH triggered isolated adrecocorticotrophic hormone deficiency (IAD). The common clinical manifestations of IAD were fatigue, nausea and vomiting, weight loss, hypoglycemia, hyponatremia and refractory hypotension.The patient's symptoms were highly consistent with IAD.

Finally, we performed pituitary MRI imaging(Figure 1), which revealed normal pituitary gland. The patient's family complained of absolute low blood pressure (<100 mmHg)，hyperthermia with confused during the syncopal episode thus adrenal crisis as the most reasonable diagnosis. After administration of hydrocortisone sodium succinate (0.15g ivdrip bid) and continuous fluid resuscitation, the patient's condition gradually improved. After discharge, he continued to be given prednisone 10 mg qd (8a) and 5 mg qd (5p) orally. After 3 months' follow-up, the patient did not have syncope again and the symptoms of fever, fatigue, anorexia, nausea and vomiting improved significantly. In addition, there was no recurrence of adrenal crisis or other immune-related adverse symptoms during the follow-up period.

Here we introduced a case of adrenal crisis after treatment with PD-1 (Tislelizumab), which was a 3–4 grade irAE related to PD-1. Several cases with immunotherapy-induced adrenal crisis have been reported, most of which manifested as high-grade fever, persistent hyponatremia or acute abdomen while recurrent syncope is rare, nonspecific symptoms made the diagnosis of diseases difficult. Due to enormous psychological pressure, despite its immense clinical benefits the patient has to stop treatment. Clinical physicians should grow cognition on irAEs in order to identify the events timely and reduce the discontinuation of ICIs.

According to the ASCO Guideline (12), the routine endocrine examination should be taken to evaluate the endocrine gland or organ. In this case we confirmed the diagnose of central hypoadrenocorticism through endocrine examination. We then traced the patients’ medical history to figure out the potential cause. The patient had no previous history of taking, inhaling or injecting steroids, no history of opioids use. Besides treated with PD-1 for eight cycles, there were no other relevant reasons and incentives. Therefore, we considered whether there were PD-1 related adverse drug reactions. Among which, immune-related hypophysitis (irH) has attracted our attention,which is defined by the occurrence, in patients treated with ICIs, of functional defect of one or more pituitary axes with or without slight pituitary MRI abnormalities (13). The exact pathogenesis of irH is still unknown. CTLA-4 and PD-1/PDL-1 related hypophysitis are currently known to have different clinical features, which may suggest different underlying mechanisms. CTLA-4 related hypophysitis manifests as frequently impairment TSH and LH / FSH secretion accompanied by impairment ACTH secretion (14), a greater propensity for type II hypersensitivity reactions associated with off target effects of CTLA-4 in the pituitary (15). In contrast, PD-1 associated hypophysitis is less frequent (16), most patients have a specifically impairment of ACTH only, presenting as isolated ACTH deficiency (IAD) (17).The pituitary gland of autopsy cases show evidence of type IV hypersensitivity by cytotoxic T lymphocytes (15). Different clinical presentations are presented depending on the different specific target gland axis of injury.

Due to the lack of specific clinical manifestations and accurate onset time, the diagnosis of irH is difficult. At present, the diagnosis is mainly based on biochemical and imaging examinations. Specific immune biomarkers for its diagnosis are not currently available, with the most common biochemical evidence being deficiency of pituitary hormones. Imaging can rely on pituitary MRI to provide diagnostic evidence: pituitary enlargement, stalk thickening and enhancement with allogeneic or heterologous contrast media are present on MRI in 77% of patients with IRH, whereas 23% − 33% of patients do not show abnormalities on MRI (15). Multiple studies have suggested that hypophysitis induced by PD-1 / PD-L1 inhibitors may lack the typical pituitary enlargement compared to CTLA-4 inhibitors (18, 19, 20). Therefore, imaging studies showing a normal appearance of the pituitary gland do not rule out hypophysitis (21). In addition, the diagnosis of hypophysitis may lag a few weeks after imaging shows pituitary enlargement (22).

According to the 2022 NCCN guidelines for irH, MRI should be performed if the patient has symptoms during treatment (23). Recent study suggested that brain MRI after receiving ICI therapy should be compared with previous ones to monitor changes in pituitary size,which may foreshadow impending anterior pituitary hormone dysfunction is about to occur (21). An enlarged pituitary gland, as indicated by imaging studies, is important to exclude metastatic disease besides suspecting hypophysitis (22). Several studies showed that ICIs related central adrenocortical dysfunction appears to be permanent (21, 22, 24, 25, 26). However, most of these reports were central hypoadrenocorticism caused by another immune checkpoint inhibitor CTLA-4 drug. So far, there is a lack of histocytological evidence to prove whether pituitary adrenal axis function could be restored (27, 28). To sum up, hormone replacement therapy should not be delayed with waiting for a pituitary gland MRI when endocrine examination prompts central hypoadrenocorticism (29).

The initial clinical manifestations of IAD lack specificity which delayed in diagnosis and eventually progress to adrenal crisis threatening the patient's life.The main clinical manifestations of adrenal crisis are severe hypotension or hypovolemic shock, acute abdomen symptoms, vomiting, hyperthermia or hypothermia and hypoglycemia. Among them, hypotension is a core symptom in the diagnosis of adrenal crisis. But seemingly normal blood pressure could not rule out a crisis. According to the adverse event evaluation criteria (CTCAE), adrenocortical insufficiency is usually grade 1–2 irAEs, while grade 3–4 irAEs especially adrenal crisis are rarely reported.In a large meta-analysis study containing 160 clinical trials and 40432 patients, Jingli et al. found that among patients using ICIs, the incidence of all grade and severe grade hypoadrenalism was 2.43% and 0.15%, respectively (6). This case is a case of grade 3–4 irAEs induced by Tislelizumab who presented with adrenal crisis. Symptoms of our patient were unremarkable and could be easily overlooked if an irAE not been suspected. Although adrenal crisis is rare, it is a life-threatening side effect of ICIs that requires immediate recognition and treatment with intravenous glucocorticoids. Therefore, a deep understanding of irAEs as well as adrenal crisis, early diagnosis and treatment is significantly important. When immunotherapy related adrenal crisis occurs, an initial intravenous or intramuscular bolus of 100mg hydrocortisone in addition to supportive fluid therapy is required, as well as a continuous intravenous infusion of 200 mg hydrocortisone q24h (daily) or an intravenous or intramuscular bolus of 50 mg hydrocortisone q6h (or 50 mg four times daily) (10).

The recommended duration is 24-48h until the patient can take oral hydrocortisone (11). Glucocorticoid replacement therapy should be the primary treatment when the patient's condition is stable. Our patient had no history of underlying endocrine diseases such as diabetes, so there were no specific restrictions on the dose of cortisol to be administered. In patients with diabetes, choosing the appropriate cortisol dose that in turn maximizes benefits and reduce associated side effects is a challenge. Considering that high-dose cortisol may aggravate the underlying disease or lead to new disease (30), the potential benefit of high-dose glucocorticoid treatment should be balanced against efficacy loss due to anticancer immunotherapy. Although this issue remains controversial (26), the dose of cortisol should be reduced appropriately. For adults, the oral maintenance dose of hydrocortisone needs to be 15–25 mg per day (31). The hydrocortisone dose should then be gradually reduced according to the patient's clinical manifestations, with close monitoring of blood pressure and recurrence of clinical symptoms.

For patients who develop endocrine diseases that can be controlled using hormone replacement therapy, there is no need to discontinue ICIs even its grade 3–4 irAEs (32, 33). Theoretically, during the treatment period of ICIs, at the same time as the immune system's reduced tolerance to triggering irAEs, its ability of recognizing and killing cancer cells is enhanced, so the occurrence of irAEs may be a positive predictor of treatment response (21). Our patient underwent imaging examinations showed no metastasis and recurrence of the tumor, indicating that this patient achieved a complete response to the treatment with Tislelizumab. Meanwhile, several studies have shown a positive correlation between the development of irAEs as a result of ICIs therapy and improved tumor response and survival. However, for grade 3–4 irAEs, especially life-threatening side effects that required urgent hospitalization for corresponding symptomatic supportive care. After adverse reactions disappearance the restore of ICIs requires consideration of many situations, such as previous tumor reactions, treatment duration, toxicity type and severity, toxicity resolution time, availability of alternative therapies, and patient's condition (12). Multiple studies have confirmed a significantly increased incidence of irAEs with combination of ICIs and it is not recommended to switch to a new another ICI (26, 34, 35, 36). After a consult with an oncologist on this patient's condition, he recommended an antibody-drug conjugate (ADC) therapy. At our later follow-up visit, the patient decided to discontinue ICIs therapy and switch to ADC to continue the anti-tumor treatment.

In addition, a growing number of clinical cases prove that endocrine diseases such as late-onset AC still occur after the termination of ICI therapy (37, 38), which also prove that the antitumor effects of ICIs can be long-term in vivo and expressed (38, 39). Therefore,always be alert to the possibility of irAEs even after the discontinuation of ICIs. Current medical examination methods cannot distinguish between immunologic and non-immunologic related causes and specific immunological biomarkers deprivation make it rough for clinicians capturing irAEs (40). Because of their specificity of presentation, atypical timing, and clinical coexisting with other diseases, irAEs may be more difficult to diagnose and identify (40, 41, 42). Especially for immune checkpoint inhibitors, risk factors predicting these events have yet to emerge. It is a challenge that cannot predict who will develop severe or permanent toxicity (1). Before giving treatment to patients with PD-1/PD-L1 inhibitors, it is necessary to inquire about the history of endocrine diseases and autoimmune diseases in detail. Conducting reasonable baseline screening, regularly monitor changes in endocrine indicators, increase vigilance against possible related symptoms and signs, detect and promptly handle irAEs as soon as possible. Once determining the dose of hormones and the types of anti-tumor drugs, it is necessary to further provide patients with the popularization of common adverse reactions to ICI and conduct regular follow-up visits. We believe that self education and management of such patients play an important role in the progress of the disease. Identify early to limit toxicities while maximize anti-tumor efficacy to reduce the interruption of immunotherapy.

With the increase of clinical practice of tumor immunotherapy, the occurrence of immune related adverse reactions will constantly increase. Specialists of different Departments may receive referrals for patients suffering from specific symptom of adverse events in their field of expertise. However, as irAEs are multisystem damage with more non-specific symptoms, except for specialists, general practitioners should play a greater role in the management of cancer treatment. Identifying and characterizing irAEs is a cornerstone in ascertain the impact of cancer treatment on patients and healthcare professionals (43). Cancer survivors are often troubled by the long-term consequences of cancer and its treatment (44). Because primary care is integrated and accessible healthcare services, most patients consult the general practitioners in the first situation once they have sympotoms.Lower grade irAEs can be captured and under control, so as to divert medical resources pressure and and financial pressure away from tertiary health care to primary health care. As gatekeeper to further services, general practitioner shuold play a greater role to improve the quality of care for cancer survivors.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author Contributions

All authors contributed to the manuscript writing and preparation of the figures. All authors contributed to the article and approved the submitted version.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

Not applicable. The patient’s family provided consent for the publication of the images. The patient’s identity has been kept confidential.

Funding

None.

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Table 1 Laboratory measurements

Parameter	Value	Normal range
High-sensitivity C-reactive protein(mg/L)	42.98	0-10
Blood glucose(mmol/L)	4.01	3.90-6.10
Sodium(mmol/L)	142	137-147
Potassium(mmol/L)	3.69	3.50-5.30
Glomerular filtration rate(ml/min)	105.35
Progesterone(nmol/L)	0.590	<0.474
Luteinizing hormone(mIU/ml)	9.04	1.70-8.60
Thyroglobulin(ng/ml)	95.06	1.40-78.0
Ferritin(ng/ml)	818.00	13-400
Neuron-specific enolase(ng/ml)	16.50	0.0-16.3

Table 2 Diurnal rhythm changes of serum ACTH and cortisol

	8am	4pm	0am
Cortisol（ug/dl）	0.16	0.20	0.15
ACTH（pg/ml）	4.47	2.37	2.16

ACTH: Adrenocorticotropic hormone

No competing interests reported.

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Adrenal crisis mainly manifested as recurrent syncope secondary to Tislelizumab:a case report and literature review

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