Successful Steroid Treatment of Pembrolizumab-induced Agranulocytosis That Developed after Splenectomy in a Patient with Non-small-cell Lung Cancer

Abstract

Neutropenia, a rare immune-related adverse event, affects patients receiving treatment with immune checkpoint inhibitors (ICIs). We herein report a case of pembrolizumab-induced agranulocytosis. An 83-year-old man was diagnosed with advanced-stage lung carcinoma concomitant with splenomegaly complicated by hypersplenism, causing pancytopenia. To avoid the risk of bone marrow suppression due to cytotoxic chemotherapy, pembrolizumab monotherapy was chosen. However, the patient developed agranulocytosis despite the resolution of pancytopenia through splenectomy performed after the fourth pembrolizumab cycle. Neutrophil counts improved after steroid treatment but not after granulocyte colony-stimulating factor treatment. This case demonstrated that neutropenia can sometimes develop abruptly after several ICI therapy cycles.

Introduction

The recent development of immune checkpoint inhibitors (ICIs), such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, has led to substantial progress in lung cancer treatment (1). Pembrolizumab, a fully humanized monoclonal immunoglobulin (Ig)G4-kappa isotype antibody against PD-1, binds to the PD-1 receptor located on activated T-cells and blocks the interaction with PD-L1 expressed on tumor cells, resulting in antitumor activities (2).

Since first-line pembrolizumab monotherapy has resulted in a significantly longer overall survival than platinum-based chemotherapy in patients with a PD-L1 tumor proportion score (TPS) of ≥1%, this is the only drug to be approved as a single ICI agent for first-line lung cancer treatment (3). Furthermore, the safety and efficacy of pembrolizumab monotherapy were found to be good in elderly patients, while platinum-based cytotoxic agents often cause severe adverse events, such as leukopenia and fatigue, in these populations (4).

However, ICIs induce the following immune-related adverse events (irAEs) involving various organs: rash, colitis, hepatitis, thyroiditis, and pneumonitis (5). Hematological irAEs (hem-irAEs) are rare but potentially life-threatening adverse events (6,7).

We herein report a case in which pembrolizumab-induced agranulocytosis and febrile neutropenia occurred after splenectomy, and appropriate steroid treatment successfully prevented fatal complications.

Case Report

An 83-year-old former smoker (60 pack-years) was admitted to our hospital with a chief complaint of worsening exertional dyspnea. He had a history of chronic obstructive pulmonary disease (COPD), for which he had been treated with a long-acting muscarinic antagonist (LAMA). Chest computed tomography (CT) revealed pre-existing upper lobe-predominant emphysema with new-onset left unilateral pleural effusion. In addition, abdominal CT revealed splenomegaly (Fig. 1A-D). Thoracentesis of the left pleural effusion did not reveal any particular diagnostic findings.

Figure 1.

Imaging findings at the first admission. A chest radiograph showing the blunting of the left costophrenic angle (A). A CT image showing centriacinar emphysema in the upper lobes (B) and a significant amount of pleural effusion in the left thoracic cavity (C). An abdominal CT image revealing an enlarged spleen (splenomegaly) (D). 18F-FDG PET/CT showing the uptake of FDG in part of the left pleura (white arrow) (E) and the diffuse uptake of FDG in the enlarged spleen (F). 18F-FDG PET/CT: 18F-fluorodeoxyglucose positron emission tomography/computed tomography, CT: chest computed tomography

¹⁸F-fluorodeoxyglucose positron emission tomography/CT (¹⁸F-FDG PET/CT) showed the uptake of FDG in part of the left pleura (Fig. 1E) and the diffuse uptake of FDG in the enlarged spleen (Fig. 1F). The patient underwent video-assisted thoracoscopic surgery (VATS). A pleural biopsy from the areas of the uptake of FDG on PET-CT revealed non-small-cell carcinoma (Fig. 2A). Immunohistochemistry showed positivity for cytokeratin (AE1/AE3), thyroid transcription factor-1 (TTF-1) (Fig. 2B), and p40 (Fig. 2C) but negativity for vimentin and calretinin, suggesting carcinoma of lung origin. The results corresponding to an epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement were negative, whereas the PD-L1 tumor proportion score was positive at 1-24% (Fig. 2D). Chest CT did not reveal the primary origin of the lung cancer; therefore, we diagnosed the patient with clinical stage IVA lung non-small-cell carcinoma in cTXN0M1a PLE.

Figure 2.

Histopathological images of the surgical pleural biopsy specimen. Hematoxylin and Eosin staining showing non-small-cell carcinoma with a desmoplastic reaction (A). Immunohistochemical images showing tumor cells expressing TTF-1 (B), p40 (C), and PD-L1 (1-24%) (D). Scale bar, 200 μm (A-C) and 100 μm (D). p40: ΔNp63/p40, PD-L1: programmed death-ligand 1, TTF-1: thyroid transcription factor-1

The patient's blood cell counts gradually decreased as follows: white blood cells (WBCs) to 1,800 /μL (neutrophils, 65.0%; lymphocytes, 22.0%; atypical lymphocytes, 3.0%; monocytes, 8.0%; eosinophils, 1.0%; basophils, 1.0%), hemoglobin to 9.1 g/dL, and platelets to 64×10³/μL; these findings suggested worsening of pancytopenia, attributable to hypersplenism. Although his Eastern Cooperative Oncology Group (ECOG) performance status was 0, we decided not to administer cytotoxic chemotherapeutic agents to avoid the risk of further myelosuppression.

The patient started receiving pembrolizumab monotherapy and was subsequently discharged. Ipilimumab had not yet been approved for the treatment of lung cancer in Japan at the time. Although low-grade lymphoma, such as splenic follicular marginal zone lymphoma, was considered to be the cause of his splenomegaly and hypersplenism, diagnostic splenectomy was postponed to avoid a potential delay in his lung cancer treatment because of his underlying conditions, including an older age and impaired lung function.

A bone marrow examination revealed normocellular marrow without hematological malignancies. However, the patient developed left-sided abdominal pain after the first cycle and was admitted to our hospital for pain management. Contrast-enhanced CT showed no evidence of splenic infarction and no significant change in spleen size compared with the results of the previous examination. His abdominal pain was alleviated using an analgesic agent (acetaminophen). However, the levels of soluble interleukin-2 receptor (sIL-2R) significantly increased (4,034 U/mL) concomitantly with the further progression of pancytopenia, suggesting the presence of a hematological disease, such as lymphoma or secondary hypersplenism (Fig. 3). We decided to perform splenectomy for diagnostic purposes as well as to resolve the pancytopenia. Pneumococcal conjugate vaccines (13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine) were administered before splenectomy. Pembrolizumab treatment was resumed and repeated until splenectomy. The patient's lung cancer did not progress during treatment. Although no measurable lesions were detected other than malignant pleural effusion, follow-up imaging showed no new lesions after pembrolizumab administration.

Figure 3.

Clinical course of the patient from the first admission for VATS until the onset of agranulocytosis. Pembrolizumab was administered after the patient was diagnosed with pleural dissemination of non-small-cell lung carcinoma. Pancytopenia worsened concomitantly with an elevation in the serum level of sIL-2R. Through splenectomy, the severity of pancytopenia was reduced, and the serum sIL-2R levels were decreased. However, agranulocytosis occurred suddenly after the fifth dose of pembrolizumab. Other blood cell counts (including Hb level and PLT count) were not affected. Neu: neutrophil, PLT: platelet, sIL-2R: soluble interleukin-2 receptor, VATS: video-assisted thoracoscopic surgery

An examination of splenectomy specimens revealed splenomegaly. Histologically, enlargement of the splenic white pulp was observed in addition to congestion. Although focal B-cell aggregates were detected in portions of the white pulp, structural destruction was not observed, and infiltrated cells were polymorphic, which was inconsistent with lymphoma. However, Epstein-Barr virus-encoded small RNA in situ hybridization (EBER) staining revealed several EBER-positive cells in the spleen tissues, suggesting the presence of polymorphic lymphoproliferative disorder (Fig. 4A-D). The severity of the pancytopenia reduced and sIL-2R serum levels decreased after splenectomy (Fig 3), suggesting that these conditions were related to Epstein-Barr virus-associated lymphoproliferative disorder.

Figure 4.

Splenectomy specimens. Macroscopic findings on examining the resected specimen revealing splenomegaly with congestion (A). Histologic findings showing lymphocyte proliferation with preserved follicular structures. The infiltrated cells were polymorphic. Low-power field (B) and high-power field (C) images of the Hematoxylin and Eosin staining. A relatively large number of EBER-positive cells were detected by in situ hybridization (D). Scale bar, 1 mm (B) and 100 μm (C, D). EBER: Epstein-Barr virus-encoded small RNA

Subsequently, the patient developed agranulocytosis with a fever (38.4°C) 21 days after the fifth dose of pembrolizumab (Fig. 3). His WBC count was 5,100 /μL (neutrophils, 0%; lymphocytes, 78.0%; monocytes, 21.5%; eosinophils, 0%; basophils, 0.5%), with an absolute neutrophil count of 0. The hemoglobin level (12.0 g/dL) and platelet count (331×10³/μL) did not decrease. Other remarkable laboratory findings included an elevated C-reactive protein (CRP) level (4.80 mg/dL). His vital signs were normal, except for his fever, and a physical examination revealed no abnormalities. Chest radiography and CT showed no abnormalities. Blood culture test results on admission were negative.

He was treated with tazobactam/piperacillin (4.5 g every 6 hours) and granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia (Fig. 5). He was not taking any other medications. On considering these findings collectively, pembrolizumab-induced agranulocytosis was strongly suspected. His neutropenia temporarily improved with consecutive daily G-CSF treatment during the first emergency admission (Fig. 5). He became afebrile and was discharged from the hospital. However, he developed agranulocytosis again one month after the previous episode of febrile neutropenia (Fig. 5). Although he was afebrile and asymptomatic at the time, he was re-admitted to the hospital for the treatment of agranulocytosis. As his neutropenia did not respond to G-CSF treatment at this time, we started high-dose (125 mg/day) methylprednisolone treatment on considering the immune-related mechanism. His neutropenia rapidly improved after steroid administration. He continued to take 30 mg/day of oral prednisolone (0.5 mg/kg/day) as maintenance therapy, and the dose was tapered every 2 weeks. The neutrophil count decreased slightly with steroid dose reduction, but it remained within normal limits without any recurrence after the cessation of steroid treatment (Fig. 5). He received a meningococcal polysaccharide vaccine and Haemophilus influenzae type b conjugate vaccine for prophylaxis of overwhelming post-splenectomy infection (OPSI), and no recurrence of infection was seen.

Figure 5.

Summary of the clinical course after the first emergency admission for febrile neutropenia. Febrile neutropenia was treated with TAZ/PIPC and G-CSF during the first admission. Administration of G-CSF temporarily increased the number of neutrophils. However, agranulocytosis recurred. During the second episode, agranulocytosis did not respond to repetitive G-CSF injections. High-dose steroid treatment was initiated and dramatically improved the neutrophil count. Neutrophil counts remained within normal limits after the PSL dose was slowly tapered and discontinued. G-CSF: granulocyte colony-stimulating factor, mPSL: methylprednisolone, Neu: neutrophil, PSL: prednisolone, TAZ/PIPC: tazobactam/piperacillin

Discussion

Chemotherapy-induced myelosuppression is a common adverse event in cancer treatment, whereas ICI-induced hematological toxicities are uncommon (＜0.5%) (6). According to data from 3 French pharmacovigilance databases, neutropenia (26%), hemolytic anemia (26%), and immune thrombocytopenia (26%) are the most common events among hem-irAEs (7).

Despite the fact that hem-irAEs can lead to serious conditions (7), their clinical features, including the timing of the onset, causative mechanism, and prognosis, have not been fully elucidated. Therefore, we conducted a comprehensive search on PubMed for literature related to ICI-induced neutropenia using the terms, “nivolumab,” “pembrolizumab,” “atezolizumab,” and “ipilimumab,” which are the names of the currently available ICI agents for lung cancer treatment, and “neutropenia” or “agranulocytosis” as key words. The diagnostic criteria for agranulocytosis (neutrophil count ＜500 /μL) were met in 27 cases, among which 26 were available for a detailed review; therefore, these 26 cases were summarized along with our case, resulting in a total of 27 reviewed cases (Table).

Table.

Summary of Cases Involving ICI-induced Agranulocytosis.

Age, sex	Cancer	ICI	PMH of autoimmune disease	No. of cycles before onset	Other hem-irAEs	Other irAEs apart from hem-irAEs	Bone marrow examination results	Antineutrophil antibody	Treatment for neutropenia	Time to recovery	Ref
57, M	Lung adenocarcinoma	Nivolumab	None	3	None	Liver dysfunction (G2)	Agranulocytosis in bone marrow	Negative	G-CSF	1 day	(18)
74, F	Lung adenocarcinoma	Nivolumab	UC	2	None	Liver dysfunction (G1)	Absence of myeloid precursors	N/A	Failure to G-CSF, IVIG, and low dose steroid. Responded to high dose steroid (mPSL 3 mg/kg/day)	2 days	(19)
73, M	Lung adenocarcinoma	Nivolumab	CD	5	None	Diarrhea (CD exacerbation)	N/A	N/A	G-CSF, mPSL 1 m/kg	7 days	(20)
74, M	Lung adenocarcinoma	Nivolumab	None	11	None	None	Maturational defects in myelocytes with CD8+T cell infiltration	Negative	G-CSF, PSL 1 mg/kg. Although responded to PSL, PSL dose could not be tapered	-	(20)
73, F	Lung adenocarcinoma	Pembrolizumab	Autoimmune myositis, CD, hypothyroidism	2	None	None	N/A	N/A	SoluMedrol 40 mg q6h, IVIG, and cyclosporine A	12 days	(21)
74, M	Lung adenocarcinoma	Pembrolizumab	None	4	None	None	Normocellular marrow	N/A	Responded to PSL (80 mg/day), but relapsed after dose tapering within 1 month. Responded to PSL rechallenge	7 days	(22)
79, M	Lung adenocarcinoma	Atezolizumab	None	5	None	None	Decreased proportion of myeloid precursor cells	Negative	G-CSF	10 days	(23)
56, M	Lung adenocarcinoma	Nivolumab	None	3	Thrombocytopenia (G3)	None	Severely hypoplastic marrow, could not r/o AA	N/A	Did not respond well to G-CSF, mPSL 500 mg, and IVIG	-	(24)
67, M	Lung squamous carcinoma	Nivolumab	None	35	Thrombocytopenia (G2)	None	Hypoplastic bone marrow	Negative	G-CSF, PSL 50 mg	4 days	(25)
63, M	Lung squamous carcinoma	Nivolumab	None	1	None	Interstitial pneumonia (grade unknown)	N/A	N/A	G-CSF	N/A	(26)
82, M	Lung pleomorphic carcinoma	Pembrolizumab	None	3	None	OP (G1), ocular MG (grade unknown)	Decrease in mature neutrophils	Positive	G-CSF	7 days	(27)
83, M	NSCLC	Pembrolizumab	None	5	None	None	N/A	N/A	Responded to mPSL 125 mg/day	4 days	Our case
42, F	Melanoma	Ipilimumab	None	4	Thrombocytopenia (G4), anemia (G2)	Mild rash	Myeloid hypoplasia with marked granulocytic hypoplasia	Positive	Did not respond to G-CSF, DEX 8 mg/day, and cyclosporine. Responded to IVIG.	6 days	(28)
59, M	Melanoma	Ipilimumab+ nivolumab	None	2	None	Rash (G3), hepatitis (G3), colitis (G3)	Hypoplasia of granulocytic lineage with T-cell infiltration	N/A	G-CSF, mPSL 2 mg/kg, IVIG, MMF	6 days	(29)
49, F	Melanoma	Ipilimumab	None	3	None	None	N/A	N/A	GM-CSF, mPSL 2 mg/kg b.i.d.	10 days	(30)
70, M	Melanoma	Ipilimumab	None	*4	None	Mild pruritus	Lymphocyte infiltration	N/A	GM-CSF, PSL 1 mg/kg/day	7 days	(30)
35, M	Melanoma	Ipilimumab	None	3	Anemia (G2)	Rash (G1)	Presence of a granulocyte line with the features of rejuvenation and with preserved maturation	N/A	G-CSF, mPSL 2 mg/kg/day	8 days	(31)
75, F	Melanoma	Nivolumab	UC	14	None	Neurological symptom (grade unknown)	Granulocytic hypoplasia	N/A	Did not respond to any treatment (high-dose intravenous steroids, G-CSF, MMF, or IVIG)	-	(32)
73, M	Melanoma	Nivolumab	None	1	Anemia (G3)	None	Hypoplasia of hematopoietic cells	N/A	Improved without treatment	-	(33)
54, M	Melanoma	Ipilimumab	None	4	None	Mild rash, libido	Absence of granulocyte precursors	N/A	Responded to ATG/cyclosporine/PSL 120 mg. Relapsed due to rapid PSL dose tapering. Responded to an increase in PSL dose	9 days	(34)
51, M	Melanoma	Ipilimumab+ nivolumab	None	2	Anemia (G2)	DKA (grade unknown)	Hypocellular marrow with trilineage hypoplasia consistent with AA	N/A	mPSL 1 mg/kg q12h	Within 10 days	(35)
77, F	Melanoma	Ipilimumab	None	4	Anemia (G2), thrombocytopenia (G2)	Hyperthyroidism (grade unknown)	Hypoplastic granulocyte lineage with T cell hyperlymphocytosis	Negative	High-dose PSL 1 mg/kg/day+IVIG	7 weeks	(36)
74, F	Melanoma	Ipilimumab	None	3	Anemia (G3)	None	Myeloid hypoplasia	N/A	mPSL 1 mg/kg q12h, ATG, cyclosporine	2 days	(37)
49, F	Multiple myeloma (after alloHCT)	Pembrolizumab	None	2	None	Mild eosinophilic folliculitis	Absence of mature granulocytic elements	N/A	Did not respond to G-CSF, high dose steroid, IVIG, rituximab, cyclosporine. Improved through alloHCT	-	(38)
65, M	AML	Nivolumab	None	1	None	None	No evidence of AML relapse	N/A	G-CSF	**3 months	(39)
38, F	B-cell lymphoma	Nivolumab	None	3	None	None	N/A	Positive	Did not respond to G-CSF. Responded to IVIG and rituximab. Continued nivolumab with rituximab.	Within 3 days	(40)
64, F	Urothelial tumor	Pembrolizumab	None	8	None	HP (grade unknown)	Normocellular marrow	N/A	Course observation (neutrophil counts between 500-2,200 while pembrolizumab was continued)	-	(41)

*48 weeks after the first dose, **time to full recovery of neutrophil count

AA: aplastic anemia, allo HCT: autologous hematopoietic stem cell transplant, AML: acute myeloid leukemia, ATG: anti-thymocyte globulin, CD: Crohn’s disease, DEX: dexamethasone, DKA: diabetic ketoacidosis, G: grade, G-CSF: granulocyte colony stimulating factor, GM-CSF: granulocyte macrophage colony-stimulating factor, hem-irAEs: hematological immune-related adverse events, HP: hypersensitive pneumonitis, ICI: immune checkpoint inhibitor, IVIG: intravenous immunoglobulin, MG: myasthenia gravis, MMF: mycophenolate mofetil, mPSL: methylprednisolone, N/A: not available, NSCLC: non-small cell lung cancer, OP: organizing pneumonia, PMH: personal medical history, PSL: prednisolone, Ref: reference, UC: ulcerative colitis

The most common tumor types were lung cancer (12/27 cases), melanoma (11/27 cases), hematological malignancy (3/27 cases), and urothelial cancer (1/27 cases). No patients received concurrent cytotoxic agents when they developed ICI-induced neutropenia, although one patient received atezolizumab and bevacizumab as maintenance therapy for atezolizumab plus bevacizumab plus carboplatin plus paclitaxel treatment. The age at onset ranged from 35 to 83 years old, suggesting that ICI-related agranulocytosis is not limited to elderly patients. The median timing of the onset of adverse events was 3 cycles (range, 1-35 cycles), which was consistent with the findings in the present case. Although 4 of the 27 patients had a history of autoimmune disease, no specific trend or pattern was noted in the occurrence of ICI-related agranulocytosis. In the present case, serological markers of autoimmune disease, such as antinuclear antibody, anti-neutrophilic cytoplasmic autoantibodies, and rheumatoid factor, were not elevated upon the patient's first admission. Among the ICI-induced agranulocytosis cases, 19 involved single-lineage neutropenia, while 6 and 2 cases involved bicytopenia and pancytopenia, respectively. The mechanisms underlying ICI-induced agranulocytosis remain unclear, but some hypotheses have been proposed; specifically, T-cell activation leads to increased cytokine secretion from CD4⁺ helper T-cells, resulting in tissue infiltration of cytotoxic CD8⁺ T-cells and/or immune-related dysmaturity of hematopoietic cells (8). In most of the cases in which bone marrow biopsy specimens were collected, hypoplasia of the granulocyte lineage was found; in addition, the patients in two cases were suggested to have aplastic anemia, whereas those in another two cases had normocellular marrow. In some cases, concomitant T-cell or CD8⁺ T-cell infiltration was reported. The presence of anti-neutrophil antibodies is not necessarily essential for the diagnosis of ICI-induced agranulocytosis, but the patients in three of eight cases tested positive.

Although steroid treatment is generally recommended for irAEs, there is no consensus concerning the management of hem-irAEs, including neutropenia, according to the practice guidelines of the European Society for Medical Oncology (ESMO) (9). However, some reports do not recommend the use of systemic steroids for ICI-induced neutropenia because of the increased risk of infection (7). The actual treatment regimen chosen for ICI-induced agranulocytosis varies among the reported cases: 5 patients were treated only with a G-CSF injection, and 14 responded to treatment with systemic steroids. Most of the patients who responded to the treatment started to exhibit an increase in the neutrophil count within 10 days. Conversely, patients in whom systemic steroid treatment doses could not be tapered or patients who did not respond to any treatment had an extremely poor prognosis. High-dose steroids are important in systemic steroid treatment (8). For instance, 1 patient did not respond to prednisolone (1.5 mg/kg/day) but did respond to methylprednisolone (3 mg/kg/day). Our patient was started on 125 mg/day of methylprednisolone based on the protocol in a previous clinical trial (10). It should be noted that irAEs sometimes persist for a long time, and steroid dose tapering within a short period can induce symptom relapse (11,12). In fact, some patients have been reported to have relapses of agranulocytosis, presumably due to rapid steroid dose tapering. In our patient, the steroid dose was successfully tapered over approximately five months, and a relapse of agranulocytosis did not occur after steroid treatment cessation.

Splenectomized patients are at high risk of a serious complication known as OPSI (13). Our patient continued to receive pembrolizumab monotherapy because his tumor did not progress during treatment and because of the concern that cytotoxic agent-related myelosuppression might increase the risk of infection. However, agranulocytosis occurred abruptly after the fifth dose of pembrolizumab. Previous studies have reported that the mortality rate associated with non-chemotherapy drug-induced agranulocytosis was approximately 9-16%, but this rate has improved to approximately 5% due to the establishment of appropriate treatment options, including G-CSF (14,15); nevertheless, patients with an absolute neutrophil count of ＜100 cells/μL are at a higher risk of infection and fatal complications than those with a count of ≥100 cells/μL (16). Furthermore, post-splenectomy patients are at a risk of severe infection or death for a period of three years after the procedure, and an older age and splenectomy for hematological disorders are other risk factors for these outcomes in this patient group (17). Given that our patient was 83 years old and had undergone splenectomy a few months ago, his agranulocytosis with a fever was considered to confer a high risk for OPSI. Although the primary treatment with G-CSF injection was not sufficiently effective, appropriate steroid treatment following the diagnosis of pembrolizumab-induced agranulocytosis helped prevent fatal outcomes in this case.

We encountered a case of pembrolizumab-induced agranulocytosis. ICIs are often the preferred treatment option for cancer, especially when there are concerns regarding adverse events associated with cytotoxic agents. Although our patient had a rare condition at baseline that co-existed with non-small-cell lung cancer with hypersplenism related to an Epstein-Barr virus-associated lymphoproliferative disorder, it is important to note that ICIs can induce hematological toxicities, such as irAEs, at various timepoints. Our patient developed acute agranulocytosis after the fifth dose, and this occurred unexpectedly two months after the resolution of pancytopenia through splenectomy. The further accumulation and analysis of cases involving hem-irAEs are warranted to establish appropriate management guidelines for these uncommon but potentially fatal complications.

The authors state that they have no Conflict of Interest (COI).