Recognizing Complications in Youth With Diabetes Admitted With Diabetic Ketoacidosis Versus Hyperglycemic Hyperosmolar State.

INTRODUCTION: We compare in-hospital complications in youth with isolated diabetic ketoacidosis (DKA) to youth with hyperosmolarity. METHOD: We reviewed medical records of youth (1-20 years) admitted over two years with DKA, hyperglycemic hyperosmolar state (HHS), and hyperosmolar DKA. We evaluated outcomes, including hospital length of stay, altered mental status (AMS), and acute kidney injury (AKI). RESULTS: Of 369 admissions, 334 had isolated DKA, 32 had hyperosmolar DKA, and three had isolated HHS. Hyperosmolar youth had longer length of stay, larger initial fluid boluses, more frequent pediatric intensive care unit admissions, and increased risk of AKI and AMS. The odds of AKI were positively associated with serum osmolality and negatively associated with new-onset diabetes mellitus (DM) compared with established DM. CONCLUSIONS: In youth with DM, hyperosmolarity increases acute complications compared with isolated DKA. Larger-scale studies are needed to identify ways to prevent acute complications in youth experiencing hyperglycemic emergencies.

Inflammatory biomarkers predict higher risk of hyperglycemic crises but not outcomes in diabetic patients with COVID-19.

Background: Inflammation is a predictor of severe complications in patients with COVID-19 infection under a variety of clinical settings. A few studies suggested that COVID-19 infection was a trigger of hyperglycemic crises including diabetic ketoacidosis (DKA) and/or hyperglycemic hyperosmolar state (HHS). However, the association between inflammation and hyperglycemic crises in diabetic patients with COVID-19 infection is unclear. Methods: One hundred and twenty-four patients with type 2 diabetes mellitus (T2DM) and COVID-19 infection from January 2023 to March 2023 were retrospectively analyzed. Demographic, clinical, and laboratory data, especially inflammatory markers including white blood cell (WBC), neutrophils, neutrophil-to-lymphocyte ratio (NLR), c-reactive protein (CRP) and procalcitonin (PCT) were collected and compared between patients with or without DKA and/or HHS. Multivariable logistic regression analysis was conducted to explore the association between inflammatory biomarkers and the prevalence of hyperglycemic crises. Patients were followed up 6 months for outcomes. Results: Among 124 diabetic patients with COVID-19, 9 were diagnosed with DKA or HHS. Comparing COVID-19 without acute diabetic complications (ADC), patients with DKA or HHS showed elevated levels of c-reactive protein (CRP, P=0.0312) and procalcitonin (PCT, P=0.0270). The power of CRP and PCT to discriminate DKA or HHS with the area under the receiver operating characteristics curve (AUROC) were 0.723 and 0.794, respectively. Multivariate logistic regression indicated 1.95-fold and 1.97-fold increased risk of DKA or HHS with 1-unit increment of CRP and PCT, respectively. However, neither CRP nor PCT could predict poor outcomes in diabetic patients with COVID-19. Conclusion: In this small sample size study, we firstly found that elevated serum CRP and PCT levels increased the risk of hyperglycemic crises in T2DM patients with COVID-19 infection. More study is needed to confirm our findings.

Causas precipitantes de crisis hiperglicémicas agudas en pacientes internados en el Centro Médico Nacional - Hospital Nacional / Precipiting causes of acute hyperglycemic crisis in patients in the Centro Médico Nacional - Hospital Nacional

Introducción: las crisis hiperglicémicas agudas son las emergencias endocrinológicas más frecuentes en la práctica clínica y junto a la hipoglucemia se las describe como las complicaciones metabólicas agudas graves del paciente diabético. Objetivo: identificar las causas precipitantes de crisis hiperglicémicas agudas en pacientes internados en el Centro Médico - Hospital Nacional. Metodología: estudio observacional, descriptivo, de corte transversal de pacientes internados en el Centro Médico Hospital Nacional, durante el periodo de mayo 2021 a octubre del 2023. Los datos fueron obtenidos con la revisión de las fichas clínicas. Resultados: de los 100 pacientes evaluados, la crisis hiperglicémica aguda más frecuente fue la Cetoacidosis diabética (CAD) 53 %, seguida del Estado hiperosmolar hiperglicémico (EHH) 25 % y el estado mixto 22 %. Los desencadenantes más frecuentes fueron el abandono del tratamiento, debut de la enfermedad e infecciones. La mortalidad global fue del 12 %. Conclusión: la causa más frecuente de descompensación fueron el abandono del tratamiento, la diabetes de novo y procesos infecciosos.

Introduction: hyperglycemic crises are the most frequent endocrinological emergencies in clinical practice and, along with hypoglycemia, are described as serious acute metabolic complications in diabetic patients. Objective: to identify the precipiting causes of acute hyperglycemic crisis in hospitalized patients in the Centro Médico Nacional - Hospital National. Methodology: this was an observational, descriptive, cross -sectional study of patients hospitalized at the Centro Médico Nacional - Hospital National, from May 2021 to October 2023. The data were obtained from a review of the clinical records. Results: Of the 100 patients evaluated, the most frequent acute hyperglycemic crisis was diabetic ketoacidosis (CAD) 53 %, followed by the hyperglycemic hyperosmolar state (EHH) 25 % and the mixed state 22 %. The most frequent triggers were the abandonment of treatment, disease debut and infections. Global mortality was 12 %. Conclusion: the most frequent causes of decompensations were abandoning treatment, novo diabetes and infectious processes.

Pediatric Hyperglycemic Hyperosmolar Syndrome: A Comprehensive Approach to Diagnosis, Management, and Complications Utilizing Novel Summarizing Acronyms.

This paper focuses on hyperglycemic hyperosmolar syndrome (HHS), a unique hyperglycemic state requiring divergent diagnosis and treatment approaches from diabetic ketoacidosis (DKA) despite some shared characteristics. We introduce the mnemonic DI-FF-ER-EN-CE-S to encapsulate unique HHS management and complications. 'DI' emphasizes the need to delay and decrease initial insulin therapy until serum glucose decline is managed by fluid resuscitation alone. 'FF' stresses the importance of double fluid replacement compared to DKA due to severe dehydration and 'ER' electrolyte replacement due to profound losses and imbalances. 'EN' denotes the potential for encephalopathy and the requirement for a controlled serum osmolality reduction. 'CE' indicates cerebral edema, a rare complication in HHS. 'S' signifies systemic multiorgan failure. We categorize the associated risks into three mnemonic groups: the 3Rs (renal failure, respiratory distress, rhabdomyolysis), the 3Hs (heart failure, hypercoagulation, hyperthermia), and AP (arrhythmias, pancreatitis) to facilitate awareness and screening of HHS.

[Treatment of acute diabetic metabolic crises in adults (Update 2023) : Hyperglycemic hyperosmolar state and ketoacidotic metabolic disorder]. / Therapie der akuten diabetischen Stoffwechselentgleisungen bei Erwachsenen (Update 2023) : Hyperglykämisch-hyperosmolare und ketoazidotische Stoffwechselentgleisung.

Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS) represent potentially life-threatening situations in adults. Therefore, rapid comprehensive diagnostic and therapeutic measures with close monitoring of vital and laboratory parameters are required. The treatment of DKA and HHS is essentially the same and replacement of the mostly substantial fluid deficit with several liters of a physiological crystalloid solution is the first and most important step. Serum potassium concentrations need to be carefully monitored to guide its substitution. Regular insulin or rapid acting insulin analogues can be initially administered as an i.v. bolus followed by continuous infusion. Insulin should be switched to subcutaneous injections only after correction of the acidosis and stable glucose concentrations within an acceptable range.

Severe hypernatremia in hyperglycemic conditions; managing it effectively: A case report.

BACKGROUND: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are common acute complications of diabetes mellitus with a high risk of mortality. When combined with hypernatremia, the complications can be even worse. Hypernatremia is a rarely associated with DKA and HHS as both are usually accompanied by normal sodium or hyponatremia. As a result, a structured and systematic treatment approach is critical. We discuss the therapeutic approach and implications of this uncommon presentation. CASE SUMMARY: A 62-year-old man with no known past medical history presented to emergency department with altered mental status. Initial work up in emergency room showed severe hyperglycemia with a glucose level of 1093 mg/dL and severe hypernatremia with a serum sodium level of 169 mEq/L. He was admitted to the intensive care unit (ICU) and was started on insulin drip as per DKA protocol. Within 12 h of ICU admission, blood sugar was 300 mg/dL. But his mental status didn't show much improvement. He was dehydrated and had a corrected serum sodium level of > 190 mEq/L. As a result, dextrose 5% in water and ringer's lactate were started. He was also given free water via an nasogastric (NG) tube and IV Desmopressin to improve his free water deficit, which improved his serum sodium to 140 mEq/L. CONCLUSION: The combination of DKA, HHS and hypernatremia is rare and extremely challenging to manage, but the most challenging part of this condition is selecting the correct type of fluids to treat these conditions. Our case illustrates that desmopressin and free water administration via the NG route can be helpful in this situation.

Pediatric management challenges of hyperglycemic hyperosmolar state: case series of Korean adolescents with type 2 diabetes.

The hyperglycemic hyperosmolar state (HHS) is considered the most fatal complication of type 2 diabetes mellitus (DM). The number of case reports describing pediatric HHS has increased recently in parallel with obesity and the prevalence of type 2 DM in pediatric patients. In this study, we investigated the patient characteristics and outcomes of HHS in 9 adolescents with obesity and type 2 DM. Almost all patients exhibited mixed clinical features of HHS and diabetic ketoacidosis (DKA), including characteristics such as hyperosmolality and ketoacidosis. These features made definitive diagnosis difficult; 5 out of 9 patients were initially diagnosed with DKA and were treated accordingly. Patients who were initially diagnosed with HHS received a more vigorous and appropriate fluid replacement than other patients did. No patients died, although 3 exhibited complications, such as arrhythmia, acute kidney injury requiring renal replacement therapy, rhabdomyolysis, and acute pancreatitis. Hyperosmolality with consequent severe dehydration is considered a significant factor contributing to the outcomes of patients with HHS. Therefore, early recognition of hyperosmolality is crucial for an appropriate diagnosis and adequate fluid rehydration to restore perfusion in the early period of treatment to improve patient outcomes for this rare but serious emerging condition in pediatric patients.

A Rare Presentation of New-Onset Type 1 Diabetes Mellitus in a Developmentally Delayed Child With an Overlap of Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State.

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are serious complications associated with diabetes mellitus (DM). HHS is a common diagnosis in adults but rare in children. DKA is a usual presentation for new-onset type 1 DM, although HHS is rarely a manifestation of new-onset type 1 DM. Diagnosis and management of HHS are challenging in pediatric patients, especially if they present with a mixed picture of HHS and DKA. We report an adolescent female with a new onset of type 1 DM presented as mixed DKA and HHS. Treatment included meticulous management of fluids and continuous insulin drip with the resolution of acidosis within 24 hours and hyperosmolar state at 96 hours of admission. Early differentiation of these two entities and meticulous fluid management improves the outcome and decreases the risk of complications such as cerebral edema, renal failure, and thrombosis, among others.

Predicting readmission due to severe hyperglycemia after a hyperglycemic crisis episode.

AIM: This study aimed to investigate the readmission pattern and risk factors for patients who experienced a hyperglycemic crisis. METHODS: Patients admitted to MacKay Memorial Hospital for diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar state (HHS) between January 2016 and April 2019 were studied. The timing of the first readmission for hyperglycemia and other causes was recorded. Kaplan-Meier analysis was used to compare patients with hyperglycemia and all-cause readmissions. Cox regression was used to identify independent predictors for hyperglycemia and all-cause readmission post-discharge. RESULTS: The study cohort included 410 patients, and 15.3 % and 46.3 % of them had hyperglycemia and all-cause readmissions, respectively. The DKA and HHS group showed a similar incidence for hyperglycemia, with the latter group showing a higher incidence of all-cause readmissions. The significant predictors of hyperglycemia readmissions included young age, smoking, hypoglycemia, higher effective osmolality, and hyperthyroidism in the DKA group and higher glycated hemoglobin level in the HHS group. CONCLUSIONS: Patients who experienced DKA and HHS had similar hyperglycemia readmission rates; however, predictors in the DKA group were not applicable to the HHS group. Designing different strategies for different types of hyperglycemic crisis is necessary for preventing readmission.

A Novel Case of Hyperglycemic Hyperosmolar State After the Use of Teprotumumab in a Patient With Thyroid Eye Disease.

Background/Objective: Teprotumumab, a novel treatment for thyroid eye disease (TED), which blocks the insulin-like growth factor 1 receptor, has been associated with improvement in proptosis and inflammatory ocular symptoms. In the original trials, hyperglycemia was reported in 5% to 12% of patients; however, none required hospitalization. We report a case of hyperglycemic hyperosmolar state after the first infusion of teprotumumab. Case Report: A 56-year-old woman with Graves' disease, severe thyroid eye disease, and prediabetes presented with polyuria, polydipsia, nausea, abdominal pain, headache, dizziness, and a fall to the emergency department 3 weeks after her first teprotumumab infusion. She was noted to have serum glucose levels of 939 mg/dL, serum bicarbonate levels of 28 meq/dL, serum osmolality of 324 mOsm/kg, and trace ketones in urine. She was treated with intravenous fluids and insulin with subsequent improvement in clinical status and biochemical profile. She was then discharged on multiple daily injections of insulin. Discussion: Hyperglycemia is a known adverse effect of insulin-like growth factor 1 receptor inhibitors like teprotumumab. The incidence of hyperglycemia in the original trials was 5% to 12%. Most cases were mild and resolved with titration of current diabetes medications. No cases of hospitalization due to severe hyperglycemia or hyperglycemic hyperosmolar state have been reported until now. Conclusion: We intend to highlight the severity of hyperglycemia that could occur with the use of teprotumumab and the need for research to evaluate the true incidence of this condition.

Emphysematous Pyelonephritis Complicated With Hyperglycemic Hyperosmolar State and Sepsis: A Case Report and Literature Review.

Emphysematous pyelonephritis (EPN) is an acute life-threatening necrotizing infection of the renal parenchyma and perirenal tissues. There are multiple treatment strategies for EPN depending on the initial classification; over the last three decades, the treatment approach has favored kidney sparing strategies and the use of nephrectomy only as salvage therapy. We report a case involving a patient with unilateral emphysematous pyelonephritis complicated with hyperglycemic hyperosmolar state (HHS), sepsis, and multiple risk factors associated with poor prognosis who was successfully treated with conservative management sparing nephrectomy. This case report aims to create awareness among clinicians that even in the presence of multiple risk factors for poor prognosis, conservative management should be considered before nephrectomy.

Severe hypernatremia in soft drink ketoacidosis and hyperglycemic hyperosmolar state at the onset of type 2 diabetes mellitus: a case series of three adolescents.

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are diabetic emergencies. Some patients with a hyperglycemic crisis can present with an overlap of DKA and HHS. The coexistence of DKA and HHS is associated with higher mortality than in isolated DKA and HHS. In addition, electrolyte derangements caused by global electrolyte imbalance are associated with potentially life-threatening complications. Here, we describe three cases of mixed DKA and HHS with severe hypernatremia at the onset of type 2 diabetes mellitus. All patients had extreme hyperglycemia and hyperosmolarity with acidosis at the onset of diabetes mellitus. They consumed 2 to 3 L/d of high-carbohydrate drinks prior to admission to relieve thirst. They showed severe hypernatremia with renal impairment. Two patients recovered completely without any complications, while one died. Severe hypernatremia with mixed DKA and HHS is rare. However, it may be associated with excess carbohydrate beverage consumption. Reduced physical activity during the COVID19 pandemic and unhealthy eating behaviors worsened the initial presentation of diabetes mellitus. We highlight the impact of lifestyle factors on mixed DKA and HHS.

Acute stroke-like deficits associated with nonketotic hyperglycemic hyperosmolar state: an illustrative case and systematic review of literature.

INTRODUCTION: Nonketotic hyperglycemic hyperosmolar state (NKHHS) is associated with a wide spectrum of neurological syndromes including acute stroke-like deficits. Clinical features and etiology have not been established yet. METHODS: Here we provide a case illustration and systematic review on non-epileptic acute neurological deficits in NKHSS. The systematic literature search followed PRISMA guidelines and a predefined protocol, including cases of NKHSS with acute stroke-like presentation. RESULTS: The database search yielded 18 cases. Hemianopia was the most common clinical presentation (73%), followed by partial or total anterior circulation syndrome (26%). Patients with symptoms of acute anterior circulation infarct were significantly older (69.5 ± 5.1 vs. 52.2 ± 13.9 years; p = 0.03) and showed higher mean glucose levels at the admission vs. those with hemianopia (674.8 ± 197.2 vs. 529.4 ± 190.8 mg/dL; p = 0.16). Brain MRI was performed in 89% of patients, resulting abnormal in 71% of them, especially hemianopic (91%). Subcortical hypointensities in T2-FLAIR MR sequences were present in all the analyzed cases. Cortical DWI hyperintensities were also common (64%). EEG showed diffuse or focal slow wave activity in 68% of patients, especially with visual hallucinations (85%). Neurological symptoms completely resolved in 78% of patients within 6 (IQR 3-10) days, following aggressive treatment and glucose normalization. CONCLUSIONS: Our results suggest neuronal dysfunction on a metabolic basis as the leading cause of acute neurological deficits in NKHHS. Despite the generally favorable prognosis, prompt identification and aggressive treatment are crucial to avoid irreversible damage. Larger cohort studies are needed to confirm our findings.

New strategies of diagnostic and therapeutic approach to emergencies in the evolution of patients with diabetes mellitus (Review).

Diabetes mellitus, known as the most widespread disease in the world, along with four other chronic diseases, involves major expenditures and significant human resources for care, thus representing a burden on any type of health care system especially due to its rapid evolution of acute and chronic complications. For the emergency department (ED), the requirements of patients with acute complications of diabetes, determine expenses which are three times higher than those for non-diabetic patients and their hospitalizations are four times more frequent. The acute complications for which patients with diabetes most frequently require the ED are hypoglycemic, hyperosmolar, or ketoacidosis coma as well as alterations of the general condition that is typical of hypoglycemia, diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state and new-onset hyperglycemia. Hypoglycemia and the Somogyi phenomenon are the most common complications of type 1 diabetes but they can also occur in patients with type 2 diabetes who are treated with insulin through its overdose. DKA can occur in type 1 and 2 diabetes either by administering inadequate doses of insulin or due to the existence of precipitating factors such as stress, acute myocardial infarction, infections, sepsis, and/or gastrointestinal bleeding. Hyperosmolar hyperglycemic status is the most common complication in patients with type 2 diabetes and DKA. Treating the acute complications of diabetes in the ED involves, besides taking immediate measures to assess and maintain vital functions, monitoring patients, assessing blood sugar, electrolytes, urea, creatinine, and bicarbonate, and applying appropriate immediate therapeutic measures for each type of acute diabetes complication.

Analysis of demographic and clinical characteristics of 1668 patients with different types of hyperglycemic crisis / 中华内分泌外科杂志

Objective:To analyze and compare the demographic and clinical characteristics of patients with different types of hyperglycemic crisis, so as to provide clinical basis for the prevention and treatment of hyperglycemic crisis.Methods:The data of patients with hyperglycemic crisis in six First-level general hospitals in Chongqing from Jan. 2015 to Dec. 2020 were retrospectively collected and divided into diabetic ketoacidosis (DKA) , hyperglycemic hyperosmolar state (HHS) and diabetic ketoacidosis with hyperglycemic hyperosmotic state (DKA-HHS) . The demographic and clinical characteristics of each group were analyzed by descriptive method.Results:A total of 1668 patients were collected, among whom1388 were DKA, 113 were HHS and 167 were DKA-HHS. The proportion of T2DM in DKA was 90.1%, the proportion of urban residents’ medical insurance, farmers and retirees was higher in the three groups, and the incidence of hyperglycemic crisis in patients above 60 years old was the highest in all age groups. The incidence of DKA and HHS changed little during the six years, but increased significantly in the DKA-HHS group. Shock, disturbance of consciousness, hospitalization expenses and mortality in the DKA-HHS group were higher than those in the other two groups.Conclusions:There are differences in demographic and clinical characteristics among different types of hyperglycemic crisis. Clinically, more attention should be paid to patients above 60 years old and patients with hyperglycemic crisis such as DKA-HHS. Health education and guidance for diabetic patients in high-risk groups should be strengthened in order to reduce the occurrence of diabetic hyperglycemic crisis.

Diagnosis and Management of the Critically Ill Adult Patient with Hyperglycemic Hyperosmolar State.

BACKGROUND: Hyperglycemic hyperosmolar state is a life-threatening complication of diabetes mellitus. Therefore, it is important for emergency physicians to be aware of this unique diagnosis and treatment considerations. OBJECTIVE: This manuscript reviews the emergency department evaluation and management of the adult patient with hyperglycemic hyperosmolar state. DISCUSSION: Hyperglycemic hyperosmolar state is diagnosed by an elevated glucose, elevated serum osmolality, minimal or absent ketones, and a neurologic abnormality, most commonly altered mental status. Treatment involves fluid resuscitation and correction of electrolyte abnormalities. It is important to monitor these patients closely to avoid overcorrection of osmolality, sodium, and other electrolytes. These patients are critically ill and generally require admission to an intensive care unit. CONCLUSIONS: Hyperglycemic hyperosmolar state is associated with significant morbidity and mortality. It is important for clinicians to be aware of the current evidence regarding the diagnosis, management, and disposition of these patients.

An extremely high blood glucose level in a child with hyperglycemic hyperosmolar state and type 1 diabetes.

OBJECTIVES: Hyperglycemic hyperosmolar state (HHS) is one of the most severe acute complications of diabetes mellitus (DM) characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis. What is new? Since HHS in the pediatric population is rare and potentially life-threatening, every reported case is very valuable for raising awareness among healthcare professionals. CASE PRESENTATION: A 7-year-old boy with previously diagnosed Joubert syndrome was admitted due to vomiting, polydipsia and polyuria started several days earlier. He was severely dehydrated, and the initial blood glucose level was 115 mmol/L. Based on clinical manifestations and laboratory results, he was diagnosed with T1DM and HHS. The treatment with intravenous fluid was started and insulin administration began later. He was discharged after 10 days without any complications related to HHS. CONCLUSIONS: Since HHS has a high mortality rate, early recognition, and proper management are necessary for a better outcome.

A Complicated Case of COVID-19 and Hyperglycemic Hyperosmolar Syndrome in an Adolescent Male.

Emerging data demonstrate that comorbid conditions and older age are contributing factors to COVID-19 severity in children. Studies involving youth with COVID-19 and diabetes are lacking. We report the case of a critically ill adolescent male with obesity, type 2 diabetes, and COVID-19 who presented with hyperglycemic hyperosmolar syndrome (HHS). This case highlights a challenge for clinicians in distinguishing severe complications of COVID-19 from those seen in HHS. Youth with obesity and type 2 diabetes may represent a high-risk group for severe COVID-19 disease, an entity that to date has been well-recognized in adults but remains rare in children and adolescents.

Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor.

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insulin treatment to control his blood glucose, but his HHS recurred. We discontinued the ceritinib for other side effects and noticed the HHS disappeared. Our findings suggest that ceritinib can cause HHS and that HHS may recur even after dose reductions.