Immune checkpoint inhibitors have progressed rapidly over the past decade and have become one of the most promising oncology treatments. However, immune checkpoint inhibitors reduce T-cell tolerance and lead to a unique spectrum of immune-related adverse events (IRAE). IRAE can involve multiple systems, including endocrine, gastrointestinal, respiratory and skin systems and there is no predictive marker with high specificity and sensitivity. Mild IRAE can be alleviated by discontinuing immune checkpoint inhibitors while severe IRAEs require active intervention. The first-line treatment is glucocorticoids, and immunosuppressants can be considered in refractory cases. However the optimal choice of immunosuppressants is currently controversial. This review provides an overview of the epidemiology and possible mechanisms of immune-related adverse events, outlines some promising predictive biomarkers, and describes several immunotherapy-related organ toxicity and management.
Humans ; Immunologic Factors/adverse effects* ; Immunosuppressive Agents ; Immunotherapy/adverse effects*

Anti-Bacterial Agents ; adverse effects ; Humans ; Immunoglobulins, Intravenous ; therapeutic use ; Immunologic Factors ; therapeutic use ; Levofloxacin ; Ofloxacin ; adverse effects ; Stevens-Johnson Syndrome ; drug therapy ; etiology

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.
CTLA-4 Antigen ; Diabetes Mellitus, Type 1/chemically induced* ; Humans ; Immune Checkpoint Inhibitors ; Immunologic Factors/therapeutic use* ; Immunotherapy/adverse effects* ; Neoplasms/drug therapy*

BACKGROUND/AIMS: The clinical course of patients with inflammatory bowel disease (IBD) frequently leads to the use of immunosuppressants and immunomodulators. We investigated the risk of postoperative infection in patients with IBD undergoing elective bowel surgery and whether the use of corticosteroid (CS) and/or 6-mercaptopurine/ azathioprine (6-MP/AZA) before surgery was associated with the increased risk of postoperative infection. METHODS: Patients who were diagnosed as Crohn's disease (n=25) or ulcerative colitis (n=19) and underwent elective bowel surgery between 1986 and 2005 were identified. Medical records were retrospectively analyzed including age, sex, duration of disease, indication for surgery, duration of surgery, type of surgery, type of postoperative infection, admission period, usage of CS and 6-MP/AZA, and preoperative laboratory values. There were 27 patients receiving CS alone, 6 patients receiving 6-MP/AZA alone or with CS, and 16 patients receiving neither CS nor 6-MP/AZA. RESULTS: There were 17 postoperative infections (38.6%) among IBD patients who had undergone surgery and wound infection was the most common type of infection (76.5%). In IBD patients, patients receiving CS had higher postoperative infection rate than those patients receiving neither CS nor 6-MP/AZA (p=0.039). Patients receiving CS in conjunction with 6-MP/AZA did not have significantly higher postoperative infection rate than those with CS only (p=0.415). CONCLUSIONS: Preoperative use of CS in patients with IBD is associated with the increased risk of postoperative infections. Addition of 6-MP/AZA in patients receiving CS does not increase the risk of postoperative infections.
Colitis, Ulcerative/drug therapy/*surgery ; Crohn Disease/drug therapy/*surgery ; Humans ; Immunologic Factors/*adverse effects/therapeutic use ; Immunosuppressive Agents/*adverse effects/therapeutic use ; Infection/epidemiology/*etiology ; Postoperative Complications/epidemiology/*etiology ; Retrospective Studies

PURPOSE: To investigate the clinical effects of a single high dose intravenous immunoglobulin (IVIG) combined with initial dexamethasone as a primary treatment on Kawasaki disease (KD). MATERIALS AND METHODS: Between January 2008 and December 2010, we reviewed the medical records of 216 patients with complete KD patients that were admitted to a single medical center. 106 patients were treated with a single high dose of IVIG (2 g/kg) alone and 110 patients received IVIG and dexamethasone (0.3 mg/kg per day for three days). RESULTS: The combined IVIG plus dexamethasone patient group had a significantly shorter febrile period and duration of hospital stay (1.4+/-0.7 days vs. 2.0+/-1.2 days, p<0.001; 5.8+/-1.7 days vs. 6.9+/-2.5 days, p<0.001, respectively) than the IVIG alone group. The combined IVIG plus dexamethasone group required IVIG retreatment significantly less than the IVIG only group (12.7% vs. 32%, p=0.003). After completion of the initial IVIG, C-reactive protein levels in the combined IVIG plus dexamethasone group were significantly lower than those in the IVIG only group (2.7+/-4.0 mg/dL vs. 4.6+/-8.7 mg/dL, p=0.03). In the combined IVIG plus dexamethasone group, the incidence of coronary artery lesions tended to be lower without worse outcomes at admission after initial infusion of IVIG and in follow-up at two months; however, the differences were not significant (8.2% vs. 11.3%, p=0.22; 0.9% vs. 2.8%, p=0.29). CONCLUSION: Initial combined therapy with dexamethasone and a single high-dose of IVIG resulted in an improved clinical course, in particular a shorter febrile period, less IVIG retreatment, and shorter hospital stay without worse coronary outcomes.
Child, Preschool ; Dexamethasone/administration & dosage/adverse effects/*therapeutic use ; Female ; Fever/drug therapy ; Glucocorticoids/administration & dosage/adverse effects/*therapeutic use ; Humans ; Immunoglobulins, Intravenous/administration & dosage/adverse effects/therapeutic use ; Immunologic Factors/administration & dosage/adverse effects/*therapeutic use ; Infant ; Length of Stay ; Male ; Mucocutaneous Lymph Node Syndrome/*drug therapy ; Treatment Outcome

OBJECTIVETo investigate on the expression of some cytokines and other immunity makers right after the operation, the effect of femoral nailing on systemic immunity and sought to differentiate any differences between reamed and unreamed IMN.

METHODSFifty-nine patients presenting with acute femoral fractured including 55 male and 4 female, 32.1 years old on average, are divided into 2 group depend on ISS. All patients were treated by close reduction and intramedullary nail for fixation. In group 1, 23 reamed and 23 unreamed; in group 2, 7 reamed and 6 unreamed. Venous blood samples were taken at 24 hr pre-operationally, and 1 hr, 24 hr, 48 hr post operationally. Serum TNF, IL-6, IL-8, IL-10 were measured by enzyme-linked immunosorbent assay. CRP was measured by protein assay apparatus. We also collected venous samples from 22 healthy uninjured volunteers, which formed control group.

RESULTSAll immune marks were elevated post operation, for IL-6, IL-8, IL-10, this elevation began at 1 hr after operation, reached to the peak at 24 hr, and then down but never to the normal at 48 hr. For TNF and CRP, the level were raised at 24 hr, and then fallen at 48 hr. All mediators were raised significantly above the control group (< 0.05). Between reamed and unreamed patients both in group 1 and group 2, Although there was a trend towards higher levels of TNF, IL-6, IL-8, IL-10 and CRP in RFN than in the URFN, no significant difference was found except that there was a greater release of serum IL-10 in RFN than in URFN at 24 hr post operation (P = 0.047). Two patients have become SIRS, but the markers have shown no significant difference with those that have no SIRS symptoms.

CONCLUSIONSTo the patient not injured severely, using IMN for treatment will make the inflammatory mediators re-released on higher level than normal, which will be balanced by immunity itself soon, so IMN won't make any damage severely. And no significant difference were found between reamed and unreamed nail. But the changing of IL-10 show us that after IMN, especially the reamed nailing, the level of anti-inflammatory mediators will show the difference more apparently between RFN and URFN while the patient got injured more severely. Under this condition, the RFN will aggravate the restrain of immunity.

Adult ; Biomarkers ; blood ; Female ; Femoral Fractures ; immunology ; surgery ; Fracture Fixation, Intramedullary ; adverse effects ; methods ; Fractures, Closed ; immunology ; surgery ; Humans ; Interleukin-10 ; blood ; Interleukin-6 ; blood ; Interleukin-8 ; blood ; Male ; Middle Aged ; Monitoring, Immunologic ; Postoperative Period ; Tumor Necrosis Factors ; metabolism

OBJECTIVETo determine risk factors of invasive fungal infections (IFI) in patients admitted to non-hematological oncology department and pediatric intensive care unit (PICU), in order to improve diagnostic level of invasive fungal infections.

METHODWe retrospectively assessed 85 hospitalized pediatric patients with invasive fungal infections in Beijing Children's Hospital Affiliated to Capital Medical University from Jan.2007 to Nov.2012. All the cases were either from non-hematological oncology department or the PICU.We reviewed risk factors of invasive fungal infections.

RESULTAmong 85 patients, 42 had invasive candida infection, 20 invasive aspergillus infection, 21 cryptococcus infection, 1 Histoplasma capsulatum infection and 1 Mucor mucedo infection.In the 42 patients with invasive candida infection, 5 were young infants, 3 had combined immunodeficiency, 1 cellular immunodeficiency, 25 secondary infection due to long term use of corticosteroids and/or combined use of more than 2 kinds of antibiotics with primary disease, 5 prior intestinal tract surgery or chronic diarrheal disease, 1 reflux gastritis.In the 20 patients with invasive aspergillosis infection, 10 patients had chronic granulomatous disease, 5 long term use of corticosteroids ≥ 1 month, 3 long term use of corticosteroids and combined use of more than 2 kinds of antibiotics, 2 had no apparent host factors.In the 21 patients with cryptococcus infection, 2 patients had used corticosteroids ≥ 1 month, 2 had immunodeficiency mainly for lack of antibodies, while others had no apparent host factors. The child with Mucor mucedo infection had diabetes mellitus. And the one with Histoplasma capsulatum infection had immunodeficiency.

CONCLUSIONHigh risk factors for IFI in patients admitted to non-hematological oncology department and PICU are primary immunodeficiency disease and long term use of corticosteroids and/or long term combined use of more than 2 kinds of antibiotics. Besides, young infant is also a high risk factor for invasive candida infection. Most of the cryptococcus infections and certain aspergillosis had no obvious host factors.

Adolescent ; Adrenal Cortex Hormones ; administration & dosage ; adverse effects ; Age Factors ; Anti-Bacterial Agents ; administration & dosage ; adverse effects ; Aspergillosis ; diagnosis ; etiology ; microbiology ; Aspergillus ; isolation & purification ; Candida ; isolation & purification ; Child ; Child, Preschool ; Cross Infection ; epidemiology ; microbiology ; Female ; Humans ; Immunologic Deficiency Syndromes ; complications ; Infant ; Infant, Newborn ; Male ; Multivariate Analysis ; Mycoses ; diagnosis ; etiology ; microbiology ; Retrospective Studies ; Risk Factors

OBJECTIVEThe expression of CD25, CD45RA, CD45RO on umbilical cord blood mononuclear cells (CBMCs) and CD3(+) T lymphocytes was investigated to explore the mechanism of immunosuppressive effects of intravenous immunoglobulin on neonatal immune function.

METHODSUmbilical cord blood mononuclear cells and CD3(+) T lymphocytes isolated from 8 neonates were studied. The expression of CD25, CD45RA, CD45RO on umbilical cord blood mononuclear cells (CBMCs) and CD3(+) T lymphocytes induced with various stimuli of different combinations of IVIG and phytohemagglutinin (PHA) including (1) control group, (2) PHA activation group, (3) IVIG pre-inhibition group, (4) PHA pre-activation group, (5) PHA+IVIG group was measured with four-color immunofluorescence antibodies staining-flow cytometric technique. The results were also compared with peripheral blood mononuclear cells of 8 adults (PBMCs).

RESULTSIVIG inhibited the PHA-induced proliferation of CBMCs as reflected by the decreased expression of CD25 and CD45RO. The amounts of CD25(+) and CD4(+)CD45RO(+) CBMCs reached 77.52% +/- 2.31% and 64.29% +/- 3.09% after PHA use. But a decreased response in CD25(+) (7.66% +/- 1.20% and 7.78% +/- 1.46%) and CD4(+)CD45RO(+) CBMC (3.18% +/- 1.90% and 3.11% +/- 0.08%) was observed when IVIG was added in both IVIG pre-inhibition group and PHA+IVIG group. As compared with PBMCs, IVIG failed to induce the increase of the expression of CD45RA in CBMCs whereas CD45RA(+) PBMCs increased from 54.93% +/- 3.63% to 72.77% +/- 0.39% in IVIG pre-inhibition group. Moreover, IVIG inhibited the expression of CD25 and CD45RO on cord blood CD3(+) T lymphocytes no matter whether they were activated with PHA or not. The amounts of CD25(+) and CD4(+)CD45RO(+) CD3(+) T lymphocytes reached 97.92% +/- 2.19% and 80.41% +/- 5.57% after PHA use. But a decreased response in CD25(+) CBMCs (77.29% +/- 0.63%, 51.48% +/- 1.85% and 62.73% +/- 1.24%) and CD4(+)CD45RO(+) CD3(+) T lymphocytes (35.47% +/- 2.55%, 40.14% +/- 1.16% and 36.41% +/- 2.96%) was observed when IVIG was added in IVIG pre-inhibition group, PHA pre-activation group and PHA+IVIG group, and the degree of inhibition of IVIG on cord blood CD3(+) T lymphocytes was much lower than that of CBMCs.

CONCLUSIONSCord blood T lymphocytes activation was inhibited by IVIG through the inhibition of CD25(+) CBMCs expression and the prevention of transformation from CD4(+)CD45RA(+) cells into CD4(+)CD45RO(+) cells. This IVIG-mediated suppression of activation in cord blood T cells may be derived from the indirect effect of other immune cells or molecules other than the direct effects on T cells. IVIG failed to induce the increase of expression of CD45RA in CBMCs, which may be related to the fact that majority of CBMCs were CD45RA(+) cells, but this may not rule out that the immunosuppressive effect of IVIG could be accomplished by the increase of CD45RA(+) cells in adult peripheral blood mononuclear cells. The suppressive effect of IVIG on CD4(+)CD45RO(+) T lymphocytes may account for its inhibitory effect on immunoglobulin production of neonates' B cells. Considering that naïve CD45RA(+) cells dominate in neonates and IVIG can inhibit transformation from CD4(+)CD45RA(+) cells into CD4(+)CD45RO(+) cells, it is recommended that IVIG should be used properly in neonates, otherwise it may deteriorate their poor immune function especially when it is used for prophylaxis or as a treatment of neonatal non-infectious diseases, and its immunosuppressive action will increase the susceptibility of neonates to infection.

Adult ; CD3 Complex ; biosynthesis ; immunology ; Cell Survival ; drug effects ; Cells, Cultured ; Female ; Fetal Blood ; cytology ; immunology ; Flow Cytometry ; Humans ; Immunoglobulins, Intravenous ; administration & dosage ; adverse effects ; immunology ; Immunologic Factors ; adverse effects ; Immunosuppressive Agents ; administration & dosage ; adverse effects ; immunology ; Infant, Newborn ; Injections, Intravenous ; Interleukin-2 Receptor alpha Subunit ; biosynthesis ; immunology ; Leukocyte Common Antigens ; biosynthesis ; immunology ; Leukocytes, Mononuclear ; cytology ; drug effects ; immunology ; Lymphocytes ; cytology ; drug effects ; immunology ; Male

OBJECTIVETo analyze the safety and efficacy of anti-CD20 monoclonal antibody in treatment of severe pediatric systemic lupus erythematosus (PSLE).

METHODThe diagnosis of PSLE was made according to the criteria for the classification of systemic lupus erythematosus revised by the American College of Rheumatology in 1997. Severe cases with PSLE was selected by the following criteria: age ≤ 16 years, number of important organs involved > 1, SLEDAI score > 10 points and poor response to conventional immunosuppressive treatment. These patients received 2 doses of 375 mg/m(2) rituximab (RTX), 2 weeks apart. Clinical, laboratory findings and drug side effects were recorded at RTX initiation, 2 weeks, 1 month, 3, 6 and 12 months after infusion.

RESULTA total of 20 patients. Male to female ratio was 1:3, were enrolled. They were 5-16 years old. The course of disease was (3.0 ± 2.5) years (range: 1 month-7 years), patients were followed up for 12 - 36 months [median: (27.0 ± 7.8) months]. Delirium and cognitive disorders were significantly improved in 10 cases of lupus encephalopathy after 1 month. Lupus nephritis in children were eased slowly, 14/15 patients with lupus nephritis were improved after 2-3 months. Four cases of lupus pneumonia were significantly improved within 1 month. Decreased blood cells counts were relieved at 1 month in 16/18 cases. Cellular immune function was assessed 2 weeks after application of anti-CD20 monoclonal antibody; we found B-cell clearance in 19 patients (95%). B lymphocyte count of 18 patients (90%) was restored within one year. SLEDAI score was reduced obviously. Dose of corticosteroid ranged from (45.0 ± 4.7) mg/m(2) before drug use to (12.0 ± 2.7) mg/m(2) 12 months later (P < 0.001). After the drug use, 5 patients had pneumonia within 6 months; 2 cases who suffered from aspergillus pneumonia and Pneumocystis carinii pneumonia respectively were severe. They accepted mechanical ventilation and anti-inflammatory support after being transferred to the intensive care unit, and their conditions improved at last. No death occurred. In 2 patients the disease recurred with B-cell recovery after 15 months and 18 months. Administration of another cycle of rituximab resulted in remission again in one case but not in the other.

CONCLUSIONAnti-CD20 monoclonal antibody is effective and safe in treatment of severe PSLE. But severe infections may occur in some cases. Focusing on prevention and early treatment can reduce the probability of adverse reactions.

Adolescent ; Antibodies, Monoclonal, Murine-Derived ; administration & dosage ; adverse effects ; therapeutic use ; B-Lymphocytes ; drug effects ; immunology ; Biomarkers ; blood ; Child ; Child, Preschool ; Cyclophosphamide ; administration & dosage ; Female ; Follow-Up Studies ; Glucocorticoids ; administration & dosage ; therapeutic use ; Humans ; Immunologic Factors ; administration & dosage ; adverse effects ; therapeutic use ; Lupus Erythematosus, Systemic ; complications ; drug therapy ; immunology ; Lupus Nephritis ; etiology ; pathology ; Male ; Pneumonia ; etiology ; pathology ; Prednisolone ; administration & dosage ; therapeutic use ; Rituximab ; Severity of Illness Index ; Treatment Outcome

OBJECTIVETo study the impact and mechanism of Shengmai Injection (SMI) on the immunological function changes after cardiopulmonary bypass.

METHODSForty patients with rheumatic heart valve disease were selected and assigned randomly to two groups: 20 in the control group and 20 in the SMI group. Peripheral blood samples were taken at various time points, i.e. 3 days before operation (T1), 10 min after terminal of CPB (T2), the first (T3), third (T4), and seventh (T5) day after operation, for counting white blood cell (WBC), neutrophils and lymphocytes; percentage of T lymphocytes (CD3+ mononuclear cells) and its subsets (CD4+ and CD8+) to calculate CD4+/CD8+ ratio; and the serum content of immunoglobulins (IgG, IgA, IgM) as well as serum concentration of interleukin-8 (IL-8) and interleukin-10 (IL-10) were assayed.

RESULTSCompared with the control group, in the SMI group, WBC and neutrophil count were lower at T2 (P < 0.01); percentages of CD3+ and CD4+ lower at T4 and T5 (P < 0.05 or P < 0.01); percentage of CD8+ higher at T2 to T5 (P < 0.05 or P < 0.01); CD4+/CD8+ ratio lower at T3 to T5 (P < 0.05 or P < 0.01); IgG lower at T2 (P < 0.05); IgA higher at T3 (P < 0.05); IgM higher at T3 to T5 (P < 0.05); IL-8 lower at T2 to T4 (P < 0.05); and IL-10 higher at T2 (P < 0.05).

CONCLUSIONApplication of SMI in the perioperative period can enhance the humoral immunity and inhibit the cellular immunity after CPB, it could also reduce the systemic inflammatory reaction and improve the prognosis of patients.

Adult ; Cardiopulmonary Bypass ; adverse effects ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Heart Valve Prosthesis Implantation ; Humans ; Immunoglobulins ; blood ; Immunologic Factors ; administration & dosage ; Injections, Intravenous ; Interleukins ; blood ; Male ; Middle Aged ; Perioperative Care ; Phytotherapy ; Rheumatic Heart Disease ; immunology ; surgery ; T-Lymphocyte Subsets ; immunology