Previously, it was reported that multiple patients had hemolytic anemia associated with cimetidine administration, while only one patient who had received intravenous cimetidine was serologically diagnosed with drug-induced immune hemolytic anemia (DIIHA) caused by cimetidine-dependent antibodies. However, the ability of oral cimetidine intake to induce the production of antibodies has not been examined. In this study, we report a 44-year-old male patient in whom oral cimetidine administration resulted in cimetidine-dependent antibodies and drug-independent non-specific antibodies, leading to the development of DIIHA. Serological tests showed that the results of direct antiglobulin test (DAT) for anti-IgG (3+) and anti-C3d (1+) were positive. The IgM and IgG cimetidine-dependent antibodies (the highest total titer reached 4,096) were detected in the plasma incubated with O-type RBCs and 1 mg/mL cimetidine or the plasma incubated with cimetidine-coated RBCs. IgG-type drug-independent non-specific antibodies were detected in blood samples collected at days 13, 34, 41, and 82 post-drug intake. This is the first study to report that oral administration of cimetidine can elicit the production of cimetidine-dependent antibodies, leading to DIIHA, and the production of drug-independent non-specific antibodies, resulting in hemolytic anemia independent of cimetidine. Presence of pathogenic antibodies were detectable longer than 41 days. This suggests that patients with DIIHA caused by cimetidine need to be given necessary medical monitoring within 41 days after cimetidine intake.

There has previously been a report of a patient developing haemolytic anaemia following exposure to cefoperazone. Another case has been reported involving the detection of cefoperazone-dependent antibodies in the absence of immune haemolytic anaemia. To date, no serological evidence has been reported to suggest that cefoperazone can lead to drug-induced immune haemolytic anaemia (DIIHA). This report aims to fill these gaps in knowledge by describing a case of DIIHA caused by cefoperazone-dependent antibodies. A 59-year-old man developed fatal haemolytic anaemia while receiving cefoperazone-tazobactam or cefoperazone-sulbactam for the treatment of a lung infection that occurred after craniocerebral surgery. This eventually led to renal function impairment. Prior to the discontinuation of cefoperazone treatment, the patient showed strong positive (4+) results for both anti-IgG and anti-C3d direct antiglobulin test (DAT), while cefoperazone-dependent IgM and IgG antibodies were detected. The patient's plasma and O-type RBCs were incubated with tazobactam or sulbactam solution at 37°C for 3 h, the results of DAT for anti-IgG and anti-C3d were both positive. Forty-three days after the discontinuation of cefoperazone, the results of DAT for anti-IgG and anti-C3d were negative. Meanwhile incubation of the patient's fresh serum and his own RBCs with cefoperazone at 37°C, gave rise to mild haemolysis, and the results of DAT for both anti-IgG and anti-C3d were positive. It is suggested that cefoperazone-dependent antibodies can activate complement, and the non-immunologic protein adsorption effect of tazobactam or sulbactam can enhance IgG and complement binding to RBCs. This may promote the formation of immunocomplexes and complement activation, thereby aggravating haemolysis.

Background Piperacillin is one of the most common drugs that cause drug-induced immune hemolytic anemia, but a complete description of the serological features and course of the disease is rare. This study completely describes the serological characteristics and course of a patient with hypertensive nephropathy who developed drug-induced immune hemolytic anemia and worsened renal function during repeated administration of piperacillin-tazobactam. Case presentation A 79-year-old male patient with hypertensive nephropathy who developed severe hemolytic anemia and worsened renal function during intravenous piperacillin-tazobactam anti-infective treatment due to lung infection. Serological tests showed that the result of the direct antiglobulin test for anti-IgG was positive (4 +) and anti-C3d was negative, and the irregular red blood cell antibody screening test was negative. Plasma samples collected at different times from 2 days before to 12 days after the discontinuation of piperacillin-tazobactam administration were incubated with piperacillin solution and red blood cells of O-type healthy blood donors at 37 °C, IgG piperacillin-dependent antibodies were detected, and the highest titer was 128. However, no tazobactam-dependent antibody was detected in any plasma samples. Therefore, the patient was diagnosed with piperacillin-induced immune hemolytic anemia. Although blood transfusion and continuous renal replacement therapy were given, the patient died of multiple organ failure 15 days after the administration of piperacillin-tazobactam was stopped. Conclusion This is the first complete description of the disease course and serological changes of piperacillin-induced immune hemolytic anemia, which is bound to help deepen the understanding of drug-induced immune hemolytic anemia and draw profound lessons from it.

BackgroundABO blood type incompatibility hemolytic disease of newborn (ABO-HDN) and drug-induced immune hemolytic anemia (DIIHA) due to non-immunologic protein adsorption (NIPA) mainly cause extravascular hemolysis. All the reported severe DIIHA were caused by drug-induced antibodies, and rare report of acute intravascular hemolysis was caused by the NIPA mechanism or ABO-HDN.Case presentationWe report the first case of acute intravascular hemolysis induced by cefotaxime sodium - sulbactam sodium (CTX - SBT) in a case of ABO-HDN which resulted in death at 55 h after birth. The mother’s blood type was O and RhD-positive, and the newborn’s blood type was B and RhD-positive. No irregular red blood cell (RBC) antibodies or drug-dependent antibodies related to CTX or SBT was detected in the mother’s plasma and the plasma or the RBC acid eluent of the newborn. Before the newborn received CTX - SBT treatment, the result of direct antiglobulin test (DAT) was negative while anti-B was positive (2 +) in both plasma and acid eluent. After the newborn received CTX - SBT treatment, the results of DAT for anti-IgG and anti-C3d were both positive, while anti-B was not detected in plasma, but stronger anti-B (3 +) was detected in acid eluent. In vitro experiments confirmed that NIPA of SBT promoted the specific binding of maternal-derived IgG anti-B to B antigen on RBCs of the newborn, thereby inducing acute intravascular hemolysis.ConclusionThe NIPA effect of SBT promoted the specific binding of mother-derived IgG anti-B in newborn’s plasma to the newborn’s RBC B antigens and formed an immune complex, and then activated complement, which led to acute intravascular hemolysis. Drugs such as SBT with NIPA effect should not be used for newborns with HDN.

Background: Severe drug-induced immune hemolytic anaemia (DIIHA) cases leading to death are very rare. Among the reported cases of DIIHA, the serological characteristics and course of the disease are rarely described completely. Piperacillin is a semi-synthetic penicillin against pseudomonas widely used in the treatment of bacterial infections. It is one of the most common drugs that cause DIIHA. Methods: In this study, a 79-year-old male patient with hypertensive nephropathy who developed severe hemolytic anemia during intravenous piperacillin-tazobactam anti-infective treatment due to lung infection, and worsened renal function. Serological tests included direct antiglobulin test (DAT), acid elution test, irregular red blood cell (RBC) antibody detection, and the drug-dependent antibodies associated with piperacillin or tazobactam were detected by the standard methods for the detection of drug-dependent antibodies both in the presence of soluble drug and with drug-coated RBCs. Fully described the patient's course of disease and the serological changes after stopping the administration of piperacillin-tazobactam.Results: Serological tests showed that the results of DAT for anti-IgG was positive (4+) and anti-C3d was negative. The IgG piperacillin-dependent antibodies (the highest titer reached 128) were detected in the plasma incubated with O-type RBCs and 3 mg/mL piperacillin. But the plasma or the acid eluent incubated with piperacillin-coated RBCs, or the acid eluent incubated with O-type RBCs and 3 mg/mL piperacillin did not detect antibodies. The patient was diagnosed as piperacillin-induced DIIHA. Although blood transfusion and continuous renal replacement therapy were given, the patient still died of multiple organ failure 15 days after the administration of piperacillin-tazobactam was stopped.Conclusions: DIIHA caused by piperacillin exacerbated renal damage and was an important cause of the patient's eventual death from multiple organ failure. Which has helped to deepen the understanding of DIIHA and draw lessons from it.