Piperacillin-induced mild haemolytic anaemia in a 44-year-old patient with cystic fibrosis

Abstract

Piperacillin–tazobactam is an antipseudomonal antibiotic frequently used in patients with cystic fibrosis (CF) to treat pulmonary exacerbations. Drug-induced immune haemolytic anaemia is a rare complication during treatment with piperacillin. So far, piperacillin-induced immune haemolytic anaemia (PIHA) is regarded as an acute and severe haemolytic anaemia resulting into life-threatening events. Here we report on a patient with mild PIHA, which did not result in any clinical symptoms or necessity for treatment. To the best of our knowledge, this is the first case report of PIHA without an acute severe haemolytic anaemia. Further research is needed to clarify if this case is a solitary clinical manifestation of PIHA or if mild clinical courses of PIHA might be under-reported. Cases of PIHA have been largely reported in patients with CF. This unequal distribution maybe due to the frequent administration of piperacillin for pulmonary exacerbation in patients with CF or due to CF-related cofactors of yet unknown aetiology.

Background

Piperacillin–tazobactam is an antipseudomonal antibiotic, frequently used in patients with cystic fibrosis (CF) to treat pulmonary exacerbations. Drug-induced immune haemolytic anaemia (DIHA) is a complication during treatment with piperacillin. In general, drug-induced haemolytic anaemia is a rare cause for anaemia.¹ About 130 drugs have been identified until now, the most common being piperacillin, cefotetan and ceftriaxone.²

Piperacillin was first reported to cause drug-induced haemolytic anaemia in 1986.³ Most of the subsequent cases have been associated with drugs containing piperacillin and a β lactamase inhibitor, mostly tazobactam.^4–12

So far, piperacillin-induced immune haemolytic anaemia (PIHA) has been described as an acute and severe haemolytic anaemia resulting into life-threatening events.⁷ Interestingly, the majority of the patients reported with PIHA in previous studies suffered from CF.^{7 9}

This unequal distribution could be because patients with CF are recurrently exposed to piperacillin. However, piperacillin also is a commonly used drug for the treatment of pulmonary and urinary tract infections in different patient groups where immune haemolytic anaemia has not been reported as frequently.⁷ In general, in patients with CF the prevalence of adverse reactions to antibiotics is high.¹³ This hypersensitivity is of yet unclear aetiology and of variably reported prevalence,¹⁴ possibly due to unequal study cohorts. Whether patients with CF have a specific vulnerability for PIHA remains unclear.

Case presentation

A 44-year-old female patient with CF was hospitalised with increased sputum production, fatigue, fever and loss of body weight; symptoms characteristic of pulmonary exacerbation. The physical examination revealed crepitation on the right lung with mild rhonchus. Blood analysis showed increased inflammatory markers (C reactive protein (CrP) of 147.5 mg/L and leucocytes of 13.79/nL with neutrophils of 68.5%). Haemoglobin (12.3 mg/dL), serum electrolytes and renal parameters were normal.

The patient had no immunohaematological diagnosis and no history of red blood cell, platelet or plasma transfusion.

Owing to chronic colonisation with Stenotrophomonas maltophilia, she was treated intravenously with piperacillin and tazobactam and tobramycin for this pulmonary exacerbation.

Owing to recurrent pulmonary exacerbation, the patient had previously received multiple courses of intravenous antibiotic treatment, including at least 15–20 courses of treatment with piperacillin and tazobactam, without documentation of any adverse effects.

During this clinical course, the patient received piperacillin 4 g+tazobactam 0.5 g thrice and tobramycin 340 mg once per day for 14 days intravenously.

Investigations

During the whole period of the treatment, the patient presented with stable cardiovascular signs. Before discharge, a routine laboratory test was performed which revealed a significant decrease in the haemoglobin concentration from 12.3 mg/dL at admission to 8.6 mg/dL on day 14 of admission. Further laboratory tests indicated a haemolytic process. The reticulocyte count was 13.6%, serum lactate dehydrogenase was 276 U/L and haptoglobin was 0.18 g/L. Urine examination was normal.

The direct antiglobulin test (DAT) was found to be strongly positive for IgG (4+) and for C3d (3+) and weakly positive for IgA (2+). An eluate prepared from the patient's red blood cells failed to react in the absence of the drug but showed weakly positive reactions in the presence of piperacillin. The antibody-screening test was negative with an initial sample in the absence of the drug but was positive with a second sample collected shortly after the administration of piperacillin. Drug-dependent antibodies to piperacillin were detected in both samples, but not to tazobactam or tobramycin.

After the discontinuation of medication, the haemoglobin levels recovered spontaneously to 10.4 mg/dL with a reticulocyte count of 10.2% on the third day after discontinuing piperacillin. The serum lactate dehydrogenase and haptoglobin returned to normal levels. At this point, the DAT was still positive with a serological profile that showed anti-IgG (4+), anti-C3d (2+) and anti-IgA (2+), a negative eluate and a negative antibody-screening test in the absence of piperacillin, but with positive reactions after adding the drug.

Outcome and follow-up

Three weeks after the discontinuation of piperacillin haemoglobin (11.3 mg/dL) had almost returned to normal with normal reticulocyte count (1.8%).

After this initial event, treatment with piperacillin was strictly avoided. In the follow-up after 12 months, there was no evidence for anaemia or haemolysis in the monitored blood count.

Discussion

DIHA is a rare complication with an estimated incidence of about one to four cases per million individuals per year.⁹ Cephalosporins and penicillins are the antibiotics most frequently associated with DIHA.^{9 15} Reports of DIHA attributed to piperacillin are increasing, especially in patients with CF.^{4–12 16} Whether this unequal distribution is due to the frequent usage of piperacillin for pulmonary exacerbation in patients with CF or due to CF-related promoting cofactors, such as hyperinflammation, still need to be clarified.^{7 13 14 16}

Piperacillin is assumed to cause hapten-induced intravascular haemolysis via complement activation, leading to potentially life-threatening events. To the best of our knowledge, 38 cases of piperacillin-induced anaemia have been published so far.^{4–12 16} Piperacillin-induced haemolysis has been reported to result in acute profound anaemia with haemoglobin levels as low as 1.6 g/dL, hypovolemic shock, renal failure and fatal outcome.⁷

In contrast to these cases, we report on a patient with a mild decrease in the haemoglobin level that did not result in any clinical symptoms or require any medical treatment. After the discontinuation of the treatment with piperacillin, the haemoglobin concentration spontaneously returned to normal level. To the best of our knowledge, this is the only reported case of PIHA without any acute severe clinical course. Further investigation is needed to clarify if this case is a solitary clinical manifestation of PIHA or if mild courses of PIHA might be under-reported, especially in patients with CF.

Generally, due to the low incidence, clinical and serological data on PIHA are still scarce. In addition, the clinical presentation and serological findings in PIHA are variable, which may lead to difficulties in diagnosis and possible misdiagnosis of for example, autoimmune haemolytic anaemia.^{9 15}

In conclusion, awareness of this rare but severe adverse drug reaction is essential for prompt and adequate management. Monitoring of the blood count should be conducted whenever piperacillin is administered. Special consideration has to be given to patients with CF, since they seem to be at a higher risk for PIHA due to frequent and prolonged treatment with piperacillin and/or other still unknown factors.

Currently, the treatment options of patients with mild PIHA remain unclear. Further research is needed to clarify if mild PIHA should result into a lifelong abstinence from piperacillin.

Learning points.

• Drug-induced immune haemolytic anaemia is considered a rare and generally severe complication during treatment with piperacillin.

• To the best of our knowledge, this is the first report on a patient with mild piperacillin-induced immune haemolytic anaemia (PIHA), which did not result in any clinical symptoms or require any medical treatment.

• Further investigation is needed to clarify if this case report is a unique clinical manifestation of PIHA or if mild clinical courses of PIHA might be under-reported.

• Special consideration has to be given to patients with CF, since they seem to be at higher risk for PIHA due to frequent and prolonged treatment with piperacillin and/or other still unknown factors.