HighlightsAbstract

We report the first case of immune complex type hemolytic anemia by initial micafungin administration that was given as prophylaxis to a 42-year-old Japanese man receiving chemotherapy for primary amyloidosis. The few cases found in the literature were associated with secondary administration to cause immune hemolysis attacks. Despite its rarity, the present case calls for increased awareness of micafungin-induced hemolytic anemia upon initial administration.

Keywords

Introduction

Drug-induced hemolytic anemia occurs via immune destruction of red blood cells (RBCs) or destruction due to oxidant injury. Immune-mediated drug-induced hemolysis is mediated by drug-dependent or drug-independent antibodies. The mechanism of drug-dependent reactions can be subdivided into penicillin type, immune complex type, and passive absorption. Immune complex type drug-induced hemolysis is known to be triggered by multiple administrations of the causative drug, in which the complex can bind to the RBCs and cause complement activation (Garratty et al. 2010, Grabe et al. 2011). Micafungin, a kind of echinocandin antifungal agent, has come to occupy an increasingly important position in the treatment and prophylaxis of diverse fungal infections, which can also combat azole-resistant strains (Pappas et al. 2016). Its specific fungicidal activity relies on the inhibition of β-1,3-glucan synthase, resulting in growth inhibition of hyphal tips (Hatano et al. 2002). Other than common adverse events, such as rash, flushing, digestive symptoms, and hepatic dysfunction, micafungin rarely causes acute hemolysis. A few previous case reports showed a resumption of micafungin could trigger acute hemolytic attack via drug-anti-drug immune complex formation (Nanri et al. 2009, Yoshizawa et al. 2010). Here we describe a rarely encountered case of immune complex type hemolytic anemia just after initial micafungin administration.

Case Presentation

A 42-year-old Japanese man with primary amyloidosis, hypertension, and hypothyroidism was admitted with acute abdominal pain to the intensive care unit (ICU) of our hospital. One year before this admission, the patient had received subcutaneous bortezomib and oral dexamethasone as the first course of treatment for primary amyloidosis with involvement of the liver, kidneys, and autonomic nervous system. Since a contrast-enhanced computed tomography (CT) examination for the present abdominal pain revealed hepatic hemorrhage, the patient underwent catheter embolization of the right hepatic artery and inferior phrenic artery on the admission day (day 0). The patient recovered from related hemorrhagic shock with fluid replacement and RBC and plasma transfusions, however, hepatic hemorrhage persisted even after the intervention, forcing him to have absolute bed rest for two more weeks. On day 3 in the ICU, administration of prednisolone (10 mg/day) and itraconazole (200 mg/day) via nasogastric tube was initiated for replacement of oral dexamethasone and prophylaxis of fungal infection respectively. On day 5, the tube was removed and total parenteral nutrition was started mainly due to transfer from the ICU to a general ward. At the same time, the administration of itraconazole was stopped due to worsening of hepatic dysfunction. Hepatic hemorrhage and liver dysfunction showed gradual improvement on day 14; during treatment of hepatic hemorrhage, transfusions of 1,960 mL and 480 mL of allogeneic ABO- RhD-compatible RBC (from day 0 to day 4) and plasma (day 3) were required. Afterwards, with no more requirement of blood transfusion, his hemoglobin (Hb) level was 8.8 g/dL on day 14 (Figure 1A). Due to persisting oral intake difficulty of the patient, a continuous infusion of prednisolone (10 mg/day) and a drip infusion of micafungin (150 mg/day) was initiated as replacement on day 15. Dyspnea, flushing, and back pain developed three minutes after its administration. With the oxygen saturation of 79% on ambient air, supplemental oxygen therapy of 8 L/min from a non-rebreathing mask was started. Micafungin was discontinued immediately as it was suspected of being a causative agent. Ninety minutes later, shivering developed with body temperature elevation up to 40.4°C, and soon afterward dark urine was noted. Dipstick test of the urine was strongly positive for blood and no erythrocytes were detected in the urine sediment. Hb level rapidly decreased to 7.3 g/dL, and lactate dehydrogenase (LDH) level was 1104 U/L (normal range, 124 to 222), indirect bilirubin 2.2 mg/dL (normal range, below 1.2) and haptoglobin Figure 1A). Creatine kinase level was 35 U/L (normal range, 59 to 248), suggesting that rhabdomyolysis was an unlikely cause of dark urine. Additional abdominal CT scan revealed no recurrence of hepatic or splenic hemorrhage. Blood cultures were negative. With oxygen supplementation and drip infusion of 50 mg hydrocortisone, the related symptoms, such as fever, dyspnea, flushing, and back pain, almost disappeared 8 hours after the onset and micafungin cessation. Levels of LDH and indirect bilirubin normalized on day 21 and microscopic hematuria completely resolved on day 28.

Figure. 1(A) Transitive graph of laboratory data during hemolysis in this case. Hb; hemoglobin, LDH; lactic dehydrogenase, MCFG; micafungin

Show full caption

(B) Results of direct anti-globulin test (AGT) and immune complex test for this case. AHG; Anti-Human Globulin, CPFG; caspofungin, C; Complement, PBS; Phosphate Buffered Saline

With suspicion of micafungin-induced hemolysis (Hill et al. 2017, Zantek et al. 2012), a direct anti-globulin test (AGT) was performed. The patient's post-micafungin RBCs showed agglutination not with anti-IgG but with poly-specific anti-globulin and anti-C3b/C3d anti-globulin while pre-micafungin RBCs had no agglutination with these agents. By immune complex test (Garratty et al. 2009), ficin-treated type O RBCs showed agglutination in a mixture of post-micafungin serum and micafungin with or without complement, but no agglutination was noted in a mixture of post-micafungin serum and caspofungin, another echinocandin agent (Figure 1B). These data indicate that antibody which can bind to micafungin was produced after the initial micafungin administration, leading to immune complex type hemolytic anemia in this case, not caused by drug-independent antibodies.

Discussion

This is, to the best of our knowledge, the first report of a case of immune complex type hemolytic anemia following initial micafungin administration, which is a striking contrast to previous reports (Nanri et al. 2009, Yoshizawa et al. 2010). Typically, the development of drug-induced hemolytic anemia of immune complex type requires sensitization and re-administration of the causative drug. This type can cause fatal intravascular hemolysis and show strong positivity in the related immune complex test (Garratty et al. 2012), which requires prompt cessation of the suspected drug. Considering the short interval between the hepatic hemorrhage and the micafungin-induced hemolytic anemia, delayed cessation of the drug might have led to fatal outcome in this case, indicating the importance of careful monitoring of patient at first-time administration and prompt cessation of micafungin. Additionally, it was speculated that continuous corticosteroid treatment for primary amyloidosis might ameliorate the hemolytic attack and weaken the related in vitro agglutination (Figure 1B). This case had no prior history of micafungin administration. Despite structural similarity between micafungin and caspofungin (Mroczyńska et al. 2020), the reactivity of the patient's serum was specific to micafungin, supporting our final diagnosis. However, we could not rule out the possibility that some other previously administered agents with structural similarity to micafungin triggered antibody formation.

In conclusion, despite the rarity, the present case should remind clinicians of micafungin-induced hemolytic anemia even upon initial administration.

Funding source

No funding to declare.

Ethical approval

Informed consent was obtained from the patient for publication of this case report.

Conflict of interest

No potential conflict of interest is reported by the authors.

Author contribution

HI wrote this manuscript. HI, TS, and MI analyzed and interpreted the patient data on hemolysis. TS, HY, TS, TT and SY. revised this manuscript. All authors read and approved the final manuscript.

References

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Article InfoPublication History

Accepted: July 7, 2022

Received in revised form: June 24, 2022

Received: May 14, 2022

Publication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.ijid.2022.07.023

Copyright

© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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