Immune Reconstitution Inflammatory Syndrome Associated with Hepatosplenic Candidiasis in a Patient with Acute Myeloblastic Leukemia: Possible Pathogenesis and Treatment in the Light of Current Knowledge

Case Report

Austin Hematol. 2021; 6(2): 1039.

Immune Reconstitution Inflammatory Syndrome Associated with Hepatosplenic Candidiasis in a Patient with Acute Myeloblastic Leukemia: Possible Pathogenesis and Treatment in the Light of Current Knowledge

Bicakci Z1*, Koca D2 and Bozbeyoglu G3

¹Pediatric Hematology and Oncology, Faculty of Medicine, Istanbul Medeniyet University, Turkey

²Hematology and Oncology Specialist, Pediatric Hematology and Oncology, Faculty of Medicine, Istanbul Medeniyet University, Turkey

³Department of Radiology, Faculty of Medicine, Istanbul Medeniyet University, Turkey

*Corresponding author: Biçakçi Z, Pediatric Hematology and Oncology, Faculty of Medicine, Istanbul Medeniyet University, Turkey

Received: May 26, 2021; Accepted: June 21, 2021; Published: June 28, 2021

Abstract

Acquired immune deficiencies caused by different etiologies, promote invasive fungal infections. When this immunity begins to improve, it can induce an excessive inflammatory response defined as Immune Reconstitution Inflammatory Syndrome (IRIS). Hepatosplenic Candidiasis (HSC) can be considered a form of IRIS syndrome as it occurs following neutrophil recovery in patients treated for acute leukemia. Differentiating IRIS from a single fungal infection or treatment failure due to a similar clinical picture is a real diagnostic problem. Misdiagnosis and subsequently ineffective treatment with antifungal therapy instead of anti-inflammatory drugs, may lead fatal course of the disease.

A deep and prolonged neutropenia developed after the first induction chemotherapy in our two and a half-year-old male patient who was followed up in our clinic with the diagnosis of Acute Myeloblastic Leukemia (AML). Our patient had fever, abdominal pain as well as his Gamma Glutamyl Transferase (GGT) and Alkaline Phosphatase (ALP) levels increased during neutropenia recovery. He was diagnosed with hepatosplenic candidiasis, by observing ‘target like abscesses’ on dynamic Magnetic Resonance Imaging (MRI) taken for his newly developing symptoms and laboratory findings while recovering neutropenia. After his first and third induction chemotherapy courses, his fever persisted although antifungal therapy, steroid treatment was initiated considering IRIS. After his re-intensification course, because of the same flare-up symptoms, we started immunglobulin in addition to steroid. With methylprednisolone and intravenous immunoglobulin, his symptoms improved and significant regression was observed in the lesions ‘target-like abscesses’ on MRI and in the laboratory values.

Result: IRIS should be considered for patients with hepatic candidiasis whose have persistent fever despite appropriate antifungal therapy. Glucocorticoid should be started first for an anti-inflammatory effect.

Keywords: Immune reconstitution inflammatory syndrome; Antiinflammatory cytokines; Hepatosplenic candidiasis; Interferon gamma; Proinflammatory cytokines

Introduction

Candida is a common patogen worlwide. It can contribute high mortality and morbidity to cancer patients by causing invasive candidiasis infection. Hepatosplenic Candidiasis (HSC), also called ‘chronic disseminated candidiasis’, is a part of severe invasive Candida infection occurs with distinct involvement in the liver, spleen, sometimes kidneys, and other organs. The incidence of HSC in patients with acute leukemia ranges from 2.0% to 7.4%. HSC is a unique clinical finding for invasive candidiasis. It occurs following neutrophil recovery after chemotherapy in patients with acute leukemia and effects organs as liver and spleen. The patogenesis of HSC is unknown. Studies suggest that Candida species colonized in the intestines owing to mucosal damage after chemotheraphy and by passing portosplenic circulation, they invade and proliferate to the hepatosplenic sinusoids [1].

Acquired immune deficiencies caused by different etiologies, including Human Immunodeficiency Viruse (HIV), antineoplastic drugs, immunosuppressive therapy used in solid organ recipients, immunomodulator drugs and other biologic agents, all encourage invasive fungal infections. Subsequent immune recovery induces excessive inflammatory response called Immune Reconstitution Inflammatory Syndrome (IRIS) that conduce significant morbidity and mortality in patients. Hepatosplenic Candidiasis (HSC) can be considered a form of IRIS syndrome as it occurs following neutrophil recovery in patients treated for acute leukemia. Differentiating IRIS from a single fungal infection or treatment failure due to a similar clinical picture is a real dilemma. Diagnostic faults following ineffective treatment with antifungal therapy instead of anti inflammatory drugs, may lead fatal course of the disease [2].

We aimed to present our case who developed HCS and IRIS after recovery from prolonged neutropenia and how we treated, due to its rarity.

Our aim is to present a case with HSC/IRIS who remained neutropenic for a long time after acute myeloblastic leukemia induction treatment and developed an excessive inflammatory response during neutrophil recovery.

Case Presentation

Our case is two and a half years old male patient. He was applied to another hospital for his fever, pain, swelling and redness behind the right ear. A postauricular mass was detected on Magnetic Resonance Imaging (MRI) and excisional biopsy performed. The biopsy result reported as ‘ALL or AML is considered first’. Although his family taken the report, they hadn’t been, apply any doctor for a while. Seven months after biopsy, he was admitted to our hospital with complaints of cough, fever, generalized pain and abdominal swelling.

On physical examination, he had pallor, jaundice, left orbital propitosis, massive hepatosplenomegaly, and right postauricular lymphadenopathy. Laboratory tests was performed. The patient’s leukocytes 9200/uL, neutrophiles 1120/uL, Hb 5.9g/dl, HCT 18%, MCV 82.1fl, thrombocytes 38.000/uL, CRP 4.17mg/dL, LDH 369U/L, Uric Acid 2.7mg/dL, GGT 350U/L, ALP 311U/L, ALT 79U/L, AST 38U/L, Urea 13mg/dL, Creatinine 0.47mg/dL, Na 132mEq/L, K 3.7mEq/L, Albumin 3.32g/L, Ca 7.7mg/dL, Total bilirubin 4.36mg/ dL, direct bilirubin 3.57mg/dL, Amylase 240U/L, Lipase 668U/L.

He had pansitopenia, and there were blasts on his peripheral blood smear. We performed bone marrow aspirate. Blasts were observed on his bone marrow aspiration smears. Also flow cytometry detected blasts at a range of 67% and blasts were positive for CD13, CD33, HLA-DR, and Myeloperoxidase. We diagnosed acute myeloid leukemia to your patient with these results. We started AML-BFM 2019 protocol. In his genetic results, the MLL gene rearrangement (46, XY INS (10:11) (p12; q23q13) [14]/46, XY [2]) was positive, so we considered the patient to be at High Risk (HR). After the initial induction chemotherapy (AIE), a complete molecular response was achieved (No blasts and 11q23 rearrangement detected on flow cytometry).

Magnetic resonance imaging of the head revealed an 18x13x15 mm enhancing a mass lesion (myeloid sarcoma) in the left orbital area settled in intraconal legion. In addition to there were two mass lesions (chloroma) which nearly obliterated both maxillary sinuses. After first induction therapy, all of lesions were disappeared on his MRI.

Significant filling defect was observed in the right transverse sinus and proximal to the sigmoid sinus in magnetic resonance venography, and the appearance was reported to be consistent with dural sinus vein thrombosis. Subcutaneous enoxaparin was started at a dosage of 200mg/kg/d (twice a day) for sinus vein thrombosis. After four days of enoxaparin administration, despite platelet transfusion, his platelets could not be increased above 50,000/mm3. Therefore, enoxaparin could not to be applied and port catheter could not to be inserted. Platelet refractoriness due to sinus vein thrombosis was considered. During therapy his sinus vein thrombosis was regressed on MRI venography, and his platelets levels rose up to 50,000/mm3. Enoxaparin was continued.

Severe neutropenia was occurred after first induction chemotherapy. The patient’s neutropenic situation continued approximately twenty days. Appropriate antibiotic therapy was used for fever in neutropenic period. While his neutrophil counts was rising up, fever was started intermittently. Because of fever and increased direct bilirubin, GGT and ALP levels, hepatic candidiasis was considered. In abdominal MRI revealed multiple cystic lesions that was hypointense in T1A series, and hyperintense in T2A series with heterogeneous internal structure, in the liver paranchyma. The largest lesion was 20x23 mm in size in the liver right lobe 8th segment. After intravenous contrast application, some lesions (abcesses) were showed enhancement in the form of peripheral rim (target-like) and not enhancing in the central part were observed. Cystic lesions in the spleen and both kidneys, mostly in the liver, showed diffusion restriction compatible with abscess. With these findings were diagnosed as hepatosplenic candidiasis (Figure 1). Amphotericin B was started to the patient at a 5mg/kg/d dosage. Ursodeoxycholic aside was added his therapy for intrahepatic cholestasis (30mg/kg/d). In his follow up; his fever continued, and Vancomycin Resistant Enterococcus Faecalis (VRE) was isolated from his blood culture. We started linezolid (Minimal inhibitory concentration (MIC): 2). Although treatment, his fever did not decrease and he got worse. Laboratory findings related infections and cholestasis had not declined. Linezolid was changed with tigecycline (MIC: 0.12). On physical examination, he had severe oral mucositis and abdominal tenderness, therefore his oral intake was discontinued and total parenteral nutrition was started. Hypoalbuminemia was occurred, supportive treatment was given as albumin infusions. Together with these treatment changes, he had got better and his fever had decreased. His laboratory markers had decreased also. Intermittent fever was started, and his GGT and ALP levels was increased again despite of healing for his physical findings and rising his neutrophil counts. We suspected that the patient had IRIS, and we started methyl prednisolone at a dosage of 1mg/kg/d for 1 week. The patient’s fever disappeared immediately, and methyl prednisolone was tapered and stopped at the end of the third week.

Citation:Bicakci Z, Koca D and Bozbeyoglu G. Immune Reconstitution Inflammatory Syndrome Associated with Hepatosplenic Candidiasis in a Patient with Acute Myeloblastic Leukemia: Possible Pathogenesis and Treatment in the Light of Current Knowledge. Austin Hematol. 2021; 6(2): 1039.