Fatal Invasive Pulmonary Aspergillosis after Combined Induction with Rituximab and Antithymocyte Globulin for Kidney Transplantation in a Sensitized Recipient, and Early Rejection Therapy with Plasmapheresis and Low-dose Immunoglobulin
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(2) Da Wun Jeong, et al: IPA after Combined Induction for KTP. months after combined induction therapy using rituximab. mofetil. Antibacterial and antiviral prophylaxis included. and antithymocyte globulin, in addition to early rejection. sulfamethoxazole-trimethoprim and valganciclovir after. therapy for graft dysfunction soon after deceased donor. KTP, but antifungal prophylaxis was not given. At 50 days. KTP. The patient recovered with intensive antifungal treat-. after KTP, she was admitted to the hospital because of a. ment and lung lobectomy for a necrotic cavity, and had. cough with sputum production. On admission, blood pres-. good allograft function without intermittent hemodialysis.. sure was 145/75 mmHg, heart rate was 83 beats per minute, o body temperature was 37.6 C, and body mass index was 2 26.64 kg/m (height 160.8 cm, weight 68.2 kg); her lungs. CASE REPORT. were without rales, wheezing, or rhonchi, and there were A 57-year-old woman with diabetes mellitus and end-. no other significant findings on physical or neurologic. stage renal disease had been on peritoneal dialysis for 4. examination. Admission laboratory evaluation showed WBCs. years, and was changed to intermittent hemodialysis 1 year. 3 6,950/mm , C-reactive protein increased to 12.5 mg/dL, Cr. prior to surgery. She underwent deceased donor KTP with. 1.7 mg/dL, tacrolimus level 4.5 ng/mL, and hyperglycemia. 2. combination induction therapy using rituximab (300 mg/m ). (random glucose 432 mg/dL). Chest X-ray showed con-. and antithymocyte globulin (1.5 mg/kg/day for 4 days) be-. solidation and a lesion in the right lower lobe. Further inves-. cause of high-grade sensitization to HLA (PRA titer: class. tigation was needed to confirm the diagnosis. High-reso-. I 22%, class II 51%); she was given tacrolimus, mycopheno-. lution computed tomography (CT) showed fibrotic con-. late mofetil, and prednisolone for immunosuppression. Four. solidation and a peripheral ground glass opacity pattern in. days after KTP, she developed an edematous left leg; acute. the right lower lobe (Fig. 1A). We started antibiotic therapy. deep vein thrombosis was diagnosed by Doppler ultra-. (piperacillin, tazobactam) pending the differential workup. sonography; enoxaparin and anticoagulation therapy were. for pneumonia in early post-KTP patients, to rule out. started, and an inferior vena cava filter was inserted. Five. Pneumocystis carinii (PCP), cytomegalovirus (CMV), IPA,. days after KTP, her urine output decreased to less than 20. bacterial pneumonia, and pulmonary tuberculosis (TB), de-. mL/hr; her creatinine (Cr) increased from 7.18 to 7.9 and. spite the low probability. The sputum culture and stain for. her tacrolimus level was 4.4 ng/mL. She then developed. acid-fast bacilli and the blood culture were negative; the. generalized edema. Kidney color Doppler ultrasonography. CMV polymerase chain reaction (PCR), PCP PCR, and TB. revealed a slightly increased segmental arterial resistive in-. PCR were negative, but a positive test for Aspergillus anti-. dex in the renal allograft (resistive index, 1). For this rea-. gen (1.39) was reported on day 7. Although bronchoscopy. son, we could not perform an immediate allograft biopsy.. did not identify a lesion, bronchoalveolar lavage (BAL) and. Without biopsy-proven acute antibody-mediated rejection. sputum cytology also found Aspergillus. We started vor-. (AMR), even in the absence of donor-specific antibodies. iconazole as an antifungal agent and reduced tacrolimus. (DSA) in a highly sensitized patient with an expected high. from 7 mg/day (3.5 mg twice daily) to 2 mg/day. The ta-. incidence of early AMR, we started intravenous methyl-. crolimus level was 15.8 ng/mL, so we gradually reduced all. prednisolone (500 mg daily for 3 days), in addition to plas-. immunosuppressant agents. However, her chest X-ray. mapheresis and 3 doses of low-dose immunoglobulin (100. showed a worsening pleural effusion. The effusion was. mg/kg body weight). Allograft function gradually im-. treated by percutaneous drain insertion and the exudate was. proved, but allograft biopsy performed 3 weeks after KTP. analyzed. We then added micafungin. However, she needed. diagnosed calcineurin inhibitor toxicity, rather than re-. intubation and mechanical ventilation in the intensive care. jection. Discharge Cr was 1.4 mg/dL; because of leukopenia. unit for 5 days, and all immunosuppressive agents were. (white blood cell [WBC] count 1,500/L, absolute neu-. stopped. The Cr decreased from 1.7 to 1.08. As soon as her. trophil count 1,155), low-dose immunosuppressive agents. condition improved, we restarted tacrolimus 0.5 mg and. were given, including tacrolimus (7 mg/day), sirolimus (1. added mycophenolate mofetil and prednisolone 5 mg on day. mg/day), and prednisolone (10 mg), but not mycophenolate. 20. On day 29, the pleural effusion was found to be increas-. 53.
(3) J Korean Soc TransplantㆍMarch 2017ㆍVolume 31ㆍIssue 1. Fig. 1. (A) On hospital day (HD) 1, high-resolution computed tomography (CT) shows fibrotic consolidation and a peripheral ground glass opacity in the right lower lobe. (B, C) Follow-up enhanced chest CT on HD 82. (B) It shows increasing right loculated pleural effusion. (C) It shows a necrotic cavitary lesion at risk of developing a bronchopleural fistula.. Fig. 2. (A) On hospital day (HD) 39, percutaneous needle biopsy demonstrated Aspergillus (HE stain, ×400). Microscopic examination shows fungal hyphae with septated acute branching (45o). (B) On HD 101, right lower lung lobectomy demonstrated Aspergillus, too (periodic acid Schiff stain, ×400).. ing rapidly, and we performed a percutaneous needle biopsy. follow-up chest CT showed an increasing right loculated. that was reported as necrotizing granulomatous inflamma-. pleural effusion (Fig. 1B) and a necrotic cavitary lesion,. tion with Aspergillus (Fig. 2). Therefore, we diagnosed pri-. with the potential for development of a bronchopleural fis-. mary antifungal therapy failure and changed to secondary. tula (Fig. 1C). On day 101, right lower lung lobectomy was. agents, including combined amphotericin B and anidula-. performed, and an Aspergillus lesion was removed; we stop-. fungin; we again reduced and gradually stopped the im-. ped antifungal agents 40 days after surgery. Graft function. munosuppressive agents, and only used maintenance pre-. improved and Cr decreased to 1.4 mg/dL, with no further. dnisolone 7.5 mg. Thereafter, Cr increased from 1.08 to 3.6. need for hemodialysis (Fig. 3). A low tacrolimus level (1.5. mg/dL, and graft function worsened; we restarted inter-. to 2.9 ng/mL) was maintained.. mittent hemodialysis for fluid volume control. On day 82,. 54.
(4) Da Wun Jeong, et al: IPA after Combined Induction for KTP. Fig. 3. The patient had improved allograft function with no further need for hemodialysis (HD), following recovery with intensive antifungal treatment and lung lobectomy for a necrotic cavity. This figure also shows the immunosuppressant schedule and tacrolimus levels.. DISCUSSION. well as hyperglycemia; all could increase vulnerability to infection. Almost half of the episodes of IPA occur within. Aspergillus is introduced to the lower respiratory tract by. the first 3 to 6 months after transplantation, and this patient. inhalation of infectious spores in patients with severe illness.. was diagnosed in the first 2 months after transplantation.. The diagnosis of IPA remains challenging, and early diag-. Risk factors for early IPA within the first 180 days after. nosis of IPA in severely immunocompromised patients is. KTP include pretransplant chronic obstructive pulmonary. difficult; a high index of suspicion is necessary in patients. disease, impaired graft function, bloodstream infection, and. with risk factors. Symptoms are nonspecific and patients. acute graft rejection within 3 months prior to the diagnosis. may present with fever, cough, sputum, and pleuritic chest. of IPA(9). Combined induction therapy using rituximab and. pain, as well as hemoptysis in neutropenic patients. The gold. antithymocyte globulin, with early rejection therapy for. standard in the diagnosis of IPA is histopathological exami-. graft dysfunction, including plasmapheresis and low-dose. nation of lung tissue obtained by thoracoscopic or open lung. immunoglobulin, contributed to near-fatal IPA in this case.. biopsy(5). Bronchoscopy with BAL is helpful, and recent. Kamar et al.(10) found that with rituximab therapy, 9.1%. advances in the diagnosis of IPA include detection of. of KTP patients died due to opportunistic infectious disease,. Aspergillus antigens in body fluids; these include gal-. and the rate was significantly higher than in a control group. actomannan and -D glucan.. (1.6%). Chung et al.(11) investigated the effect of com-. The major risk factor for IPA is immunodeficiency,. bined use of rituximab and pretransplantation plasmaphe-. which occurs with neutropenia, hematopoietic stem cell. resis on posttransplant infection. The overall prevalence of. transplantation, solid organ transplantation, prolonged ther-. infection was significantly higher and the infection-free. apy with high dose corticosteroids, hematological malig-. survival rate was lower in the combined rituximab and plas-. nancy, cytotoxic therapy, advanced acquired immune defi-. mapheresis group than in those receiving only rituximab or. ciency syndrome, and chronic granulomatous disease(6-8).. in controls. Fungal infections developed only in the ritux-. The present case was a kidney transplant recipient, with. imab plus plasmapheresis group; after antirejection therapy,. neutropenia and steroid therapy as added risk factors, as. a significantly higher infection rate developed in the ritux-. 55.
(5) J Korean Soc TransplantㆍMarch 2017ㆍVolume 31ㆍIssue 1. imab plus plasmapheresis group than in controls (P＜. suspicion of IPA. A new broad-spectrum triazole, vor-. 0.05)(11). Combination therapy resulted in severe and sus-. iconazole, has been approved for initial treatment of IPA,. tained impairment of humoral immunity in this case, and. and is currently considered the treatment of choice; another. can result in a higher overall incidence of infection includ-. broad spectrum triazole, posaconazole, is effective and safe. ing IPA. Early AMR can be severe and a major cause of. as salvage therapy in patients with IPA refractory to stand-. early graft loss. Thus, we recommend aggressive, early. ard treatment(13). The combination of caspofungin and lip-. treatment of AMR in most cases. We also need to obtain. osomal amphotericin B as salvage therapy showed an overall. a biopsy and serum DSA for differential diagnosis, to de-. response rate of 42%(14). The duration of IPA therapy. termine increasing Cr is due to acute rejection, dehydration,. should be individualized for the patient’s clinical and radio-. or an elevated tacrolimus level. If AMR is strongly sus-. logical response. The treatment is often prolonged, lasting. pected, we should treat preemptively, and can stop therapy. several months to ＞1 year. Surgical resection generally. when AMR is ruled out. However, in this case, we could. plays a limited role in management of IPA, but is used with. not obtain an immediate allograft biopsy to document AMR,. invasion of bone, epidural abscesses, massive hemoptysis, or. because of anticoagulation therapy with bleeding risk in the. involvement of the great vessels or pericardium(15).. first few days after transplantation. Because this was a high-. There have been other case reports of kidney transplant. ly sensitized patient with an expected high incidence of ear-. recipients with invasive Aspergillus infections of the lung,. ly AMR, we started plasmapheresis, low-dose intravenous. liver, and skin without allograft failure(16-18), that re-. immunoglobulin (IVIG), and steroids, which increase vul-. quired removal of the infected allograft. However, in this. nerability to opportunistic infections. However, another. case, near-fatal invasive pulmonary Aspergillus infection. treatment option that combines a steroid pulse with high-. and allograft failure requiring hemodialysis were con-. dose IVIG is less likely to lead to opportunistic infection.. currently treated with antifungal agents and surgery, as well. Common adverse events associated with IVIG include mild. as by careful stopping and restarting immunosuppressant. fever, chills, and headache; rare, serious side effects such. agents. This suggests that antifungal prophylaxis, including. as hemolytic anemia, aseptic meningitis, anaphylactic re-. intensive combination induction therapy, should be consid-. actions, and vascular thrombosis have been reported(12). As. ered for those at higher risk of invasive aspergillosis.. in this case, if allograft biopsy cannot be obtain for sus-. Current data support the use of antifungal prophylaxis in. pected AMR, high-dose IVIG may be a better option than. liver, lung, small bowel, heart, and pancreatic solid organ. combined plasmapheresis and steroid pulse therapy, to re-. transplant recipients. Because of the rarity of cases and lack. duce opportunistic infection risk. Lopez-Medrano et al.(4). of data, antifungal prophylaxis after KTP is not currently. assessed risk factors for graft loss among survivors at 12. recommended(19), but there are patients who seem to be. weeks after the diagnosis of IPA. The use of acute renal. at increased risk. Therefore, a strategy is needed to identify. replacement therapy and need for intensive care unit admis-. those patients at high risk for IPA. Panackal et al.(20) re-. sion, either within the 3 months prior to or at the time of. ported that the factors associated with increased risk for as-. diagnosis of IPA, in addition to use of amphotericin B-con-. pergillosis included graft failure requiring prolonged hemo-. taining regimens, were risk factors(4). Graft function in this. dialysis and extended posttransplant corticosteroid use.. patient worsened and intermittent hemodialysis was required. Linden et al.(21) reported that initial antilymphocyte in-. during amphotericin therapy and prior to control of IPA;. duction therapy and/or treatment of rejection increased risk. however, the patient gradually recovered and she regained. for invasive aspergillosis. Therefore, as in our case, high-. good allograft function without need for intermittent. ly-sensitized kidney transplant recipients who receive in-. hemodialysis.. tensive combination induction therapy should be considered. Despite the use of several new antifungal agents, treat-. for antifungal prophylaxis, especially in the presence of. ment of IPA remains difficult and mortality rates are still. graft failure requiring prolonged hemodialysis, or extended. high. Thus, therapy should start as soon as there is clinical. posttransplant corticosteroid use.. 56.
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