Copyright ⓒ the Korean Society for Transplantation, 2017

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

Da Wun Jeong, M.D.1, Sang-Ho Lee, M.D.1, Ju-Young Moon, M.D.1, Yang-Gyun Kim, M.D.1, Yu Ho Lee, M.D.1, Kipyo Kim, M.D.1, Hochul Park, M.D.2 and Sun Hyung Joo, M.D.2

Division of Nephrology, Department of Internal Medicine1, Department of Surgery2, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea

A high degree of sensitization to human leukocyte antigen requires more intensive induction therapy; however, this increases

vulnerability to opportunistic infections following kidney transplantation. Although recent studies have suggested that combined

induction therapy with antithymocyte globulin and rituximab would be more effective in highly sensitized kidney recipients, we

experienced a case of near-fatal invasive pulmonary aspergillosis 2 months after combined induction and early rejection therapy

for graft dysfunction. Fortunately, the patient recovered with intensive antifungal treatment and lung lobectomy for a necrotic

cavity. Antifungal prophylaxis should be considered in cases undergoing intensive induction therapy.

Key Words: Invasive pulmonary aspergillosis, Combined desensitization induction, Kidney transplantation

중심 단어: 침습적 폐 아스퍼질로시스, 병합유도요법, 신장이식

Received December 18, 2016 Revised February 14, 2017Accepted February 15, 2017

Corresponding author: Sang-Ho Lee

Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University Schoolof Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, KoreaTel: 82-2-440-1919, Fax: 82-2-440-8150E-mail: lshkidney@khu.ac.kr

Case Report

INTRODUCTION

Patients who undergo kidney transplantation (KTP) re-

quire life-long immunosuppressive treatment to prevent

graft rejection. High-grade sensitization to human leukocyte

antigen (HLA) and ABO incompatibility require use of pre-

transplantation preparative therapy, such as rituximab ad-

ministration and plasmapheresis. Laftavi et al.(1) reported

that combination induction therapy with addition of ritux-

imab to rabbit antithymocyte globulin (rATG) resulted in

superior graft survival at 5 years, compared to that using

rATG alone in KTP recipients with panel reactive antibody

(PRA) levels ＞50%. Yin et al.(2) described seven patients

who received a single dose of 600 mg rituximab (375 mg/m2)

infusion on the day before surgery and polyclonal antibody

(antithymocyte globulin) on the day of surgery; this proto-

col reduced the occurrence of postoperative humoral re-

jection in highly sensitized renal transplant recipients. However,

such therapy increases the risk of developing opportunistic

infections including invasive pulmonary aspergillosis (IPA).

The incidence rate of IPA after KTP is 0.4%, in comparison

with 1.3% and 1.9% after heart and liver transplantation,

respectively(3). Nevertheless, KTP recipients have the high-

est burden of posttransplant IPA because KTP is the most

frequently performed transplant procedure worldwide. Six-

and 12-week survival rates for IPA after KTP were 68.8%

and 60.7%, respectively, and 22.1% of survivors experienced

graft loss(4). We report a case of near-fatal early IPA 2

J Korean Soc Transplant 2017;31:52-57 https://doi.org/10.4285/jkstn.2017.31.1.52

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Da Wun Jeong, et al: IPA after Combined Induction for KTP

months after combined induction therapy using rituximab

and antithymocyte globulin, in addition to early rejection

therapy for graft dysfunction soon after deceased donor

KTP. The patient recovered with intensive antifungal treat-

ment and lung lobectomy for a necrotic cavity, and had

good allograft function without intermittent hemodialysis.

CASE REPORT

A 57-year-old woman with diabetes mellitus and end-

stage renal disease had been on peritoneal dialysis for 4

years, and was changed to intermittent hemodialysis 1 year

prior to surgery. She underwent deceased donor KTP with

combination induction therapy using rituximab (300 mg/m2)

and antithymocyte globulin (1.5 mg/kg/day for 4 days) be-

cause of high-grade sensitization to HLA (PRA titer: class

I 22%, class II 51%); she was given tacrolimus, mycopheno-

late mofetil, and prednisolone for immunosuppression. Four

days after KTP, she developed an edematous left leg; acute

deep vein thrombosis was diagnosed by Doppler ultra-

sonography; enoxaparin and anticoagulation therapy were

started, and an inferior vena cava filter was inserted. Five

days after KTP, her urine output decreased to less than 20

mL/hr; her creatinine (Cr) increased from 7.18 to 7.9 and

her tacrolimus level was 4.4 ng/mL. She then developed

generalized edema. Kidney color Doppler ultrasonography

revealed a slightly increased segmental arterial resistive in-

dex in the renal allograft (resistive index, 1). For this rea-

son, we could not perform an immediate allograft biopsy.

Without biopsy-proven acute antibody-mediated rejection

(AMR), even in the absence of donor-specific antibodies

(DSA) in a highly sensitized patient with an expected high

incidence of early AMR, we started intravenous methyl-

prednisolone (500 mg daily for 3 days), in addition to plas-

mapheresis and 3 doses of low-dose immunoglobulin (100

mg/kg body weight). Allograft function gradually im-

proved, but allograft biopsy performed 3 weeks after KTP

diagnosed calcineurin inhibitor toxicity, rather than re-

jection. Discharge Cr was 1.4 mg/dL; because of leukopenia

(white blood cell [WBC] count 1,500/L, absolute neu-

trophil count 1,155), low-dose immunosuppressive agents

were given, including tacrolimus (7 mg/day), sirolimus (1

mg/day), and prednisolone (10 mg), but not mycophenolate

mofetil. Antibacterial and antiviral prophylaxis included

sulfamethoxazole-trimethoprim and valganciclovir after

KTP, but antifungal prophylaxis was not given. At 50 days

after KTP, she was admitted to the hospital because of a

cough with sputum production. On admission, blood pres-

sure was 145/75 mmHg, heart rate was 83 beats per minute,

body temperature was 37.6oC, and body mass index was

26.64 kg/m2 (height 160.8 cm, weight 68.2 kg); her lungs

were without rales, wheezing, or rhonchi, and there were

no other significant findings on physical or neurologic

examination. Admission laboratory evaluation showed WBCs

6,950/mm3, C-reactive protein increased to 12.5 mg/dL, Cr

1.7 mg/dL, tacrolimus level 4.5 ng/mL, and hyperglycemia

(random glucose 432 mg/dL). Chest X-ray showed con-

solidation and a lesion in the right lower lobe. Further inves-

tigation was needed to confirm the diagnosis. High-reso-

lution computed tomography (CT) showed fibrotic con-

solidation and a peripheral ground glass opacity pattern in

the right lower lobe (Fig. 1A). We started antibiotic therapy

(piperacillin, tazobactam) pending the differential workup

for pneumonia in early post-KTP patients, to rule out

Pneumocystis carinii (PCP), cytomegalovirus (CMV), IPA,

bacterial pneumonia, and pulmonary tuberculosis (TB), de-

spite the low probability. The sputum culture and stain for

acid-fast bacilli and the blood culture were negative; the

CMV polymerase chain reaction (PCR), PCP PCR, and TB

PCR were negative, but a positive test for Aspergillus anti-

gen (1.39) was reported on day 7. Although bronchoscopy

did not identify a lesion, bronchoalveolar lavage (BAL) and

sputum cytology also found Aspergillus. We started vor-

iconazole as an antifungal agent and reduced tacrolimus

from 7 mg/day (3.5 mg twice daily) to 2 mg/day. The ta-

crolimus level was 15.8 ng/mL, so we gradually reduced all

immunosuppressant agents. However, her chest X-ray

showed a worsening pleural effusion. The effusion was

treated by percutaneous drain insertion and the exudate was

analyzed. We then added micafungin. However, she needed

intubation and mechanical ventilation in the intensive care

unit for 5 days, and all immunosuppressive agents were

stopped. The Cr decreased from 1.7 to 1.08. As soon as her

condition improved, we restarted tacrolimus 0.5 mg and

added mycophenolate mofetil and prednisolone 5 mg on day

20. On day 29, the pleural effusion was found to be increas-

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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

that was reported as necrotizing granulomatous inflamma-

tion with Aspergillus (Fig. 2). Therefore, we diagnosed pri-

mary antifungal therapy failure and changed to secondary

agents, including combined amphotericin B and anidula-

fungin; we again reduced and gradually stopped the im-

munosuppressive agents, and only used maintenance pre-

dnisolone 7.5 mg. Thereafter, Cr increased from 1.08 to 3.6

mg/dL, and graft function worsened; we restarted inter-

mittent hemodialysis for fluid volume control. On day 82,

follow-up chest CT showed an increasing right loculated

pleural effusion (Fig. 1B) and a necrotic cavitary lesion,

with the potential for development of a bronchopleural fis-

tula (Fig. 1C). On day 101, right lower lung lobectomy was

performed, and an Aspergillus lesion was removed; we stop-

ped antifungal agents 40 days after surgery. Graft function

improved and Cr decreased to 1.4 mg/dL, with no further

need for hemodialysis (Fig. 3). A low tacrolimus level (1.5

to 2.9 ng/mL) was maintained.

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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

Aspergillus is introduced to the lower respiratory tract by

inhalation of infectious spores in patients with severe illness.

The diagnosis of IPA remains challenging, and early diag-

nosis of IPA in severely immunocompromised patients is

difficult; a high index of suspicion is necessary in patients

with risk factors. Symptoms are nonspecific and patients

may present with fever, cough, sputum, and pleuritic chest

pain, as well as hemoptysis in neutropenic patients. The gold

standard in the diagnosis of IPA is histopathological exami-

nation of lung tissue obtained by thoracoscopic or open lung

biopsy(5). Bronchoscopy with BAL is helpful, and recent

advances in the diagnosis of IPA include detection of

Aspergillus antigens in body fluids; these include gal-

actomannan and -D glucan.

The major risk factor for IPA is immunodeficiency,

which occurs with neutropenia, hematopoietic stem cell

transplantation, solid organ transplantation, prolonged ther-

apy with high dose corticosteroids, hematological malig-

nancy, cytotoxic therapy, advanced acquired immune defi-

ciency syndrome, and chronic granulomatous disease(6-8).

The present case was a kidney transplant recipient, with

neutropenia and steroid therapy as added risk factors, as

well as hyperglycemia; all could increase vulnerability to

infection. Almost half of the episodes of IPA occur within

the first 3 to 6 months after transplantation, and this patient

was diagnosed in the first 2 months after transplantation.

Risk factors for early IPA within the first 180 days after

KTP include pretransplant chronic obstructive pulmonary

disease, impaired graft function, bloodstream infection, and

acute graft rejection within 3 months prior to the diagnosis

of IPA(9). Combined induction therapy using rituximab and

antithymocyte globulin, with early rejection therapy for

graft dysfunction, including plasmapheresis and low-dose

immunoglobulin, contributed to near-fatal IPA in this case.

Kamar et al.(10) found that with rituximab therapy, 9.1%

of KTP patients died due to opportunistic infectious disease,

and the rate was significantly higher than in a control group

(1.6%). Chung et al.(11) investigated the effect of com-

bined use of rituximab and pretransplantation plasmaphe-

resis on posttransplant infection. The overall prevalence of

infection was significantly higher and the infection-free

survival rate was lower in the combined rituximab and plas-

mapheresis group than in those receiving only rituximab or

in controls. Fungal infections developed only in the ritux-

imab plus plasmapheresis group; after antirejection therapy,

a significantly higher infection rate developed in the ritux-

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J Korean Soc TransplantㆍMarch 2017ㆍVolume 31ㆍIssue 1

imab plus plasmapheresis group than in controls (P＜

0.05)(11). Combination therapy resulted in severe and sus-

tained impairment of humoral immunity in this case, and

can result in a higher overall incidence of infection includ-

ing IPA. Early AMR can be severe and a major cause of

early graft loss. Thus, we recommend aggressive, early

treatment of AMR in most cases. We also need to obtain

a biopsy and serum DSA for differential diagnosis, to de-

termine increasing Cr is due to acute rejection, dehydration,

or an elevated tacrolimus level. If AMR is strongly sus-

pected, we should treat preemptively, and can stop therapy

when AMR is ruled out. However, in this case, we could

not obtain an immediate allograft biopsy to document AMR,

because of anticoagulation therapy with bleeding risk in the

first few days after transplantation. Because this was a high-

ly sensitized patient with an expected high incidence of ear-

ly AMR, we started plasmapheresis, low-dose intravenous

immunoglobulin (IVIG), and steroids, which increase vul-

nerability to opportunistic infections. However, another

treatment option that combines a steroid pulse with high-

dose IVIG is less likely to lead to opportunistic infection.

Common adverse events associated with IVIG include mild

fever, chills, and headache; rare, serious side effects such

as hemolytic anemia, aseptic meningitis, anaphylactic re-

actions, and vascular thrombosis have been reported(12). As

in this case, if allograft biopsy cannot be obtain for sus-

pected AMR, high-dose IVIG may be a better option than

combined plasmapheresis and steroid pulse therapy, to re-

duce opportunistic infection risk. Lopez-Medrano et al.(4)

assessed risk factors for graft loss among survivors at 12

weeks after the diagnosis of IPA. The use of acute renal

replacement therapy and need for intensive care unit admis-

sion, either within the 3 months prior to or at the time of

diagnosis of IPA, in addition to use of amphotericin B-con-

taining regimens, were risk factors(4). Graft function in this

patient worsened and intermittent hemodialysis was required

during amphotericin therapy and prior to control of IPA;

however, the patient gradually recovered and she regained

good allograft function without need for intermittent

hemodialysis.

Despite the use of several new antifungal agents, treat-

ment of IPA remains difficult and mortality rates are still

high. Thus, therapy should start as soon as there is clinical

suspicion of IPA. A new broad-spectrum triazole, vor-

iconazole, has been approved for initial treatment of IPA,

and is currently considered the treatment of choice; another

broad spectrum triazole, posaconazole, is effective and safe

as salvage therapy in patients with IPA refractory to stand-

ard treatment(13). The combination of caspofungin and lip-

osomal amphotericin B as salvage therapy showed an overall

response rate of 42%(14). The duration of IPA therapy

should be individualized for the patient’s clinical and radio-logical response. The treatment is often prolonged, lasting

several months to ＞1 year. Surgical resection generally

plays a limited role in management of IPA, but is used with

invasion of bone, epidural abscesses, massive hemoptysis, or

involvement of the great vessels or pericardium(15).

There have been other case reports of kidney transplant

recipients with invasive Aspergillus infections of the lung,

liver, and skin without allograft failure(16-18), that re-

quired removal of the infected allograft. However, in this

case, near-fatal invasive pulmonary Aspergillus infection

and allograft failure requiring hemodialysis were con-

currently treated with antifungal agents and surgery, as well

as by careful stopping and restarting immunosuppressant

agents. This suggests that antifungal prophylaxis, including

intensive combination induction therapy, should be consid-

ered for those at higher risk of invasive aspergillosis.

Current data support the use of antifungal prophylaxis in

liver, lung, small bowel, heart, and pancreatic solid organ

transplant recipients. Because of the rarity of cases and lack

of data, antifungal prophylaxis after KTP is not currently

recommended(19), but there are patients who seem to be

at increased risk. Therefore, a strategy is needed to identify

those patients at high risk for IPA. Panackal et al.(20) re-

ported that the factors associated with increased risk for as-

pergillosis included graft failure requiring prolonged hemo-

dialysis and extended posttransplant corticosteroid use.

Linden et al.(21) reported that initial antilymphocyte in-

duction therapy and/or treatment of rejection increased risk

for invasive aspergillosis. Therefore, as in our case, high-

ly-sensitized kidney transplant recipients who receive in-

tensive combination induction therapy should be considered

for antifungal prophylaxis, especially in the presence of

graft failure requiring prolonged hemodialysis, or extended

posttransplant corticosteroid use.

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Da Wun Jeong, et al: IPA after Combined Induction for KTP

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