A Rare Case of Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome Leading to Hemodialysis and Multiple Infections: A Case Report and Literature Review

Authors: Yohei Iwashige, Shinya Yamamoto, Kaoru Ohue, Hisashi Sugimoto, Hiroyuki Yabumoto, Ryo Kamimatsuse, Hisashi Kamido, Ryota Akagi, Minami Matsumoto, Kanae Yamamoto-Nonaka, Sachiko Minamiguchi, Motoko Yanagita

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe drug eruption that causes multiple organ damage. The renal impairment in these patients usually improves with immunosuppressants, but subsequent infections often develop. We herein report a rare case of DRESS syndrome leading to hemodialysis and multiple infections with Pneumocystis pneumonia, cytomegalovirus and Aspergillus despite the administration of low-dose prednisolone. We also present a literature review of cases requiring dialysis after DRESS syndrome. In patients with chronic kidney disease, it is important to be alert for not only the development of DRESS syndrome but also subsequent infections.

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but serious adverse effect of medications. Complications such as liver, lung, and kidney damage are severe and require immunosuppressive therapy. Acute liver failure, fulminant myocarditis, and hemophagocytic syndrome are fatal with a mortality rate of approximately 10%. Renal involvement occurs in 12-40% of patients with DRESS syndrome but is usually mild and resolves over time without obvious sequelae (1). However, only a few cases lead to end-stage renal failure requiring continuous dialysis (2). Reactivation of herpesviruses, such as human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), and cytomegalovirus (CMV), often develops shortly after the onset of DRESS syndrome (1). CMV, in particular, has been reported to be involved in fatal diseases, such as pneumonia, gastrointestinal hemorrhaging, and myocarditis (3). DRESS syndrome often results in a temporary immunocompromised state after its onset.

We herein report a rare case of a patient with DRESS syndrome leading to hemodialysis and multiple infections of Pneumocystis pneumonia (PCP), CMV infection, and Aspergillus infection despite the administration of low-dose prednisolone. We also present a literature review on cases requiring dialysis after DRESS syndrome.

Case Report

An 86-year-old Japanese man with chronic kidney disease (CKD) due to nephrosclerosis presented to the hospital with complaints of abdominal pain. He had a medical history of abdominal aortic aneurysms, left iliac artery aneurysms, and complete atrioventricular block.

His height was 156 cm, his weight was 45.6 kg, and his body mass index (BMI) was 18.7 kg/m^2^. His body temperature was 36.2°C, heart rate was 50 beats/minute, and blood pressure was 120/60 mmHg. The white blood cell count was 11,500/mL, C-reactive protein (CRP) levels were 4.0 mg/dL, and creatinine levels were 3.3 mg/dL (CKD stage 5) without hematuria. His renal function had not changed from regular clinic visits.

Contrast-enhanced computed tomography (CT) showed perigraft fluid collection and air (Fig. 1a). A physical examination revealed tenderness in the area consistent with the lesion. In addition, fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT also showed some accumulation in the same area (Fig. 1b). Finally, he was diagnosed with graft infection and admitted to our hospital.

Blood cultures on admission were negative, and a physical examination revealed no evidence of a Janeway lesion or Osler's nodes. Echocardiography showed no vegetation, and contrast-enhanced CT revealed no evidence of infarction. Based on these results, we excluded infectious endocarditis.

Graft removal was not performed because the procedure is highly invasive for older people. Therefore, antibiotic therapy with piperacillin/tazobactam 2.25 g intravenously every 8 hours was initiated. Subsequently, the abdominal pain improved, and CRP levels decreased to less than 1.0 mg/dL. On day 31 after admission, he was transferred to another hospital and switched from piperacillin/tazobactam to amoxicillin-clavulanate treatment (amoxicillin 1,000 mg-clavulanate 250 mg/day). Two weeks later, a widespread rash appeared. He was readmitted to our hospital because of oliguria and renal dysfunction. At the time, he was being administered febuxostat 10 mg/day, galantamine 8 mg/day, amlodipine 5 mg/day, tolvaptan 7.5 mg/day, spironolactone 25 mg/day, azosemide 60 mg/day, trichlormethiazide 1 mg/day, fexofenadine 240 mg/day, esomeprazole 20 mg/day, gabapentin 50 mg/day, and probiotics.

On readmission, he was afebrile and gained 5 kg in weight compared with the previous measurement at discharge. A physical examination revealed no abdominal pain. Edema on his extremities and an erythematous maculopapular rash on the bilateral upper and lower extremities and trunk were evident (Fig. 2a). Blood tests showed leukocytosis, eosinophilia, atypical lymphocytes, and increased liver enzymes and CRP levels (Table 1). Creatinine levels increased from baseline of 3.3 to 7.9 mg/dL. An analysis of urine collected by catheter revealed ＞100 nonglomerular red blood cells/high-power field (catheter-associated urethral injury) and a urine protein-to-creatinine ratio of 0.8 g/gCre (albuminuria 187.1 mg/gCr), which had not increased from the time of regular clinic visits. Serological tests for Mycoplasma pneumoniae, Chlamydophila pneumoniae, hepatitis virus, CMV, EBV, and HHV-6 were all negative. Blood cultures were also negative. The fractional excretion of sodium (FENa) was 0.87%, and fractional excretion of urea nitrogen (FEUN) was 12.6%, which were both low and suggestive of prerenal acute kidney injury (AKI). Urinary β2-microglobulin (β2-MG) levels were low (0.071 mg/L). CT showed no evidence of hydronephrosis or renal enlargement (Fig. 1c) or exacerbation of abdominal aortic graft infection. An ultrasound examination showed a collapsed inferior vena cava (IVC). A histopathological examination of the skin biopsy specimen revealed interface dermatitis with eosinophils and dyskeratosis (Fig. 3a-d).

The patient fulfilled six of the criteria for the diagnosis of DRESS eosinophilia, atypical lymphocytes, skin rash over 50% of the body surface area, a characteristic skin rash, liver involvement, and the exclusion of other etiologies, including EBV infection, toxic shock syndrome, lymphoma, Sézary syndrome, vasculitis, and systemic lupus erythematosus. Based on these findings, the patient was diagnosed with DRESS syndrome.

Amoxicillin-clavulanate treatment, which carried a risk of causing DRESS syndrome, was discontinued and switched to other antibiotic drugs (Fig. 4). On hospital day 2, hemodialysis was initiated because of renal failure. In addition, oral prednisolone was initiated because of severe skin rash and liver injury. Considering the patient's advanced age and ongoing abdominal aortic graft infection treatment, low-dose prednisolone (10 mg/day) was administered. After the initiation of prednisolone, the skin rash and edema resolved markedly (Fig. 2b), and the CRP levels decreased quickly (Fig. 4). The levels of liver enzymes also decreased after prednisolone treatment. However, because of the lack of improvement in urine output and persistent azotemia, the patient required continuous hemodialysis. Severe cardiac dysfunction also made fluid control without hemodialysis difficult.

On hospital day 37, the patient developed dyspnea without fluid retention. Chest CT showed ground-glass attenuation in the bilateral lung fields (Fig. 5a, b). High levels of βD glucan, a positive Aspergillus antigen test, and CMV antigen were detected. In addition, sputum polymerase chain reaction (PCR) testing revealed Pneumocystis infection. The patient was finally diagnosed with PCP complicated by fungal and CMV infections and was treated with micafungin, voriconazole, ganciclovir, and trimethoprim-sulfamethoxazole (TMP-SMX). TMP-SMX dosing was changed to pentamidine due to pancytopenia. Micafungin was switched to voriconazole, as Aspergillus antigen was detected, and voriconazole was used for 12 weeks. Ganciclovir required five weeks of treatment until CMV antigen findings turned negative. Pentamidine was given for four weeks for PCP and then reduced to a prophylactic dose and continued. Prednisolone was temporarily increased to 40 mg/day for PCP and then reduced to 10 mg/day. During this time, there was no worsening of DRESS syndrome. Finally, respiratory status improved, follow-up CT showed decreased ground-glass attenuation (Fig. 5c), and the levels of β-d-glucan decreased to 53.1 pg/mL on hospital day 103. On hospital day 112, the patient was discharged without recovery of the renal function after several infections following successful treatment of DRESS syndrome.

Discussion

We encountered a rare case of DRESS syndrome leading to hemodialysis and multiple opportunistic infections. Although the patient required maintenance hemodialysis because of exacerbation of CKD, DRESS syndrome was successfully treated with prednisolone without worsening graft infection. The clinical course of this case was characterized by the development of opportunistic infections despite administration of low doses of prednisolone. Recent reports have suggested that DRESS syndrome subsequently induces an immunocompromised state. Therefore, we quickly detected PCP, CMV, and fungal infections and successfully treated them with each therapeutic agent.

DRESS syndrome is a rare but serious adverse effect of certain medications, such as allopurinol, antibiotics, and anticonvulsants. Piperacillin/tazobactam and amoxicillin used in this case have also been reported as causes (4-7). In a report on allopurinol-induced DRESS syndrome, drug dosage, age, female sex, renal disease, and cardiovascular disease were risk factors for DRESS syndrome (8). The average time from the start of drug administration to the onset of DRESS syndrome was 29.26 days (9). Long-term and high-dose antibiotic administration can also be risk factors for developing a T-cell-mediated drug reaction, including DRESS syndrome (9). Therefore, in our patient, because of his advanced age, renal disease, cardiovascular disease, and the need for long-term use of antibiotics for graft infection, the patient was considered at high risk for DRESS syndrome. In addition, we speculate that prerenal AKI may lead to an increase in plasma drug concentration, which can trigger DRESS syndrome. As demonstrated here, clinicians should be alert for DRESS syndrome in patients with renal dysfunction or in dialysis patients complicated by refractory infections requiring long-term and adequate dosages of antibiotic treatment, such as osteomyelitis and pyogenic spondylitis.

One of the unique features of this case is that DRESS syndrome led to AKI, resulting in maintenance hemodialysis. Although there have been several reports of DRESS syndrome causing interstitial nephritis (10-12), kidney injury usually improves with systemic corticosteroid administration, even in severe cases. In the present patient, although a renal biopsy could not be performed due to renal atrophy, the lack of kidney enlargement and absence of elevated urinary β2-MG levels were not consistent with the features of interstitial nephritis. Although glomerulonephritis after persistent infection often occurs, we consider that glomerulonephritis was not involved in the decline in the renal function in this case, as glomerular hematuria, elevation of blood pressure, and hypocomplementemia were not observed.

However, despite the marked weight gain, FENa and FEUN levels were extremely low, and the IVC diameter collapsed, indicating intravascular dehydration. Based on these findings, we assume that the cause of renal impairment was not interstitial nephritis or infection-related glomerulonephritis but prerenal AKI due to intravascular dehydration caused by inflammation and increased vascular permeability due to DRESS syndrome. Prerenal AKI is generally considered reversible; however, although there are no reports focusing exclusively on prerenal AKI, it has been reported that advanced CKD increases the risk of end-stage renal failure after AKI (13). In addition, the progression of AKI to CKD was more frequent in patients with sepsis than general population (14). Therefore, in this patient, the presence of severe CKD and subsequent multiple infections may have made it irreversible.

We analyzed 10 case reports in which DRESS syndrome/drug-induced hypersensitivity syndrome (DIHS) led to renal dysfunction requiring hemodialysis (2,10,15-21) (Table 2). Two of the 10 cases, including the present case, resulted in maintenance hemodialysis. In the remaining eight cases, hemodialysis was discontinued. The two patients who continued on maintenance hemodialysis had relatively high creatinine levels, and the present patient had more advanced CKD than any other patient. No similarities between the two cases were found except for renal dysfunction on admission. Patients with DRESS syndrome who require hemodialysis often discontinue hemodialysis. However, when the baseline CKD is advanced, as in this case, the patient may be transferred to maintenance hemodialysis.

Immediate discontinuation of the suspected drug is paramount when treating DRESS syndrome. It has also been suggested that prednisolone or its equivalent should be started at 0.5-1.0 mg/kg/day, and the dosage should be reduced over 2-3 months (1). In our patient, given the persistence of graft infection and lack of a critical condition, such as severe acute liver failure, fulminant myocarditis, or hemophagocytic syndrome, we chose to administer low-dose prednisolone (10 mg/day). After the administration of prednisolone, the inflammation, allergic-like symptoms, and skin rash improved quickly. Subsequently, there was no evidence of the development of any conditions known to be long-term sequelae of DRESS syndrome, including type 1 diabetes mellitus, thyroid diseases, and autoimmune diseases.

It is noteworthy in this case that multiple infections developed approximately 1 month after the onset of DRESS syndrome. Tests for Aspergillus antigen, CMV antigen, βD glucan, and sputum PCR for Pneumocystis were positive, indicating overlapping infections. Although the incidence of PCP has been reported to be very low if the initial dose of corticosteroids is ＜15 mg/day of prednisolone equivalent (22), our patient developed PCP and other multiple opportunistic infections despite the low dose of prednisolone (10 mg/day). DRESS syndrome has been reported to be involved in a temporarily immunocompromised state after the onset due to increased numbers of regulatory T cells and hypogammaglobulinemia (3). We speculate that, in addition to the immunocompromised state due to his advanced age (23), CKD (24), and hypoalbuminemia (25), the immunocompromised state due to DRESS syndrome and the use of prednisolone may have rendered the patient susceptible to multiple opportunistic infections.

In DRESS syndrome, herpesvirus reactivation may be recognized as immune reconstitution inflammatory syndrome (IRIS), which occurs with immune recovery from an immunocompromised state. Therefore, the appearance of pneumonia in this patient may also be interpreted as IRIS due to recovery from an immunocompromised state caused by treatment for DRESS syndrome. It is difficult to determine whether the pneumonia in this patient was a simple opportunistic infection due to the immunocompromised state or a manifestation of pneumonia as IRIS.

In addition, no PCP prophylaxis, such as TMP-SMX, was given to this patient at the start of prednisolone administration. PCP prophylaxis during treatment with 10 mg prednisolone was considered to be more of a risk than a benefit (22), as TMP-SMX may exacerbate DRESS syndrome, and PCP is very rare within six weeks of starting low-dose prednisolone (26). However, given the immunocompromised status of DRESS syndrome itself, it may have been necessary to consider starting TMP-SMX as soon as DRESS syndrome improved.

Conclusion

We report a rare case of DRESS syndrome leading to hemodialysis and multiple opportunistic infections. Although the patient required maintenance hemodialysis due to exacerbation of CKD, DRESS syndrome was successfully treated with prednisolone without worsening of the graft infection. This case's clinical course was characterized by the development of opportunistic infections, which might have been caused by an immunocompromised state or IRIS after DRESS syndrome. We quickly detected PCP, CMV infection, and fungal infection and successfully treated them with each therapeutic agent. Clinicians should be aware of the potential complications of DRESS syndrome and subsequent infections when using antibiotics for long periods, particularly in patients with CKD.

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

The authors state that they have no Conflict of Interest (COI).

Yohei Iwashige and Shinya Yamamoto contributed equally to this work.