DRESS’ed in Shock and Delay in Eosinophilia Resolution: Management Dilemmas in a Complex Case of Vancomycin-Induced DRESS Syndrome

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare hypersensitivity reaction to a medication that can affect multiple organ systems, with mortality rates approaching up to 10% [1–3]. Frequently implicated triggers include anticonvulsants, allopurinol, and certain antibiotics, such as vancomycin [1–3]. The exact pathophysiology of DRESS is not known, but a drug-mediated inflammatory T-cell response and viral reactivation are commonly proposed pathogenic mechanisms for the syndrome [1]. Viral reactivation, especially human herpesviruses 6 (HHV-6), Epstein-Barr virus (EBV), and cytomegalovirus (CMV), is frequent and has been linked to increased severity of disease, organ dysfunction, poorer outcomes, and recurrent flares [4].

DRESS syndrome has a wide range of presentations and levels of severity, given the multitude of different organ systems it can affect. This can lead to misdiagnosis of other disease processes and delays in treatment. Although many patients with DRESS syndrome are treated on standard hospital floors, severe cases can require intensive care [5]. In a cohort study of 41 patients with vancomycin-associated DRESS syndrome, it was characterized by frequent hepatic involvement (76%), renal dysfunction (61%), lung involvement (24%), and little gastrointestinal involvement (2%). Two deaths were reported [6].

It is generally agreed that severe cases of DRESS syndrome should be treated with systemic corticosteroids, but there is no standard treatment guideline for the corticosteroid dosing and duration [1]. Severe cases requiring intensive care are infrequently encountered, and knowledge of trends in hematological/blood count response following commencement of systemic steroid therapy would benefit clinical practice considerations in making decisions on need for management adjustments [1]. In this case report of severe vancomycin-induced DRESS syndrome, we will discuss the presenting features, diagnosis, unusual aspects of its clinical course, and management to underscore the importance of early case recognition.

Case Report

Six weeks before the development of DRESS syndrome, a 61-year-old woman was admitted to the hospital for abdominal pain. She was found to have a splenic infarct, and, subsequently, aortic valve endocarditis detected on transthoracic and transesophageal echocardiography (TTE and TEE), secondary to Enterococcus faecium on blood cultures. This was further complicated by left parietal and left frontal septic embolic stroke and osteomyelitis of thoracic vertebrae 10 and 11. She underwent aortic valve replacement via sternotomy with a 21-mm Edwards Inspiris pericardial valve on day 12 of admission, with the native valve being culture negative. Her antibiotic course during that admission is outlined in Figure 1. Antibiotics were administered via a peripherally inserted central catheter (PICC) line.

A total of 6 weeks of antibiotics was planned, with day 1 of antibiotics counted from day 7 of admission, when cultures were negative. Vancomycin was stopped on day 30 of the antibiotic course due to elevated vancomycin trough at 32 μg/mL (reference range, 10–20 μg/mL) and an acute kidney injury (AKI) (Figure 1). At approximately the same time, she developed a multitude of symptoms that led to her subsequent hospital presentation 3 days later (Figure 1). She initially presented to a peripheral hospital due to a 3-day history of worsening lethargy, confusion, fevers, dyspnea, and watery diarrhea, and a 1-day history of sudden onset, diffuse erythematous rash involving the palms and feet. Her rash was without associated pain, although she did have pruritus.

Her past medical history included coronary artery disease with previous stenting, heart failure, with improved ejection fraction (last known left ventricular ejection fraction [LVEF] of 50% to 55% from a TTE just before she underwent aortic valve replacement), deep venous thrombosis on anticoagulation with apixaban, paroxysmal atrial fibrillation, chronic obstructive pulmonary disease on 2 to 2.5 L of oxygen at baseline, and fibromyalgia with chronic pain managed with opioids and gabapentin. Otherwise, she had no new prescription or over-the-counter medication exposure in the past year other than the vancomycin she was discharged on. She had a history of urticaria (hives) in response to amoxicillin and sulfonamide antibiotics. She was fully vaccinated for her age.

At the emergency department (ED) of the peripheral hospital, she was given intravenous (IV) dexamethasone 10 mg, diphenhydramine 50 mg IV, famotidine 20 mg IV, and a normal saline bolus and infusion due to concern for an allergic reaction. Following these interventions in the ED on her reassessment, the rash appeared improved, but the dyspnea remained; therefore, she was admitted to the medicine service for concerns of a possible heart failure exacerbation with AKI. Following admission, she was deemed not to be in heart failure exacerbation and was continued on IV fluids for the AKI with anuria. The rash was assessed as an allergic reaction to vancomycin, with no further interventions, given it had already been discontinued. The next day, she became hypotensive and was started on antibiotics with ceftazidime IV and azithromycin IV for possible hospital-acquired pneumonia and linezolid IV as a substitute for vancomycin. However, her condition continued to deteriorate, and the rash worsened. Her systolic blood pressure dropped as low as 64 mmHg and remained within that range despite the administration of approximately 5 L of IV fluids through bolus and continuous IV infusion of normal saline. Therefore, the team contacted our intensivist for transfer, and, per his recommendation, she was started on continuous norepinephrine IV initially at 2 mcg/min, eventually escalating to 5 mcg/min, and given 1 dose of IV hydrocortisone 50 mg. She was then transferred from the peripheral hospital to the intensive care unit (ICU) of our facility.

On presentation to our facility, she was on 4 L of oxygen via nasal cannula with an oxygen saturation of 96% and respiratory rate of 21 breaths per minute. She was on 5 mcg/min of norepinephrine with a systolic blood pressure of 118 mmHg and diastolic blood pressure of 74 mmHg (mean arterial pressure of 89 mmHg). Her heart rate was 82 beats per minute, she had a temperature of 39.7°C, and her weight was 78 kg. On examination, she was acutely ill appearing and had obesity and anasarca. Ocular examination revealed her pupils to be equal, round, and reactive to light bilaterally with intact extraocular movements and absence of conjunctival injection or discharge. Mucous membranes were moist without oral erythema, ulcers, or thrush. She had good dentition. Her neck was supple without masses or lymphadenopathy. She had a clean sternal scar without erythema, calor, and drainage. Her heart had a regular rate and rhythm, normal S1 and S2, with a soft holosystolic murmur in the right second intercostal space. She did not have jugular venous distension, and her extremities were warm and well perfused. Her bilateral radial and dorsalis pedis pulses were 2+. She did not appear in respiratory distress, and the chest was symmetrical with equal chest expansion and clear to auscultation bilaterally. Her abdomen was protuberant, soft, non-tender to palpation, without hepatosplenomegaly, with normal bowel sounds. She had a diffuse, macular, confluent, blanchable, and erythematous rash, mainly distributed over the thorax and abdomen, but it also involved the face, arms, legs, palms, and soles of the feet (Figure 2). It was without desquamation, scale, drainage, bullae, vesicles, or ulcers on presentation. No musculoskeletal deformities were noted. She had 1+ pitting pedal edema bilaterally, with no clubbing or cyanosis. On neurological examination, she was drowsy but arousable to loud voice and touch. The Glasgow Coma Scale score was 14: eyes, 3; verbal, 5; and motor, 6. She was oriented to herself, place, and time but unable to provide a complete history. She was without any major motor or sensory deficits and had normal muscular tone and intact 2+ reflexes throughout.

Initial laboratory evaluation showed a total white blood cell count of 15 600 cells/μL, peaking at 28 400 cells/μL with steroid continuation. The absolute neutrophil count was 13 080 cells/μL (peak 23 795 cells/μL), absolute lymphocyte count 410 cells/μL (peak 4212 cells/μL), and absolute eosinophil count 790 cells/μL (peak 3749 cells/μL). Hemoglobin was 12.0 g/dL. Serum creatinine was 1.8 mg/dL from a baseline of 0.6 mg/dL, with blood urea nitrogen of 21 mg/dL. A random vancomycin level was 8 μg/mL on the day of admission. High-sensitivity troponin was 17.5 pg/mL (peak 18.6 pg/mL), and B-type natriuretic peptide was 1110 pg/mL. Urinalysis and urine microscopy revealed turbid urine with protein, coarse granular casts (1–9 per low power field), minimal white blood cells (0–2 per high power field), and minimal red blood cells (0–2 per high power field).

Computed tomography (CT) of the chest without IV contrast revealed bibasilar atelectasis, trace bilateral pleural effusions, and enlarged mediastinal lymph nodes. CT of the abdomen without IV or oral contrast demonstrated diffuse subcutaneous edema, mildly enlarged bilateral inguinal lymph nodes, and a fat-containing periumbilical hernia. TTE showed a poorly visualized aortic valve that was moderately stenosed by Doppler, with no visible vegetations, LVEF 45% to 50%, no pericardial effusion, trace mitral regurgitation, a hypokinetic apical septum and an akinetic apical lateral wall, similar to a prior echocardiogram. Ultrasound examinations of the kidneys and bladder were unremarkable. The nephrology team assessed her kidney dysfunction as possibly multifactorial from vancomycin nephrotoxicity, acute tubular necrosis, and/or acute interstitial nephritis from DRESS.

In evaluation of the etiology of the patient’s shock, we found absence of tamponade on TTE, no right heart strain to suggest obstructive shock from pulmonary embolism, alongside low probability of a pulmonary embolism, no significant valvular abnormalities, and absence of volume responsiveness to suggest hypovolemic shock. We considered cardiogenic shock, but as she had warm extremities, mild reduction in LVEF, and was not requiring additional inotropic support with medications such as milrinone, epinephrine, or dobutamine, it was felt to be less likely. We assessed her clinical picture to be more likely distributive shock from either sepsis or DRESS syndrome. Empiric antibiotics of ceftazidime IV and linezolid IV were continued along with doxycycline IV for coverage of atypical and tickborne organisms. She was also started on prednisone 1 mg/kg daily (80 mg daily) for possible DRESS.

Between day 2 and day 3, further workup was obtained to rule out infectious and inflammatory differentials, including multiple blood cultures (from the PICC as well), urinary antigens for Streptococcus and Legionella, respiratory viral polymerase chain reaction (PCR) panel, SARS-CoV-2 testing, tick-borne disease panel PCR with Lyme serology, stool ova and parasite microscopy, Coccidioides and Blastomyces antibodies, 1,3-β-D-glucan serum, hepatitis C antibody, HIV antigen and antibody screen, Strongyloides antibodies, complement 3, complement 4, antinuclear antibodies, and double-stranded DNA antibodies. These tests were all negative or within normal limits and were without suggestion of active infection or autoimmune disease. Following corticosteroid treatment, her oxygen requirements improved to baseline, kidney function improved, fever resolved, and she was weaned from vasopressors. Ceftazidime and linezolid were discontinued on day 2, as the ICU and the infectious disease team felt there was no evidence of infection and no need to continue therapy for endocarditis. Doxycycline was discontinued on day 3 because of a negative tick-borne illness panel. Kidney biopsy was deferred due to improved kidney function. The shock resolved with continued sole steroid therapy. She was subsequently downgraded to the hospitalist service and transferred out of the ICU.

By day 4 and day 6, EBV PCR eventually resulted as positive, although below a quantitative level; no EBV antibody testing was sent at the time the PCR was sent. Because she was improving, it was felt that additional testing for serology was not necessary, to avoid additional costs. The PCR result was felt to possibly support a diagnosis of DRESS due to the observed viral reactivation in DRESS, but was understandably not ideal to interpret in the absence of serology. CMV and HHV-6 PCR were negative. Skin punch biopsy of the chest showed spongiotic interface dermatosis; the epidermis had mild acanthosis and overlying parakeratotic scale with rare necrotic keratinocytes; the papillary dermis showed sparse lymphocytic infiltrate with numerous eosinophils, along with dilated lymphatics. Overall, this was felt by the pathologist and dermatologist to be consistent with a drug-related hypersensitivity reaction or viral exanthem. Her retrospective Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) score was “definite” at a score of 7: fever over 38.5 °C, enlarged lymph nodes at more than 2 sites, eosinophilia greater than 1500, skin rash over 50%, edema and scaling, more than 2 organs involved (AKI; myocardial involvement with troponin elevation and mild reduction in LVEF; and hypoxia), exclusion of alternative diagnosis based on initial testing from previous facility and on admission, and skin biopsy suggestive of DRESS syndrome. Diuresis commenced with furosemide 20 mg IV daily due to volume overload. Prednisone was reduced to 30 mg twice daily on day 5 due to insomnia and concerns that high-dose corticosteroids in the past had led to admissions for decompensated heart failure.

The eosinophil count continued to rise despite corticosteroids, but the erythematous rash was clearing (Figure 3). She started developing clear blistering on the chest and under the breast along with exfoliative dermatitis of the face. Her clinical status had remarkably improved along with continued improvement in kidney function with sole steroid therapy. The hematology team reviewed her case. They felt the rise in eosinophils was likely a delayed response, and predicted it would improve with continued steroid treatment, advising against additional measures or therapies such as intravenous immunoglobulins (IVIG) or cyclosporine in the interim, given obvious clinical improvement on steroids.

Between days 7 and 9, her eosinophil count started to downtrend, her kidney function continued to improve, and her rash continued to clear, with less erythema and pruritus. She felt well and was eager to go home. She was discharged on a tapering prednisone course of 50 mg daily to be reduced by 10 mg after every week until it was 10 mg daily, which she would then reduce to 5 mg daily for a week, and finally 2.5 mg for a week. She was also discharged on furosemide tablets 20 mg daily. She had a good recovery on noted follow-up clinic appointments, although she did have a brief admission for decompensated heart failure in the second week after discharge that was managed with 3 days of IV diuretics. Afterward, she had no further ED visits or admissions. Eventual flow cytometry results revealed mature neutrophilia with occasional immature granulocytes and granulocytic dysplasia, but no monotypic B-cell or aberrant T-cell population. Repeat echocardiogram showed improved LVEF to 55%, with a normal bioprosthetic aortic valve function and no noted wall motion abnormalities or significant valvular abnormalities.

Discussion

DRESS syndrome is a severe adverse drug reaction with manifestations starting within 2 weeks to 3 months after drug initiation [1]. Frequently reported causes of DRESS are antiepileptic agents, allopurinol, and antibiotics, such as anti-tuberculosis medications and vancomycin [1–3]. As in our case, its presentation is characterized by various symptoms such as skin rash, fever, lymph node enlargement, and internal organ involvement [1,7]. The RegiScar can be used to assess the likelihood of DRESS syndrome, usually retrospectively, and can be recalculated based on the clinical course and further information, as patients may not score positively initially [1,8]. A reactivation of EBV, CMV, or HHV-6 helps support the diagnosis, as it occurs during DRESS syndrome and is associated with worse outcomes [1,6]. As serology was not sent, the evidence of re-activation of EBV based only on the PCR is weak.

The first major learning point from this case was the patient’s hematological response. Delayed marked eosinophilia and delayed lymphocytosis, with delayed resolution/response despite high-dose systemic steroid initiation, has not been clearly documented in the literature [1,5,13]. We prepared this case report to clearly illustrate this educational point. It can appear worrisome to clinicians and could push a decision to add further therapies alongside high-dose corticosteroids, such as cyclosporine and IVIG, early in the patient’s clinical course [1,5]. Escalation of therapy could introduce further risk of adverse drug events for the patient. However, based on this patient’s course, hematological parameters – particularly eosinophil and lymphocyte counts – can lag behind observable clinical improvement and may not be reliable indicators of systemic corticosteroid effectiveness, especially in the initial stages of treatment. The key teaching point from this case was that clinical evaluation and rash progression should take precedence over early laboratory trends, such as eosinophil counts, in determining the need to escalate therapy [1,5].

A second major point is that presentation with shock-like features and requirement for ICU level of care is not common but can occur in the most severe manifestations of the disease [1]. Like in the present case, it can be mistaken for septic shock due to its usually distributive pathophysiology but progress to worsening hemodynamics and multi-organ dysfunction despite antibiotic therapy, with eventual improvement following commencement of high-dose corticosteroids [9–11]. Presentation with cardiogenic shock following myocardial involvement has also been noted [12]. While our patient had signs of possible DRESS myocardial involvement, given transient mild reduction in LVEF, it was not deemed to be a major contributor to her shock physiology. Her shock presentation appeared predominately distributive in nature, with improvement only when systemic steroids were administered. A cardiogenic component was considered, but based on her examination findings, echocardiogram, and improvement without inotropic medications typically used for cardiogenic shock, it was eventually felt less likely. She continued to improve with sole steroid therapy long after antibiotics, which were briefly administered, were discontinued following extensive negative inflammatory and microbiological testing. Her LVEF improved on follow-up echocardiogram as well.

Guidelines for the treatment regimen and steroid dosing for severe DRESS are not established, but high-dose corticosteroids with a prolonged taper of weeks to months is believed to be ideal in cases of severe DRESS, which is characterized by major organ involvement, as proposed by a consensus statement [13]. The taper is believed to reduce the incidence of relapse or refractory presentations that can occur [13,14]. However, high-dose prolonged corticosteroids can be associated with adverse effects poorly tolerated by patients, such as heart failure exacerbation in our patient, in addition to the risk of CMV reactivation and severe systemic infections [2,3,15]. Further studies will be needed to create standard guidelines for the duration of systemic corticosteroid therapy and to determine if they can be combined with topical corticosteroid therapy in patients with severe DRESS syndrome at risk for adverse effects from systemic corticosteroids.

A third learning point we wish to add to the literature is the presentation of vancomycin-associated DRESS syndrome requiring ICU management, which is rare, but is associated with a higher likelihood of kidney impairment that may precede the onset of symptoms, and in DRESS presents as acute interstitial nephritis and/or acute tubular necrosis [1,5–17]. Instances of kidney injury preceding the rash in DRESS have been rarely noted [18]. We establish vancomycin as the likely culprit for our patient’s presentation for a few reasons. First, she was exposed to this medication the longest; she received vancomycin for 22 days of the 36 days she was actively on antibiotics. It was also the sole antibiotic she continued for an additional 8 days following discontinuation of gentamicin before the onset of symptoms. Second, of the medications she received, vancomycin was the antibiotic with the highest association with DRESS [1,19]. Finally, her Naranjo adverse drug reaction probability scale resulted “probable” with a score of 8 [20], based on answers of “Yes” on questions 1, 2, 3, 7, and 10; “No” to question 5; and “Do not know” to questions 4, 6, 8, and 9 [20].

Patients with DRESS syndrome can present with a modest increase in creatinine and blood urea nitrogen with proteinuria, with resolution after stopping the inciting medication [1]. However, their condition can progress to severe kidney failure, especially in the presence of viral reactivation and without prompt initiation of steroid management [1,4,6]. Renal replacement therapy and kidney biopsy were foregone in our case, given the improvement with prompt systemic corticosteroid treatment. Her gastrointestinal symptoms were rare manifestations of DRESS syndrome, although they improved with corticosteroids as well [5].

DRESS syndrome is marked by significant morbidity and mortality, reported up to 10%, primarily due to organ-failure complications, including liver failure, kidney failure, and myocarditis [1–3,21,22]. Prompt recognition and treatment are necessary to improve outcomes in these patients. We present this case to add knowledge on the disease process of DRESS syndrome in this patient, particularly pointing to the delayed hematologic response despite treatment initiation and distributive shock-like presentation.

Conclusions

This case highlights that critically ill patients presenting with a concerning widespread rash, hemodynamic instability, shock, and organ dysfunction should raise a suspicion of severe DRESS syndrome in the presence of potentially inciting medications. Prompt initiation of high-dose corticosteroids while treating other possible illnesses and awaiting further investigations to confirm the diagnosis may improve outcomes. We also highlight that observable clinical improvement should take precedence in the early stages of systemic steroid therapy, as eosinophilia and lymphocytosis can lag behind clinical progress. Further research is needed to establish appropriate treatment guidelines on the route, choice, dosage, and duration of treatment for severe DRESS syndrome.