Shock State

An Unrecognized and Underestimated Presentation of Drug Reaction With Eosinophilia and Systemic Symptoms

Abstract

Some patients with drug reaction with eosinophilia and systemic symptoms (DRESS) are probably admitted in intensive care unit (ICU), but data concerning their clinical features at admission are scarce. Therefore, in the present study, we used a clinical network of French intensivists to study the clinical features and evolution of DRESS patients hospitalized in ICU. A national, retrospective, multicenter study collected DRESS cases hospitalized in ICU for DRESS from 2000 to end of 2011. All files were analyzed through the RegiSCAR scoring system as “no,” “possible,” “probable,” or “definite” DRESS. Patients were included only if they had a probable or definite DRESS. Demographic, hemodynamic, biological, and infectious data were recorded. Twenty-one patients were included. Hospital mortality was 10 (47%) of 21, and 16 of 21 patients had on admission a shock state necessitating vasopressor agents. Echocardiographic ejection fraction in shock patients was depressed (47% ± 13%). Mechanical ventilation was required in 13 of 21 cases. Hepatic failure was observed in 11 of 21 cases, acute renal failure in 18 of 20 cases, and lactic acidosis in 12 of 20 patients. Initial bacteriology was negative in all patients. Human herpesvirus reactivations were found in five of 15 cases. In conclusion, shock without bacteriological documentation associated with multiple organ failure is the most common presentation of DRESS at admission in ICU and is associated with a higher mortality than previously described.

INTRODUCTION

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare life-threatening disorder usually associating exanthema with multiple organ failure due to human herpesvirus (HHV) reactivations and hypersensitivity to drugs.

Its estimated incidence ranges from 1/1,000 to 1/10,000 drug exposures (¹). Clinical features similar to those of sepsis include generalized erythematous exanthema, frequent fever, and internal organ involvement including liver, renal, and heart dysfunction, but with frequent eosinophilia and facial edema. Symptoms appear 2 to 6 weeks after the initiation of the responsible drug (²). Importantly, DRESS visceral manifestations have a prolonged course of more than 2 weeks after the drug is stopped (³). Consequently, DRESS remains an unfamiliar and probably underdiagnosed disease for nondermatologists. Moreover, the most severe cases have not been specifically studied in the literature. This syndrome has a 10% mortality rate, most commonly from fulminant hepatitis with hepatic necrosis (²). In the only article dedicated to DRESS patients admitted to intensive care unit (ICU), mortality was 20%, which is elevated when compared with the 10% reported overall mortality of DRESS (⁴). Nevertheless, data regarding clinical features at admission in ICU of patients with DRESS are scarce (^{4, 5}). Particularly, the incidence of shock appears to be low (2/15 in the study of Eshki et al. (⁶)), a surprising fact in view of the physiopathology of DRESS. In the present study, we used a clinical network of French intensivists to study the clinical features and evolution of DRESS patients hospitalized in ICU.

PATIENTS AND METHODS

Population and study design

In a retrospective and multicenter study, all 51 French university teaching hospital ICUs were contacted by e-mail. Potential DRESS cases occurring between January 2000 and January 2011 were analyzed by the same investigator and identified through a computer search based on primary and associated diagnoses including the following terms: DRESS, toxiderma, drug eruptions, drug hypersensitivity, drug toxicity, eosinophilia. All of the centers use automatic analyzers that provide eosinophil counts for each sample. Overlap with the other previous retrospective French study (⁶) or case report (⁷) was verified and eliminated because of nonconcordance for age and sex. The “Comité de Protection des Personnes EST III” waived the need for informed consent, deeming the use of these databases not to be human subject research requiring approval.

The RegiSCAR scoring system (Table 1), which grades DRESS cases as “no,” “possible,” “probable,” or “definite,” was used to classify cases, and only patients with a score of greater than 3 (probable or definite DRESS) were included (⁸).

Table 1: Scoring system for DRESS case: definite, probable, possible, or no case

Data collection

In each clinical record, the following data were collected if available at admission in ICU: age, sex, Simplified Acute Physiology Score II (SAPS II), Sequential Organ Failure Assessment, hemodynamic status, organ involvement, mortality, duration of ICU stay, and mechanical ventilation. Shock state at admission was defined by the need of vasopressor infusion and an elevated lactate level. In all cases, this definition was confirmed in the hospital report by the physician in charge. Acute renal failure was defined using RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) classification (⁹). Chronology and responsibility of each drug intake were studied, and the delay between the occurrence of the rash, the peak of eosinophilia, and the initiation of the culprit drug was calculated. Biological findings included blood cultures, leukocyte count, hepatic status, prothrombin time, serum creatinine, lactatemia, and, when available, HHV reactivation studied by polymerase chain reaction.

Statistical analysis

Statistics were performed using SAS v9.3 (SAS Institute Inc, Cary, NC). The two-tailed significance level was set at P < 0.05. Continuous variables are presented as mean ± SD, and categorical variables as percentage. Univariate comparisons were carried out using the Mann-Whitney nonparametric test.

RESULTS

Twenty-one patients were included (Fig. 1). Patients were initially admitted in a varied picture of multiple organ failures associated with shock (15/21), acute renal failure (5/21), acute hepatitis (4/21), and status epilepticus (2/21). On admission, all patients had generalized erythematous exanthema and fever.

Fig. 1: Flow chart.

Mean age was 55 ± 17 years with a mean SAPS II score of 55 ± 11. Shock patients had a higher SAPS II score (51 ± 19) when compared with nonshock patients (32 ± 17) (P < 0.01).

Potential culprit drugs

β-Lactam antibiotics (7/21), glycopeptides (2/21), anticonvulsants (6/21), allopurinol (4/21), sulfasalazine (1/21), and deferasirox (1/21) were strongly suspected to be at the origin of DRESS. All patients under allopurinol and five of six patients under antiepileptics developed a DRESS with shock state.

Hemodynamic data

When admitted in ICU, 15 of 21 patients had a hemodynamic failure requiring immediate vasopressor support (norepinephrine or epinephrine) associated with dobutamine in five cases. Six patients exhibited low diastolic pressure (<40 mmHg) and hyperkinetic state under catecholamine and were classified as vasoplegic shock. For the remaining 10 patients treated with vasopressor, no differences were found in diastolic pressure when compared with nonshock patients (Table 1). Ejection fraction measured in shock patients was 47% ± 13% versus 67% ± 15% in nonshock patients. On admission, shock patients had a severe hyperlactatemia (5.8 ± 1.6 mmol/L) when compared with nonshock patients (2.6 ± 1.2 mmol/L) (P < 0.05) (Tables 2 and 3).

Table 2: Descriptive data of patients with DRESS admitted to ICU

Table 3: Comparison between shock and nonshock patients

Other organ failures on admission

Mechanical ventilation was required in 13 (61%) of 21 cases. Among the 21 patients, hepatic failure was observed in 11 of 21 cases (aspartate aminotransferase: 513 ± 85 UI/L; alanine aminotransferase: 343 ± 80 UI/L; prothrombin time: 49% ± 20%; total bilirubinemia: 149 ± 117 μmol/L) without differences between shock and nonshock patients, and acute renal failure in 18 of 21 cases (creatinine: 4 ± 0.7 mg/dL) without differences between shock and nonshock patients. Nevertheless, dialysis or continuous hemofiltration was used in 11 of 16 shock patients and one of five nonshock patients (P < 0.01) (Tables 1 and 2).

Infectious disease documentation

Bacteriology at admission (sputum, urine, and blood culture) was negative in all patients. Reactivations of HHV were studied in 15s patients with positive results on polymerase chain reaction in five patients (three for HHV-6, one for cytomegalovirus, one for herpes simplex virus 1). There was no difference in biological assessment between shock and nonshock patients (Tables 1 and 2).

Treatments

All shock patients were treated with hydrocortisone (200–300 mg/d). Eleven of 21 patients (9/16 in shock group and 2/5 in nonshock group) were treated with systemic glucocorticoid. Three patients were treated with acyclovir and two with ganciclovir. Two patients in the shock group received intravenous gammaglobulins.

Evolution

Patients with shock had a statistically significant higher mortality (56% vs. 16% in nonshock patients, P = 0.04). The median length of stay in the ICU was 15 days (2–55 days) for nonsurvivors and 5 days (3–18 days) for survivors. One patient died of refractory shock, and the others died of multiple organ failure.

DISCUSSION

The main result of the present study is that DRESS patients admitted to ICU have a higher mortality rate (47%) compared with previously published data (10%) (²). This mortality rate was similar to that found in the most recent literature of shock (42%) (⁹). This is likely due to a high incidence of shock associated with multiple organ failure in this highly selected population. The high incidence of multiple organ failure could be attributed to the physiopathology of severe DRESS, which by definition includes multiple organ involvement. In this relatively small population, it was not possible to find a relationship between survival status and the initial culprit drug as previously described (¹⁰). Nevertheless, all patients under allopurinol treatment developed a DRESS with shock state (⁶).

In the present study, shock without bacteriological documentation was the most common presentation. Six of 16 patients had a very low diastolic arterial pressure despite vasopressor therapy, which is a good indicator of vasoplegia and hyporesponsiveness to vasopressor (¹¹). Similar to the study of Ben M’rad et al. (¹²), myocardial dysfunction was also reported in this study. From these retrospective data, it is impossible to definitively assess the mechanisms associated with shock and to differentiate pure vasoplegia from “septic-like” cardiomyopathy or DRESS-associated myocardial involvement (acute necrotizing eosinophilic myocarditis) (¹³). Interestingly, in a recent retrospective work including 15 severe DRESS patients, Eshki et al. (⁶) also reported a high incidence of multiple organ failure but with only two shock states and a lower mortality. Of particular interest, the mortality rate of our patients without shock (16%) was comparable to that observed in the study of Eshki et al. Therefore, the high mortality rate reported in the present work compared with the literature could be partially explained by the high incidence of shock in the present series (¹⁴).

Pathomechanisms involved in DRESS are currently not elucidated. Drug-induced transient immunosuppression could promote herpes family virus reactivation, possibly through genetic predispositions (¹⁵). In DRESS, herpes family virus reactivation has been reported in 76% of patients in which the main response may be related to an expansion of CD8⁺ T cells directed against Epstein-Barr virus or HHV-6 (^{16, 17}). Indeed, drug hypersensitivity and virus reactivations lead to massive proinflammatory cytokine release (¹⁸). This cytokine storm similar to that of septic shock and ischemia-reperfusion could therefore be involved in the pathomechanisms of shock state and myocardial dysfunction during DRESS (¹³).

In the present study, a high incidence of multiple organ failure was also observed in these patients without any differences in shock and nonshock patients. Liver injury could be due to eosinophilic infiltration induced by interleukin 5 or an overactivation of macrophages and T cells producing a massive release of cytokines (^{14, 19}). Likewise, the severity of renal failure in ICU-admitted patients may be related to the cytokine storm and exacerbated by shock-induced renal hypoperfusion. The importance of shock versus a specific DRESS-associated involvement is highlighted by the high incidence of renal extracorporeal epuration in shock patients.

In this preliminary work, any conclusion or advice to improve the management of these patients must be cautious. In our experience, a patient admitted to ICU for shock state with a suspected or confirmed diagnosis of DRESS should be managed as usual and most often as a septic shock according to guidelines. However, a multidisciplinary approach including dermatologists is strongly advised. The latter will establish the accountability of the drugs delivered in the past 2 months and confirm the diagnosis of DRESS. It is common that not only one but several treatments (including at times required antibiotics) are imputable and subsequently proscribed. After excluding as much as possible an infectious issue, the most probable causative drug should be discontinued, and a treatment with corticosteroids collegially and urgently discussed. The treatment of a possible viral reactivation remains debated (⁴).

Several limitations should be acknowledged in this retrospective and likely nonexhaustive study, which involved a heterogeneous management process. Thus, we could not provide information regarding initial volume status and fluid resuscitation. From the present data, it is difficult to accurately assess shock mechanism. Pure septic shock is unlikely because all bacteriologic samples were negative; pure myocardial failure was also unlikely because ejection fraction, when measured, was only slightly decreased, and only five patients were treated with dobutamine. Finally, the limited number of cases did not allow us to determine whether certain predisposing factors were at play for DRESS to be complicated by a shock state. Only a prospective, multicenter study involving a network of dermatologists and intensivists would enable to confirm these preliminary results.

CONCLUSIONS

In patients admitted to ICU with a diagnosis of DRESS, the most common clinical picture is shock with absence of any bacteriological process. As the diagnosis of DRESS is difficult to confirm, it is possible that this previously unreported high frequency of shock in patients with DRESS has led to a misdiagnosis of this syndrome in patients hospitalized in ICU for shock. Similarly to septic shock recommendations, an early recognition of this rare syndrome is necessary to stop potential dangerous drugs and to precipitously initiate specific treatment (^{20, 21}).

ACKNOWLEDGMENTS

The authors thank the following French ICUs and physicians: Laurent Argaud, Medical Intensive Care Department, Edouard Herriot Hospital, Lyon; Jean Luc Dhiel, Medical Intensive Care Department, Georges Pompidou European Hospital, AP-HP, Paris; Alain Mercat, Medical Intensive Care and Hyperbaric Department, CHU d’Angers, Angers; Julien Maizel, Medical Intensive Care Department, CHU d’Amiens, Amiens; Jean François Timsit, Medical Intensive Care Department, CHU de Grenoble, Grenoble; and Bertrand Guidet, Medical Intensive Care Department, CHU Saint Antoine, AP-HP, Paris.