Overt cytomegalovirus (CMV) disease is a serious viral infection that usually occurs in immunocompromised patients but rarely in immunocompetent patients. Cutaneous lesions, albeit rare, occur as late systemic manifestations of CMV infections and are usually fatal.
We describe 2 patients with drug-induced hypersensitivity syndrome (one end of a spectrum of severe drug eruptions) who subsequently developed cutaneous CMV ulcers at unusual sites, such as the trunk; this occurrence was immediately followed by gastrointestinal manifestations, which were fatal in 1 patient. To identify factors predictive of CMV disease, we retrospectively investigated the prevalence of CMV reactivation during drug-induced hypersensitivity syndrome in 18 patients. In this analysis, patients were divided into 2 groups depending on the positivity of CMV DNA in the blood.
Older and male patients with antecedent high human herpesvirus 6 DNA loads are at risk for CMV disease irrespective of corticosteroid administration. A rapid reduction in white blood cell numbers is also predictive of the onset of CMV disease.
Overt cytomegalovirus (CMV) disease, predominantly induced by reactivation of latent CMV, can be produced in an immunosuppressed host, such as organ transplant recipients, patients with AIDS, and those receiving immunosuppressive agents,1 but rarely in immunocompetent individuals. Although CMV disease in an immunosuppressive setting usually presents as visceral disease ranging from pneumonia to various other, widely disseminated, diseases,2 cutaneous manifestations are rare and variable; they include skin ulcerations, morbilliform eruption, purpura, vesiculobullous lesions, nodules, papular eruptions, and verrucous lesions, regardless of whether the CMV is specific or nonspecific.3- 6 These lesions occur as late systemic manifestations of CMV infections and are usually fatal.7- 9 Because the localized CMV ulceration usually seen in these patients has a predilection for the genital or perineal area,10 cutaneous ulcers located in other areas are not usually regarded as signs of cutaneous CMV infection. In particular, the development of cutaneous CMV ulcers on the trunk is rare in the human immunodeficiency virus–negative population.11 We describe 2 patients with drug-induced hypersensitivity syndrome (DIHS), a life-threatening multiorgan system reaction caused by a few drugs,12- 14 who subsequently developed cutaneous CMV ulcers on the trunk. This event was eventually followed by the development of gastrointestinal manifestations, which were fatal in one patient but not in the other. On the basis of the severity of complications caused by CMV reactivations, we retrospectively analyzed factors involved in the development of CMV disease in 18 patients with DIHS treated at Kyorin University Hospital.
A 74-year-old man had a 3-week history of progressively worsening generalized erythematous rashes. Seven weeks earlier, he had been prescribed mexiletine hydrochloride, 100 mg/d, for arrhythmia. On day 31 of medication use, the eruption began with erythema on his chest and gradually worsened during the next 2 weeks. Four days after the patient stopped treatment with mexiletine, the eruption rapidly spread across the trunk and extremities and was accompanied by a high-grade fever. He was admitted to the hospital with suspicion of having DIHS. Laboratory tests revealed leukocytosis (white blood cell count, 14 500/μL [to convert to ×109 per liter, multiply by 0.001] [reference range, 3500-8000/μL]), with eosinophilia of 17% (to convert to a proportion of 1.0, multiply by 0.01) and atypical lymphocytosis of 5% (to convert to a proportion of 1.0, multiply by 0.01), and liver dysfunction. The medical history of the patient was significant for coronary artery disease since 2001, which had required percutaneous coronary intervention.
The diagnosis of DIHS was made, and oral prednisolone (50 mg/d) therapy was begun. One week after starting systemic prednisolone therapy, there was significant improvement in his condition, and the erythematous rashes faded. On hospital day 16, 2 days after the oral prednisolone dose was tapered to 40 mg/d, he developed multiple 8- to 10-mm ulcerated erythematous plaques and papules with raised borders on his trunk (Figure 1). The eruption began suddenly, and the papules were distributed mainly on the upper back. Skin biopsy showed cytomegalic cells with a characteristic “owl's eye” intranuclear inclusion in the upper dermis (Figure 2A). The CMV infection was confirmed by the use of immunohistochemical analysis (CMV monoclonal antibody) (Dako, Cambridgeshire, England) (Figure 2B). Because his ulcerations did not improve with oral prednisolone therapy, intravenous immunoglobulin (0.1 g/kg/d) was administered, with significant improvement in his ulcerations. After the identification of CMV infection in the biopsy specimens of these cutaneous ulcers, treatment with ganciclovir (200 mg/d intravenously) was added on hospital day 50, and the oral prednisolone dose was gradually tapered to prevent relapse of various symptoms of DIHS.
Figure 1. Multiple ulcerated erythematous papules distributed across the upper back (case 1). The inset shows a close-up view of the papules.
Figure 2. Histologic and immunohistochemical findings on the border of the ulcer. A, Microscopic examination shows an acanthotic epidermis adjacent to central epidermal necrosis and a superficial perivascular infiltrate of lymphocytes and neutrophils (hematoxylin-eosin, original magnification ×40). The inset shows a higher magnification (×640) of the eosinophilic intranuclear “owl's eye” inclusion surrounded by a clear halo that sharply demarcates it from the nuclear membrane. Skin biopsy of ulcerated erythematous papules on the trunk shows cytomegalic cells with a characteristic “owl's eye” intranuclear inclusion in the upper dermis. B, Immunohistochemical detection of cytomegalovirus antigens. (cytomegalovirus monoclonal antibody, original magnification ×40). The inset shows monoclonal antibody for cytomegalovirus stains infiltrating cells around the blood vessels (original magnification ×160).
Although the ulcers showed gradual signs of healing, the patient noticed abdominal distention and lower back numbness, followed by abdominal pain on hospital day 47. On hospital day 61, he suddenly experienced hemorrhagic shock caused by gastrointestinal bleeding, which indicated the diagnosis of CMV enterocolitis; respiratory insufficiency and unconsciousness followed. He died of respiratory failure on day 84 of hospitalization. The clinical course and laboratory findings are summarized in Figure 3. A brief description of the sequential herpesvirus reactivation observed in this patient has been previously published.15
Figure 3. Clinical course and laboratory findings of case 1. CF indicates complement fixation; CMV, cytomegalovirus; EBV, Epstein-Barr virus; EIA, enzyme-based immunoassay; FA, fluorescent antibody technique; HHV-6, human herpesvirus 6; and WBC, white blood cell. To convert platelet count to ×109 per liter, multiply by 1.0; WBC count to ×109 per liter, multiply by 0.001.
An 81-year-old man was referred to Kyorin University Hospital because of a 1-week history of fever and itchy generalized erythematous rashes. One month before the eruption appeared, the patient had begun to take allopurinol, 300 mg/d, for hyperuricemia. The eruption began on the neck and chest but quickly spread across the entire body and was accompanied by a high-grade fever.
On examination, his temperature was 38.3°C and his white blood cell count was 14 200/μL, with eosinophilia of 28% without any atypical lymphocytes. Renal function tests revealed a serum creatinine level of 33.7 mg/dL (to convert to micromoles per liter, multiply by 88.4) (reference range, <22.0 mg/dL) and a serum urea nitrogen level of 34 mg/dL (to convert to millimoles per liter, multiply by 0.357) (reference range, 10-24 mg/dL). Skin examination revealed a widespread maculopapular eruption across the entire body that coalesced into purpuric erythematous plaques on the lower legs. The face was edematous and exudative, with yellowish small crusts. The suspected diagnosis was DIHS. Allopurinol therapy was discontinued on day 1 of hospitalization. Corticosteroids were withheld because of the patient’s history of hepatitis C virus infection due to blood transfusion, and he was treated with supportive therapy. Fever persisted, however, and his physical status deteriorated during the first 12 days of hospitalization. From days 12 to 25 of hospital admission, the patient received intravenous immunoglobulin (0.05 g/kg/d); his fever and skin eruptions gradually improved.
On hospital day 25, he developed a 6-mm-diameter red papule with central ulceration and urticarial erythematous lesions on his trunk. Skin biopsy of the papule taken from the trunk showed perivascular lymphohistiocytic infiltration in the dermis; cytomegalovirus antigens were detected in mononuclear cells in the upper dermis by means of immunohistochemical analysis. On the same day, his hemoglobin level suddenly decreased from 9.0 to 6.9 g/dL (to convert to grams per liter, multiply by 10.0). Emergency endoscopic examination revealed gastric “punched-out” ulcers (Figure 4). Endoscopic clipping and blood transfusion were performed immediately. On the basis of these findings, cutaneous CMV infection probably associated with CMV gastritis was diagnosed. Treatment with ganciclovir, 200 mg/d, was started. Cutaneous CMV ulcers and gastrointestinal bleeding improved after 2 weeks; the leukocyte CMV load decreased from 3.2 × 103 per 106 leukocytes to undetectable levels, and no CMV antigenemia was detected 1 month after hospital admission.
Figure 4. Arterial bleeding from “punched-out” gastric ulcerations on endoscopic examination (patient 2).
On the basis of the severity of complications caused by CMV reactivation, we reasoned that a retrospective analysis should be performed of patients who met the full criteria for DIHS.14 Between January 1, 2002, and December 31, 2006, 18 patients (10 men and 8 women; age range, 24-81 years; mean [SD] age, 50.6 [4.2] years) who developed DIHS and were treated at Kyorin University Hospital were enrolled in this study. This study was approved by the institutional review board at Kyorin University School of Medicine. Eighteen patients with DIHS were CMV seropositive and were examined for CMV load in sequential blood samples by means of polymerase chain reaction (PCR) assay at biweekly intervals for 10 weeks after onset; this was performed as part of a standard operating procedure for detecting sequential herpesvirus reactivation at the Department of Dermatology, Kyorin University School of Medicine, to analyze the temporal appearance of and complications caused by CMV reactivation. Overall, 6 of 18 patients (33%) tested were positive for CMV DNA in the blood by means of quantitative PCR assay, whereas 12 remained quantitatively PCR assay negative during surveillance, and none of these patients had evidence of CMV disease. The 6 patients in whom CMV DNA was detected at least once were included in the definition of “CMV DNA–positive DIHS.” These patients were compared with the 12 patients in whom CMV DNA was not detected, defined as “CMV DNA–negative DIHS.” On average, treatment with systemic prednisolone was initiated 3 to 5 days after the onset of symptoms suggestive of DIHS; the initial dose of prednisolone used was 0.8 to 1.0 mg/kg/d. The prednisolone dose was tapered to 50% in 6 weeks and to zero in 3 months gradually after full control was achieved. Results were analyzed for statistical significance by the use of the paired t test and Microsoft Excel (Microsoft Corporation, Redmond, Washington). Differences between groups were considered significant at P < .05.
The results of this retrospective analysis are given in Table 1 and Table 2. Patients with CMV DNA–positive DIHS had an older mean [SD] age at onset than did those with CMV DNA–negative DIHS (62.0 [7.8] vs 45.4 [4.2] years), although not significant, and a male predominance. Human herpesvirus 6 (HHV-6) reactivations were detected by means of PCR assay 3 to 4 weeks after DIHS onset in both groups. However, HHV-6 DNA loads detected were significantly higher in CMV DNA–positive DIHS than in CMV DNA–negative DIHS (1.5 × 104 vs 7.5 × 101, P = .01). No significant difference was detected in the interval between onset and HHV-6 reactivation. In 4 of the 6 patients with CMV DNA–positive DIHS, CMV DNA was initially detected 4 to 5 weeks after onset, but in 2 patients, the onset of CMV DNAemia occurred at 7 weeks. All of the patients with CMV DNA–positive DIHS were symptomatic, ranging from a low-grade fever to lumbago on detection of CMV DNA in the blood. Four patients in the CMV DNA–positive DIHS group (67%) were receiving immunosuppressive treatment with prednisolone, and 5 patients in the CMV DNA–negative DIHS group (42%) were receiving prednisolone. These results indicate that both groups included patients whose disease at presentation was sufficiently severe to warrant systemic corticosteroids. The median interval between initiation of prednisolone therapy and the onset of CMV disease was 22 days (range, 14-49 days) in the CMV DNA–positive group. Gastrointestinal CMV disease was observed in the 2 cases presented herein only immediately after detection of CMV DNA in the blood. Quantitation of PCR assay demonstrated a relationship between CMV load and disease severity: the highest level of CMV DNA (3.4 × 103 genomes per 106 leukocytes) was detected in case 1, when the patient developed fatal gastrointestinal CMV disease. White blood cell counts at the time of CMV reactivation were significantly lower than were those 1 week before CMV reactivation in CMV DNA-positive DIHS (Figure 5).
Figure 5. Alterations in white blood cell counts 1 week before and at the time of cytomegalovirus reactivation in patients with cytomegalovirus DNA–positive drug-induced hypersensitivity syndrome. The patient numbers correspond to those in Table 1. *P = .04 (paired t test). To convert white blood cell count to ×109 per liter, multiply by 0.001.
Because it is widely believed that cutaneous CMV disease arises from reactivation of a local latent virus or by autoinoculation in periorificial areas by fecal, urinary, or salivary shedding of CMV,10 CMV ulcers limited to unusual sites, such as the trunk, will go unrecognized unless a search is made to identify relevant pathogens. These cases indicate the need for monitoring of CMV reactivation even in immunocompetent patients, particularly when unexplained ulcers suddenly develop in patients with DIHS, and suggest that a high index of suspicion and early intervention may decrease morbidity, as in case 2. These cases raise the question of why CMV ulcers were exclusively located on the trunk and shoulders, where CMV ulcers are rarely seen, but not in the anogenital sites. Although comprehensive explanations are unavailable, we suggest the presence of unrelated preexisting factors that contribute to CMV reactivation in these lesions, which may increase the risk of ulceration. In view of the previous observations that anogenital ulcers frequently develop after erosive lesions associated with herpes simplex virus infection in human immunodeficiency virus–infected patients,16 a preceding herpesvirus reactivation may play a pivotal role in CMV reactivation. Given the potential interaction of HHV-6 with other herpesviruses in DIHS and the ability to activate Epstein-Barr virus, CMV, and human papillomavirus,17,18 it is attractive to suppose that the preceding HHV-6 reactivation may have induced CMV reactivation, with the result of the sequential development of CMV ulcers at a particular anatomical location. Indeed, the present sequential analyses of patients with DIHS by means of real-time PCR revealed a good correlation between the degree of preceding HHV-6 DNAemia and a clinically significant CMV reactivation as evidenced by CMV antigenemia or a dramatic increase in leukocyte CMV loads. Other studies19 in the setting of bone marrow transplantation also demonstrated that CMV reactivation is consistently preceded by HHV-6 reactivation. If so, patients with DIHS, in which HHV-6 reactivation is commonly seen, would be at risk for subsequent CMV disease.
Another intriguing question about these cases is which factors are responsible for the development of CMV ulcers, which usually occur in the setting of immunosuppression. The risk factors associated with CMV disease are those that affect cell-mediated immunity because cell-mediated immunity is the critical host defense for preventing CMV reactivation. Could the widespread reactivation of CMV be a mere complication of treatment with oral prednisolone? In fact, in case 1, overt CMV disease developed approximately 2 weeks after initiation of oral prednisolone therapy. However, after careful consideration of the timing of overt CMV ulcers, we noted that the CMV ulcers developed soon after tapering the dose of oral prednisolone. Although it is clear that long-term immunosuppression due to therapy with prednisolone will place a patient at risk for CMV reactivation, the present patient (case 1) had been taking prednisolone for only 2 weeks before the onset of CMV ulcers: such short-term prednisolone therapy is unlikely to be the major cause of CMV disease. Indeed, recent investigators20 found no significant adverse outcomes associated with short-term use of prednisolone in advanced human immunodeficiency virus infection. Alternatively, this patient may have had a background of quiescent CMV disease before the onset of DIHS. Cytomegalovirus infection may have already been established before the onset, although it had not been clinically recognized.
Unrecognized CMV infection in immunocompromised patients may often lead to exacerbation of their underlying diseases and even death, as with patient 1. Because gastrointestinal CMV diseases, in particular, are unpredictable and often take a rapidly fatal course in these settings, a high index of suspicion and early recognition are needed for efficient management of patients who undergo immunosuppressive therapy. Despite the documentation of a range of cutaneous and gastrointestinal manifestations, the synchronous occurrence of skin ulcers and gastrointestinal ulcers as shown in patients 1 and 2 herein has rarely been reported. The present cases indicate that cutaneous ulcers that occur in an unusual site as a relatively late systemic manifestation of DIHS would usually portend a fatal course. According to the retrospective study, CMV disease or CMV reactivation would occur during a predictable time course: in most patients with CMV DNA–positive DIHS, CMV DNA was detected during a critical 4- to 5-week period after onset, when patients often receive immunosuppressive agents and are at risk for infection. Consistent with this observation, Seishima et al21 noted that CMV reactivation in all 7 patients with DIHS detected on days 32 to 51 after onset, a time that corresponded to 10 to 21 days after HHV-6 reactivation; however, in these patients, no fatal CMV disease developed, and risk factors for fatal disease were not provided. The results of the retrospective study indicate that aged, particularly older than 60 years, and male patients with DIHS are at risk for overt CMV disease approximately 4 to 5 weeks after onset and that a rapid reduction in white blood cell counts may be a useful predictor of CMV disease. Thus, we, for the first time, to our knowledge, provide clinical factors predictive of the onset of fatal gastrointestinal CMV disease in settings that are not overtly immunocompromised.
Given the extremely high mortality rate of this infection, CMV disease, in particular, gastrointestinal CMV disease, must be ruled out in patients with DIHS, who developed inconspicuous ulcers 4 to 5 weeks after the onset of DIHS, coincident with a rapid reduction in white blood cell counts. Whether earlier treatment with ganciclovir would have altered the fate of these patients with CMV reactivation is unclear because previous articles22 described that many immunocompromised patients who showed cutaneous ulcers as a late systemic manifestation died within 2 weeks after onset. Nevertheless, early consideration and identification of CMV reactivation by means of PCR analyses are crucial for the establishment of the diagnosis in otherwise difficult-to-treat ulcers and for the improvement of the prognosis.
Correspondence: Yusuke Asano, MD, Department of Dermatology, Kyorin University School of Medicine, 6-20-2 Shinkawa Mitaka, Tokyo 181-8611, Japan (firstname.lastname@example.org).
Accepted for Publication: February 11, 2009.
Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Asano, Kano, and Shiohara. Acquisition of data: Asano, Kagawa, Kano, and Shiohara. Analysis and interpretation of data: Asano, Kano, and Shiohara. Drafting of the manuscript: Asano. Critical revision of the manuscript for important intellectual content: Asano, Kagawa, Kano, and Shiohara. Statistical analysis: Kano and Shiohara. Obtained funding: Kano and Shiohara. Administrative, technical, and material support: Kano. Study supervision: Shiohara.
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by a research grant-in-aid for scientific research from the Ministry of Education, Sports, Science, and Culture of Japan; by a health and labor sciences research grant from the Ministry of Health, Labor, and Welfare ofJapan; and by the Japanese Research Committee on Severe Cutaneous Adverse Reaction.
Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
Asano Y, Kagawa H, Kano Y, Shiohara T. Cytomegalovirus Disease During Severe Drug EruptionsReport of 2 Cases and Retrospective Study of 18 Patients With Drug-Induced Hypersensitivity Syndrome. Arch Dermatol. 2009;145(9):1030–1036. doi:10.1001/archdermatol.2009.195