Fulminant Type 1 Diabetes Caused by DIHS Could Be Affected by the Reactivation of HHV-6

Abstract

Context

In the previous issue of this journal, we reported that the incidence of fulminant type 1 diabetes (FT1D) due to the drug-induced hypersensitivity syndrome (DIHS) in Japan is higher than that in the general population and is associated with HLAB62. On the other hand, the reactivation of human herpesvirus 6 (HHV-6), which has been reported to be associated with DIHS, was observed at a higher frequency, but its association with the development of FT1D was unclear.

Objective

We aimed to clarify the relationship between the onset of FT1D and the reactivation of HHV-6.

Methods

We conducted a literature search for cases of DIHS-induced FT1D in addition to previously reported cases and investigated the changes in the HHV-6 antibody titer before and after the onset of FT1D.

Results

The HHV-6 antibody titer was increased just before or after the onset of FT1D in all 8 cases. In 1 case, HHV-6 DNA was also identified shortly before the onset of FT1D.

Conclusion

These results indicate for the first time that the reactivation of HHV-6 is associated with the onset of FT1D caused by DIHS.

Fulminant type 1 diabetes (FT1D), a subtype of type 1 diabetes mellitus, is characterized by rapid onset, the absence of islet-associated autoantibodies, and the nearly complete destruction of islets. A nationwide survey conducted by the Japan Diabetes Society reported that FT1D accounts for about 20% of all cases of type 1 diabetes mellitus and that about 70% of patients with FT1D had common cold-like symptoms such as fever and abdominal symptoms and more than 98% had elevated levels of pancreatic enzymes such as amylase (1). We subsequently investigated viral antibody titers in paired sera at the onset of cases meeting the diagnostic criteria for FT1D. Several viruses were detected, but no specific virus has been detected to date (2).

Drug-induced hypersensitivity syndrome (DIHS) is a severe drug eruption characterized by a drug allergy and the reactivation of the human herpesvirus 6 (HHV-6) (3). It is characterized by a delayed onset that occurs 2 to 6 weeks after taking certain drugs, such as antiepileptic drugs, and the symptoms persist after discontinuation of the causative drug. It progresses to rapidly enlarging erythema, often erythroderma. Fever, hematologic abnormalities, enlarged lymph nodes, and liver damage are observed, leading to the reactivation of HHV-6. During the course of the disease, it is characterized by a variety of organ damage, including FT1D. An association between DIHS and HHV-6 virus was first reported by Descamps et al in 1997 (4); this was subsequently confirmed by Tohyama et al in 1998 (5) and Suzuki et al in 1998 (6). In 2007, Tohyama et al (3) reported on the detecting of flaring (fever) and liver damage in the early 2 to 4 weeks of DIHS onset and attributed these effects to the reactivation of the HHV-6 virus.

In the previous issue of this journal, we reported on the characteristics of 15 cases of FT1D that developed in DIHS (7). In this study, viral antibody assays showed that HHV-6 had been reactivated in 11 of 13 patients and the reactivation of cytomegalovirus (CMV) had occurred in 4 of 7 patients. However, the relationship between these viral reactivations and the development of FT1D was unclear. To clarify the relationship between the onset of FT1D and the reactivation of HHV-6 and CMV, we conducted a literature search and collected information on changes in HHV-6 and CMV antibody titers that occurred before and after the onset of FT1D.

Subjects and Methods

We conducted a literature search for Japanese patients with FT1D associated with DIHS using the diagnostic criteria of the Japan Diabetes Society (7) and the Japanese Dermatological Association (7) that appeared in a previous issue of this journal. The methodology used is shown in Fig. 1. The Ichushi-Web (Japan Medical Abstract Society) was searched, and 100 cases related to DIHS and FT1D that were published from 2003 to 2021 were identified. In the search, 82 cases were excluded from conference proceedings, review articles, etc., as shown in Fig. 1, and the remaining 18 cases that appeared as original articles were examined. Among these, we excluded 5 cases that did not meet the diagnostic criteria for FT1D, 2 cases that did not meet the diagnostic criteria for DIHS, 4 cases of non-HIV immune reconstitution inflammatory syndrome (IRIS), 1 case of type 1 diabetes that occurred before DIHS onset, and 1 case of CMV positive at 3 weeks after diabetic ketoacidosis (DKA), for a total of 13 cases. We then selected 5 cases with data on HHV-6 or CMV or both before and after the onset of FT1D. In addition, as shown in the lower right of Fig. 1, we included 3 more cases with data on HHV-6 or CMV or both before and after the onset of FT1D from a previous report (7) and analyzed a total of 8 cases, as shown in Fig. 1. Of these cases, 2 appeared in English-language publications (8, 9) and 6 appeared in Japanese-language publications (10-15). These 8 cases were examined carefully, and the results are briefly summarized and explained in the Case Records here. The progress of each case is shown in Fig. 2, and the clinical data are summarized in Table 1. The titles of the 2 Japanese papers with English abstracts (10, 15) were taken from the English abstracts, and the titles of the 4 Japanese papers without English abstracts (11-14) were translated into English.

Statistical analyses were performed with Fisher's exact test.

Case Records (Cases 1-8)

Case 1: (8) Fig. 2A

The patient was a 77-year-old woman. One month after receiving carbamazepine for neuralgia caused by a herpes virus infection, she developed generalized erythema, fever, and hepatic disorder. She was diagnosed with DIHS and hospitalized. After discontinuation of the carbamazepine and the administration of 20 mg of prednisolone, her skin rash improved and she was discharged from the hospital. However, the next day, 22 days after the diagnosis of DIHS, she developed thirst, abdominal discomfort, a coma, and DKA and was admitted to the emergency room. She had the typical symptoms for FT1D with blood glucose 1045 mg/dL, hemoglobin A1c (HbA1c) 5.9%, and blood C-peptide reactivity (CPR) less than 0.1 ng/mL (Fig. 2A- Case 1, Table 1). A polymerase chain reaction test using stored serum that was obtained 12 days after DIHS onset detected HHV-6 DNA, which then disappeared 1 month later. HHV-6 IgG antibodies, however, were detected at both time points. The reactivation of CMV was not determined. The patient developed hemolytic anemia at the same time as the onset of DIHS.

Case 2: (9) Fig. 2B

A 46-year-old man with type 2 diabetes mellitus was on gliclazide treatment and was started on mexiletine for diabetic neuropathy. Forty-one days later, a generalized skin rash, fever, and liver damage were observed. He was then diagnosed with DIHS and hospitalized. After hospitalization, he was started on 8 mg of betamethasone and subcutaneous insulin injection. The patient progressed well, but the insulin dose was increased despite the betamethasone reduction, and on day 22 of hospitalization, the insulin dose reached a maximum of 62 units/day compared to 2 mg of betamethasone (Fig. 2B, Case 2). On day 39 of hospitalization, the insulin dose was around 40 units/day for 0.5 mg of betamethasone; blood glucose was 203 mg/dL, HbA1c was 6.3%, and no C-peptide was detected in the blood (Table 1). Based on this, it is presumed that the time when the insulin dose reached the maximum despite the reduction of betamethasone on day 22 of hospitalization was the time when blood C-peptide was depleted, ie, the onset of FT1D from type 2 diabetes mellitus (16). The absence of DKA at onset may have been due to the fact that insulin was being administered; HHV-6 IgG antibody titer was 80-fold on day 17 and increased to 320-fold on day 39 after the onset of DIHS, a 4-fold increase. The reactivation of CMV was not determined.

Case 3: (10) Fig. 2C

The patient was a 61-year-old male. After 28 days of zonisamide administration for a seizure due to cerebral hemorrhage, he was hospitalized with a generalized skin rash, fever, and lymphadenopathy and was diagnosed with DIHS. On the 14th day after the onset of DIHS, he developed DKA due to FT1D (Fig. 2C- Case 3). Blood glucose was 966 mg/dL, HbA1c was 6.5%, and urinary CPR was 0.2 μg/day (Table 1). HHV-6 IgG antibodies increased markedly, from 80-fold on day 7 to 10 to 240-fold on day 24 after DIHS onset. On the other hand, CMV IgG antibodies were increased slightly later, 18-fold on day 17 and 114-fold on day 37 after the onset of DIHS.

Case 4: (11) (HHV-6 + CMV) Fig. 2D

The patient was a 46-year-old male. After 28 days of taking salazosulfapyridine for colitis, he was hospitalized with skin rash, fever, and lymphadenopathy and diagnosed with DIHS. After hospitalization, there was a flare-up of liver dysfunction and other symptoms, which resolved after the administration of dexamethasone and γ-globulin. Eight days later (35 days after the onset of DIHS), he suddenly developed DKA (Fig. 2D, Case 4). As shown in Table 1, he was diagnosed with FT1D with blood glucose 1400 mg/dL, HbA1c 5.6%, and urinary C-peptide <3.1 μg/day; HHV-6 IgG antibodies were 10-fold higher at the onset of DIHS and rapidly increased to 2560-fold at 27 days after the onset of DIHS (just prior to the onset of FT1D), while CMV antibodies were 11-fold higher at the onset of DIHS and CMV antigenaemia (pp65 antigen) was observed at 27 days after the onset of DIHS (just before the onset of FT1D).

Case 5: (12) Fig. 2E

The patient was a 19-year-old female. After 50 days of treatment with carbamazepine for schizophrenia, she was diagnosed with DIHS due to fever, erythema, and hepatic disorder and was started on hydrocortisone at 250 mg/day. After hospitalization, pulse therapy with methylprednisolone was administered, after which prednisolone 50 mg/day was started and the dosage was gradually decreased. The skin rash and liver lesions improved, and she was discharged on the 17th day of her illness. After discharge, on the 26th day of DIHS, she developed DKA and was admitted to the hospital as an emergency case (Fig. 2E, Case 5). As shown in Table 1, she was diagnosed with FT1D with blood glucose 732 mg/dL, HbA1c 7.1%, and blood CPR 0.08 ng/mL. HHV-6 IgG antibody was reactivated by 40-fold on day 4, 80-fold on day 33, and 160-fold on day 56 after the onset of DIHS; no CMV reactivation was observed.

Case 6: (13) Fig. 2F

The patient was a 68-year-old woman. Three weeks after receiving salazosulfapyridine for rheumatoid arthritis, she was admitted to the hospital with fever and generalized skin rash. On admission, she was found to have an increased white blood cell count, atypical lymphocytes, and liver dysfunction and was diagnosed with DIHS. After careful observation for complications such as diabetes mellitus, a sharp increase in blood amylase (433 IU/L) and trypsin (5330 ng/mL) was observed 31 days after admission, and a sharp increase in blood glucose (504 mg/dL) was observed on the following 32 days (Fig. 2F, Case 6, Table 1). As shown in Table 1, in spite of a normal pH of 7.44 for the arterial blood and a nearly normal HbA1c of 6.9% (6.1% on admission), blood CPR was depleted at 0.2 ng/mL, and the glutamic acid decarboxylas antibody was negative, indicating that FT1D had developed early. According to the author, he detected FT1D as early as possible, because of the prediction that the disease had developed and regular examination of blood chemistry. HHV-6 IgG antibodies were reactivated by 20-fold on day 6 and by 160-fold on day 32 after the onset of DIHS, but CMV was not reactivated.

Case 7: (14) Fig. 2G

A 62-year-old woman with type 2 diabetes mellitus was on mitiglinide treatment and started on mexiletine for diabetic neuropathy. After 22 days of treatment, fever and generalized erythema appeared, and she was diagnosed with DIHS. Nineteen days later, the patient was admitted to the hospital with thirst, decreased level of consciousness, and DKA (Fig. 2G, Case 7). Based on blood glucose 824 mg/mL, blood C-peptide 0.2 ng/mL, and HbA1c as high as 9.3% (Table 1), she was diagnosed with FT1D that had developed from type 2 diabetes (16). The HHV-6 IgG antibody was 160-fold higher on the 19th day after the onset of DIHS (when FT1D developed) and 2560-fold higher on the 34th day. The reactivation of CMV was not determined.

Case 8: (15) Fig. 2H

The patient was a 64-year-old male. While being treated for benign prostatic hyperplasia, he started taking sulfamethoxazole/trimethoprim for a urinary tract infection. Thirteen days later, he was hospitalized with a generalized skin rash, fever, increased white blood cell count, and liver dysfunction and was diagnosed with DIHS. On the 20th day of hospitalization, as shown in Fig. 2H (Case 8) and Table 1, DKA developed, blood glucose was 792 mg/dL, HbA1c was 7.3%, insulin secretion was depleted, GAD antibody was negative, and the patient was diagnosed with FT1D. HHV-6 IgG antibody was 20-fold higher on the first day of DIHS onset and 640-fold higher on the 14th day (just before the onset of FT1D). The reactivation of CMV was not determined. Six months after the onset of DIHS, the patient developed Hashimoto's disease.

Case summary

In case 1, HHV-6 DNA was detected just prior to the onset of FT1D, and HHV-6 antibodies were also detected before and after the onset. In cases 2, 3, 5, 6, and 7, HHV-6 antibody titers increased before and after the onset of FT1D. In cases 4 and 8, the HHV-6 antibody titer increased immediately prior to the onset of FT1D. In case 4, in addition to the HHV-6 antibody titer, CMV antigen was detected immediately prior to the onset of FT1D. In addition to case 4, the CMV antibody titers were increased in case 3 at 1 month after the onset of FT1D. Thus, an association between the onset of FT1D and HHV-6 was observed in all 8 cases. In case 2 and case 7, FT1D developed from T2D.

Discussion

In the present study, we analyzed 8 patients who developed FT1D early after the onset of DIHS. The findings indicated an association between an increase in the antibody titer of the HHV-6 virus and the development of FT1D in all 8 cases as shown in Fig. 2. It should be noted here that Sekine et al (8) reported the presence of HHV-6 viral DNA in the blood immediately before the onset of FT1D (case 1). These results suggest that the reactivation of the HHV-6 virus could be a possible cause of the FT1D seen in the early stage of DIHS. These conclusions are consistent with findings reported by Tohyama et al (3) on liver injury and the reactivation of the HHV-6 virus and by Fujino et al (17) and Masaki et al (18) on encephalitis and HHV-6 virus reactivation in early DIHS onset. The present study is the first report to clarify the association between HHV-6 and the development of FT1D. However, the number of the patients in the present study was too small because of the infrequent onset FT1D associated with DIHS. As reported in the previous nationwide questionnaire survey, only 4 cases developed FT1D (0.54%) for a period of 3 years (7), which suggests the need for further investigations.

In the previous study (7) we analyzed 15 cases of FT1D caused by DIHS in 2012 and found an association with the reactivation of the HHV-6 virus, but the time from DIHS onset to the onset of FT1D varied from 14 to 199 days. In the cases of a patient who developed FT1D 89 to 199 days after DIHS onset, it is possible that the antiviral immune response (19) may have had a long-term effect on the disease. In a case report by Miyashita et al (20), the HHV-6 virus was detected in renal tubular cells in an autopsy case of a patient who had died of renal failure 79 days after DIHS onset. On the other hand, similar to the concept of the HIV IRIS (21), which is observed during the recovery period after HIV treatment, a non-HIV IRIS (22), which occurs in DIHS after treatment, has been proposed, as well.

In case 4 of the 8 cases examined in this study, the reactivation of CMV was observed simultaneously with the HHV-6 virus. It is known that in addition to the HHV-6 virus, CMV and various other herpes viruses are continuously reactivated during the course of DIHS as reported in graft vs. host disease (23). We previously reported on a case of diaminodiphenyl sulfone syndrome (now DIHS) in which CMV and the coxsackie virus B3 were activated 1 month after the onset of FT1D (24). Although excluded from this report, a case in which CMV DNA was detected in blood 3 weeks after the onset of DKA due to DIHS was also reported (25). In our previous report (7) (case 11), a case of a non-HIV IRIS who tested positive for CMV 17 days after the onset of DIHS and developed DKA 6 months later was also reported (26). The relationship between CMV and the development of FT1D needs further investigation.

Elevated pancreatic exocrine enzymes at the onset of FT1D were found in 8 of 15 patients in the previous report (7) and in 5 of the 6 patients in the present analysis (Table 1). Yoneda et al (27) reported an autopsy case of FT1D that had developed after DIHS, in which the human cytomegalovirus antigen was detected in the blood 1 week later and the patient subsequently died of sepsis 3 weeks later. He also found a large number of human cytomegalovirus-positive cells in the islets and exocrine tissue.

Regarding human leukocyte antigens class II, as shown in Table 1, all 3 cases examined had protective haplotypes. Imagawa et al (28) previously reported on a different contribution of human leukocyte antigens class II in conventional FT1D compared with typical autoimmune type 1 diabetes, in which the protective haplotype was more frequent in the former. These results are consistent with the present study, and further work will be necessary if a firm conclusion is to be reached. Clinical symptoms at the onset of FT1D in the present cases showed thirst and flu-like symptoms that were less frequent than those of conventional FT1D (29) (Supplementary Table S) (30).

We previously reported on a case of conventional FT1D, which is not related to DIHS, that develops with common cold-like symptoms such as fever or pregnancy-related symptoms before the onset (31). The Japan Diabetes Society organized a nationwide survey of 162 cases of FT1D and found that 71% of the patients had cold-like symptoms at the onset, 72% had abdominal symptoms, and 98% had elevated levels of pancreatic exocrine enzymes (1). In addition, viral antibody titers were measured before and after the onset of illness in 55 conventional FT1D cases registered with the committee (2). Seven of the 38 patients for whom paired sera were obtained showed significantly elevated antibody titers against the coxsackie virus, the rotavirus, CMV, Epstein-Barr virus, HHV-6,7, and other viruses, but no association between FT1D and any specific virus was observed.

It should be noted that the HHV-6 virus has been detected in nondiabetic and type 1 diabetic pancreatic islets of Langerhans and in exocrine tissue donated as kidney transplant donors (32, 33). A number of cases of FT1D caused by severe pancreatitis have also been reported (34-36). Furthermore, the involvement of persistent enterovirus infection in triggering islet autoimmunity and type 1 diabetes mellitus has been reported (37). Considering this, the possibility that the HHV-6 virus in pancreatic islets of Langerhans and exocrine tissues is reactivated early after the onset of DIHS, leading to the development of FT1D, cannot be excluded. Further study of a large number of cases would be needed to confirm this speculation.

Acknowledgments

We are grateful to Dr. Yoshihiro Ogawa, Dr. Fumio Umeda, and Dr. Ryuichi Sakamoto, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University for their assistance in the literature search for this study.

Disclosures

No potential conflicts of interest relevant to this article were reported.

Data Availability

Original data generated and analyzed during this study are included in this published article or in the data repositories listed in References.

References