Could HHV-6 reactivation in drug hypersensitivity trigger fulminant type 1 diabetes?

Small study demonstrates increased HHV-6 antibodies in all patients shortly before the onset of DIHS-associated fulminant diabetes.

 Fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes (T1D). It develops rapidly, is not characterized by islet-associated antibodies (as are most cases of T1D), and leads to nearly complete destruction of the pancreatic islet cells.  In Japan, FT1D constitutes about 20% of all cases of T1D. Islet destruction in the absence of destructive autoantibodies might reflect a direct cytopathic effect of a virus.

A fraction of cases of FT1D occur following drug-induced hypersensitivity syndrome (DIHS) known in Europe and the US as DRESS or drug reaction with eosiniphilia and systemic symptoms. DIHS/DRESS, in turn, is known to be accompanied by reactivation of latent HHV-6 infection in both the blood and in the skin, appearing in the blood well after the onset of rash. Of interest, it appears to reactivate first in the skin and then spread to the blood (Marcombes 2023). The high level of HHV-6 reactivation is due to the fact that HHV-6B receptor CD134/OX40 is expressed at high level in the CD4+ T cells within DIHS/DRESS lesions (Lee 2023).

Investigators from Ehime, Japan, collected information from eight cases of FT1D that developed in the weeks following DIHS.  An increase in the titers of antibodies against HHV-6 were noted in all 8 cases (as shown in Figure 1, below). 

Figure 1: Time course for the reactivation of the HHV-6 or CMV virus before and after the onset of fulminant type 1 diabetes caused by DIHS, in 8 cases. Number of days indicates the number of days since the onset of DIHS.

In the one case tested, HHV-6 DNA in blood also was detected just prior to the onset of FT1D.  Elevated pancreatic exocrine enzymes at the onset of FT1D also were noted in 5 of 6 patients tested. No attempt was made to assess the presence of HHV-6 DNA or antigens in the pancreatic tissue of any patient.

The authors cite prior research studying 162 cases of FT1D in Japan that was not associated with DIHS. In this prior report, 71% of the patients had cold-like symptoms at the onset, 72% had abdominal symptoms, and 98% had elevated levels of pancreatic exocrine enzymes (Imagawa 2003).

Previous research also has suggested that HHV-6 protein may be found in the pancreatic islet cells of people with T1D (Sabouri 2019) and that the elevated interferon -γ-protein 10 seen in DRESS/DIHS may induce autoimmunity (Yang 2020).

The Japanese report raises the possibility that in some people with FT1D, not only those with FT1D following DIHS, reactivation of HHV-6 may lead the virus to infect and destroy pancreatic endocrine (and, possibly, exocrine) cells—resulting in an unusual but devastating variant of type 1 diabetes.  Obviously, much more work—including pathological examination of pancreatic tissue in people with FT1D—will be needed to pursue this possibility.

Read the full article: Makino 2024