The Role of Na+/K+-ATPase in the Development of Hyponatrenemia under Conditions of Hypoxic Stress in Patients with SARS-CoV-2 Infection.

We studied laboratory parameters of patients with COVID-19 against the background of chronic pathologies (cardiovascular pathologies, obesity, type 2 diabetes melitus, and cardiovascular pathologies with allergy to statins). A decrease in pH and a shift in the electrolyte balance of blood plasma were revealed in all studied groups and were most pronounced in patients with cardiovascular pathologies with allergy to statin. It was found that low pH promotes destruction of lipid components of the erythrocyte membranes in patients with chronic pathologies, which was seen from a decrease in Na+/K+-ATPase activity and significant hyponatrenemia. In patients with cardiovascular pathologies and allergy to statins, erythrocyte membranes were most sensitive to a decrease in pH, while erythrocyte membranes of obese patients showed the greatest resistance to low pH and oxidative stress.

Clinical course of drug-induced hypersensitivity syndrome treated without systemic corticosteroids.

BACKGROUND/AIM: Drug-induced hypersensitivity syndrome (DIHS) is a severe reaction to drugs which characteristically occurs after a long latency period. In addition, human herpes virus 6 (HHV-6) reactivation is a characteristic finding in DIHS, which has been known to be related to disease severity. Because DIHS has generally been treated by systemic corticosteroids, the natural clinical course is not clear. METHODS: Data for patients with both DIHS and HHV-6 reactivation were retrospectively collected from four hospitals. RESULTS: Data were collected on 12 patients ranging in age from 21 to 76 years (median, 65.5). All cases had been suspected of DIHS at their initial visit, and the elevation of serum anti-HHV-6 antibody had been confirmed (4-256 times: median; 32). The culprit drugs were carbamazepine (6), salazosulfapyridine (4), mexiletine (1) and zonisamide (1). The period of latency from the first administration of the drug ranged from 15 to 50 days (median, 30). All patients were treated conservatively for DIHS without systemic corticosteroids. The peaks of the patients' symptoms and laboratory findings were as follows (days from the onset of skin lesions): fever, 4-16 (median, 10.5); liver abnormality, 3-22 (median, 7.5); leukocytosis, 7-20 (median, 9). All patients recovered without pneumonia, myocarditis, nephritis or other systemic disease, from 7 to 37 days (median, 18) after withdrawal of the drug and from 11 to 44 days (median, 21) after the onset of skin lesions. CONCLUSION: It might be unnecessary to give systemic corticosteroids immediately to all patients suspected of having DIHS.

Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system.

The DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as DIHS (drug-induced hypersensitivity syndrome), presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, producing damage in several systems, especially kidney, heart, lungs, and pancreas. The pathogenesis is related to specific drugs (especially the aromatic anticonvulsants), altered immune response, sequential reactivation of herpes virus, and association with some HLA alleles. Glucocorticoids are the basis for the treatment of the syndrome, which may be given with intravenous immunoglobulin and, in selected cases, ganciclovir. This article reviews current concepts regarding the interaction of drugs, viruses and immune responses during this complex adverse-drug reaction.

[Case of drug-induced hypersensitivity syndrome due to lamotrigine: demonstration of sequential reactivation of herpesviruses].

Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe multiorgan disorder. The reactivation of human herpesvirus-6 (HHV-6) and other human herpesviruses has been reported to be associated with its pathogenesis. We herein report a case of 14-year-old female who developed DIHS during the treatment with lamotrigine, a novel antiepileptic drug. She initially presented with fever, skin rash, cervical lymphadenopathy, leukocytosis with eosinophilia and atypical lymphocytosis, liver dysfunction and hypogammaglobulinemia. Discontinuation of the drug and administration of prednisolone led to improvement;however, tapering of prednisolone and administration of midazolam and ketamine thereafter triggered clinical deterioration. She subsequently developed hyperthyroidism followed by hypothyroidism. Herpesviral loads were determined in her peripheral blood by real-time PCR during the course of the treatment, and sequential reactivation of Epstein-Barr virus (EBV), HHV-6 and cytomegalovirus was demonstrated. EBV viremia was detected throughout the course, except for a short period when HHV-6 viremia was at the peak. HHV-6 viremia developed after the secondary deterioration. Cytomegalovirus viremia appeared transiently before the hyperthyroidic state reversed and became hypothyroidic. Although this syndrome should be regarded as a systemic reaction induced by a complex interplay among herpesviruses and the immune responses against viral infections and drugs, it remains unknown how such a sequential reactivation is related to the pathogenesis of the condition.

Carbamazepine hypersensitivity syndrome triggered by a human herpes virus reactivation in a genetically predisposed patient.

A case of severe hypersensitivity syndrome, triggered by carbamazepine in the presence of a concomitant active human herpes virus (HHV) 6 and 7 infection is described. To further understand the molecular mechanism of this adverse reaction, analyses of the genetic variants of human leukocyte antigen (HLA) and of the epoxide hydrolase gene (EPHX1), previously associated with carbamazepine hypersensitivity, were performed. A lymphocyte transformation test (LTT) was conducted in order to detect drug-specific lymphocytes. In the hypersensitive patient, 2 genetic factors previously associated with intolerance to carbamazepine were detected: the allele HLA-A*3101 and homozygosity for the variant allele of SNP rs1051740 in EPHX1. Drug-specific lymphocytes could be detected by LTT when the HHV was active (positive PCR for viral DNA and increased anti-HHV 6 IgG titer), but not when it was no longer active. In conclusion, we document a case of severe carbamazepine hypersensitivity triggered by viral reactivation in a patient presenting the interaction of 2 unfavorable genetic factors.

Systemic lupus erythematosus presenting with Kikuchi-Fujimoto's disease as a long-term sequela of drug-induced hypersensitivity syndrome. A possible role of Epstein-Barr virus reactivation.

Drug-induced hypersensitivity syndrome (DIHS) is a severe form of drug eruptions associated with viral reactivations. Autoimmune diseases have been reported to develop several months or years after the resolution of DIHS. We describe a 36-year-old man with cervical lymphadenopathy and an erythematous eruption affecting the face and neck, which evolved into clinically evident systemic lupus erythematosus. He had had an episode of DIHS 4 years previously, in which human herpesvirus-6 and Epstein-Barr virus (EBV) were reactivated. Expression of EBV-encoded RNA was detected in the lymph node. On the basis of findings in this patient, we suggest that EBV is pathogenically important in the sequence of events leading to the onset of systemic lupus erythematosus and that patients with a history of DIHS may be at a risk of eventually developing autoimmune diseases.

Diagnosis and management of HIV drug hypersensitivity.

Drug hypersensitivity reactions are an important cause of morbidity in HIV-infected patients who take complex medication regimens. Correct diagnosis and management of these reactions are essential in the clinical care of HIV disease. Trimethoprim-sulfamethoxazole, abacavir, nevirapine, atazanavir, and enfuvirtide can all cause hypersensitivity rashes. In this review, we discuss the evidence for immunologic mechanisms of hypersensitivity reactions to HIV medications, the clinical characteristics of these reactions, and guidelines that currently exist for their identification and management.

[Drug-induced hypersensitivity syndrome and HHV-6 reactivation].

Drug-induced hypersensitivity syndrome (DIHS) is an adverse reaction with clinical signs of fever, rash, and internal organ involvement. The culprit drugs of DIHS are limited to several drugs such as carbamazepine, phenytoin, phenobarbital, zonisamide, allopurinol, salazosulfapyridine, diaphenylsulphone, and mexiletine. The association of HHV-6 reactivation with DIHS has been known. Flaring of symptoms such as fever and hepatitis is closely related to HHV-6 reactivation. A combination of immunologic reaction to a drug and HHV-6 reactivation results in the severe course of DIHS.

Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus.

A 58-year-old woman with rheumatoid arthritis (RA) developed fever, skin eruptions, leukocytopenia, and thrombocytopenia, 3 weeks after treatment with sulfasalazine. A skin biopsy showed hydropic degeneration of keratinocytes and lymphocytic infiltrate. A bone marrow aspiration demonstrated an increased number of macrophages with hemophagocytosis. Although serologic tests for Epstein-Barr virus (EBV) indicated a previous infection, EBV deoxyribonucleic acid was detected in her serum by polymerase chain reaction. Cessation of sulfasalazine and administration of steroids led to dramatic improvement. This case illustrates that the hemophagocytic syndrome associated with reactivation of EBV can occur as part of drug hypersensitivity reactions in RA patients taking sulfasalazine.

Case reports and literature review: the association between reactivation of human herpes virus-6 and peripheral white blood cell count in patients with carbamazepine-induced hypersensitivity syndrome.

Eruptions induced by anticonvulsants can often be experienced clinically, and the clinical diagnosis of "drug induced hypersensitivity syndrome (HS)" was proposed to characterize these drug eruptions. Reactivation of human herpes virus-6 seems to be an integral component of HS. Previously, we experienced two cases of carbamazepine (an anticonvulsant) induced HS and both cases did not show a reactivation of human herpes virus-6 infection (no elevation of anti-human herpes virus-6 IgG titres). The features of these two cases were compared with other reported cases that presented HS with the reactivation of human herpes virus-6. In the early phase of HS, a change in peripheral white blood cell count seems to be important and could be used as an indicator to predict whether late phase HS with reactivation of human herpes virus-6 will occur, since the increase in white blood cell count is seen before the increase in anti-human herpes virus-6 titres. Reactivation of human herpes virus-6 may cause severe clinical symptoms such as encephalitis. When an increase in white blood cells are observed in HS cases at onset, immediate discontinuation of cause drug and intensive care are necessary to avoid the more severe symptoms of HS.

Human herpesvirus 6 reactivation in trichloroethylene-exposed workers suffering from generalized skin disorders accompanied by hepatic dysfunction.

Idiosyncratic generalized skin disorders resembling serious drug hypersensitivities have reportedly occurred after occupational exposure to trichloroethylene. However, factors associated with the disorders remain unknown except for trichloroethylene exposure. This study aimed at clarifying whether infectious diseases contributed to the development of rash or hepatitis in patients with trichloroethylene-related generalized skin disorders. Fifty-nine patients consecutively hospitalized between March 2002 and December 2003 and 59 healthy exposed workers selected on an age-matched basis in the patients' factories were enrolled in the study. Information on possible risk factors for rash and hepatitis was collected with structured checklists. Antibody titers were measured for hepatitis A, B and C viruses, Mycoplasma pneumoniae, herpes simplex viruses 1 and 2, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, measles and rubella virus. Thirty-six cases (59%) showed exfoliative dermatitis, 17 (28%) erythema multiforme, 4 (7%) Stevens-Johnson syndrome, and 4 (7%) toxic epidermal necrolysis. Before the onset of rash, 16 (27%) cases had received medication prescribed for the preceding fever, a main first symptom of the disorders. Marked increases in anti-human herpesvirus 6 IgG titer (> or =256), which indicated viral reactivation, were noted in 14 (25%) patients, while no abnormal increase was detected in the controls (p<0.001). Anti-measles IgM titer was positive in 2 (7%) cases but not in the controls (p=0.49). The involvement of other known risk factors of rash or hepatitis was ruled out. These results suggest that part of trichloroethylene-related generalized cutaneous disorders occurring in China and drug-induced hypersensitivity syndrome overlap in terms of human herpesvirus 6 reactivation.

[Modulation of immune system by virus infection].

Cytotoxic T lymphocytes (CTLs) undoubtedly play an important role in protection against viral infections. Virus specific CTLs recognize virus-derived peptide in the context of major histocompatibility complex (MHC) class I molecules and lyse virus-infected cells via perforin/granzyme and Fas/Fas ligand pathways. Virus infection, especially herpesviruses, induces the down-regulation of surface MHC molecules, resulting in viral escape from the immunosurveillance system. Viruses also modulate the chemokine/chemokine receptor system through various mechanisms, including virus-encoded chemokine ligand homologs which function as agonists or antagonists, virus-encoded cell-surface chemokine receptor homologs, virus-encoded secreted chemokine-binding proteins, and the down- and up- regulation of chemokines and chemokine receptors. In this review, viral subversion of the immune system focusing on MHC expression and the chemokine system is discussed. Insight into strategies used by herpesviruses to modulate MHC expression and the chemokine system might generate novel approaches for protecting and treating viral infections.

Rhinovirus inhibits IL-17A and the downstream immune responses in allergic asthma.

The proinflammatory cytokine interleukin-17A (IL-17A) is known to mediate antimicrobial activity, but its role during rhinovirus (RV) infections and in asthma needs further investigation. Therefore, we addressed the role of IL-17A during allergic asthma and antiviral immune response in human and murine immunocompetent cells. In this study we found that asthmatic children with a RV infection in their upper airways have upregulated mRNA levels of the antiviral cytokine interferon type I (IFN)-ß and the transcription factor T-box 21 (TBX21) and reduced levels of IL-17A protein in their peripheral blood mononuclear cells (PBMCs). We also found that IL-17A inhibited RV1b replication in infected human lung epithelial cells A549. Furthermore, by using gene array analysis we discovered that targeted deletion of Il17a in murine lung CD4(+) T cells impaired Oas1g mRNA downstream of Ifnß, independently from RV infection. Additionally, in PBMCs of children with a RV infection in their nasalpharyngeal fluid OAS1 gene expression was found downregulated. Finally RV1b inhibited IL-17A production in lung CD4(+) T cells in a setting of experimental asthma. These results indicate that the RV1b inhibits IL-17A in T helper type 17 cells and IL-17A clears RV1b infection in epithelial cells. In both cases IL-17A contributes to fend off RV1b infection by inducing genes downstream of interferon type I pathway.

Virus reactivation and intravenous immunoglobulin (IVIG) therapy of drug-induced hypersensitivity syndrome.

Drug-induced hypersensitivity syndrome (DIHS) is a severe multi-organ system reaction caused by specific drugs. Many reports have revealed that human herpesvirus 6 (HHV-6) reactivation contributes to the development of DIHS. In addition, recent articles have shown that reactivation of other herpesviruses such as human herpesvirus 7 (HHV-7), Epstein-Barr virus (EBV), cytomegalovirus (CMV) might be also implicated in the development of DIHS. These observations suggest that not only HHV-6 but also other herpesvirses might reactivate from the latency and play an important role in the appearance of clinical manifestations of DIHS. Several patients with DIHS were treated with intravenous immunoglobulin (IVIG) in addition to systemic corticosteroids. The results have been encouraging although virus reactivation could not be suppressed. Although the pathomechanism of IVIG treatment in patients with DIHS remains unknown, the therapeutic effects of IVIG could be dependent, in part, on functional capabilities of anti-virus IgG contained in IVIG.

Human herpesvirus 6 and drug allergy.

PURPOSE OF REVIEW: The similarity between viral skin eruption and drug-induced rash has inspired many researchers to seek an association between viral infection and drug allergy. Hypersensitivity syndrome (referred to in this review as drug-induced hypersensitivity syndrome) is one of the severe adverse reactions to drugs and was reported more than 50 years ago. However, the mechanism of drug-induced hypersensitivity syndrome has not been fully elucidated. Several groups reported the association between human herpesvirus 6 reactivation and drug-induced hypersensitivity syndrome 5 years ago. Recently, similar case reports have accumulated. Recent findings concerning human herpesvirus 6 and drug-induced hypersensitivity syndrome are reviewed here. RECENT FINDINGS: In drug-induced hypersensitivity syndrome, examination of serial serum samples revealed a marked and sudden increase in anti-human herpesvirus 6 IgG titers in the third or fourth week after the onset of clinical manifestations. In addition, active human herpesvirus 6 replication precedes the rise in antibody titers. Furthermore, the recurrence or worsening of signs and symptoms was observed concurrently with human herpesvirus 6 reactivation. In encephalitis associated with drug-induced hypersensitivity syndrome, human herpesvirus 6 DNA was detected in cerebrospinal fluid. This strongly indicates the involvement of reactivated human herpesvirus 6 in the pathogenesis of encephalitis. Similarly, reactivation of human herpesvirus 6 was observed in fulminant type 1 diabetes mellitus associated with drug-induced hypersensitivity syndrome caused by carbamazepine. SUMMARY: The reactivation of human herpesvirus 6 in drug-induced hypersensitivity syndrome is not a coincidental phenomenon. Human herpesvirus 6 reactivation plays an important role in the pathogenesis of drug-induced hypersensitivity syndrome, especially in the latter half of the clinical symptoms. Reactivated human herpesvirus 6 sometimes leads to the severe complications of drug-induced hypersensitivity syndrome, such as encephalitis and type 1 diabetes mellitus. In conclusion, drug-induced hypersensitivity syndrome is a complex disease composed of drug allergy and human herpesvirus 6.

Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome.

BACKGROUND: Drug-induced hypersensitivity syndrome is characterized by a severe, potentially fatal, multiorgan hypersensitivity reaction that usually appears after prolonged exposure to certain drugs. Its delayed onset and clinical resemblance to infectious mononucleosis suggest that underlying viral infections may trigger and activate the disease in susceptible individuals receiving these drugs. OBSERVATIONS: A 60-year-old woman developed an itchy, generalized, erythematous, confluent rash on the 39th day of receiving allopurinol therapy. Even after she discontinued treatment with allopurinol, her skin lesions progressed to severe blistering skin eruption. After the patient started oral prednisone therapy, her skin lesions resolved with desquamation. After complete resolution, rechallenge with allopurinol led to the development of an erythematous eruption. Titers of human herpesvirus 6 IgG antibodies dramatically increased with the development of the eruption. The results of a polymerase chain reaction and in situ hybridization indicated the presence of human herpesvirus 6 in the skin lesions, although human herpesvirus 7 DNA was detected only by in situ hybridization. CONCLUSION: Reactivation of human herpesvirus 6, possibly in concert with human herpesvirus 7, can contribute to the development of a severe drug-induced hypersensitivity syndrome.

Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6.

BACKGROUND: A severe adverse reaction to sulfasalazine therapy has been associated with hypersensitivity syndrome, the clinical features of which are similar to infectious mononucleosis. No serologic evidence of viral infections has been reported with this syndrome; however, human herpesvirus 6 infection has not been specifically investigated, which could cause an infectious mononucleosislike syndrome. OBSERVATIONS: We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine. The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. Clinical signs included a maculopapular rash progressing to exfoliate erythroderma, fever, and lymphadenopathy. Leukocytosis, atypical lymphocytes, liver dysfunction, and renal disturbance were also observed. In 1 patient, human herpesvirus 6 variant B was isolated from peripheral blood mononuclear cells, and in both patients anti-human herpesvirus 6 IgG titers increased considerably. CONCLUSIONS: Two cases of hypersensitivity syndrome due to sulfasalazine use were associated with the reactivation of human herpesvirus 6, which may be a required cause of hypersensitivity syndrome.