Drug-induced hypersensitivity syndrome following temozolimide for glioblastoma multiforme and the role of desensitization therapy

Introduction Temozolomide is an oral alkylating agent used as first line treatment of glioblastoma multiforme (GBM). It has also been used in the treatment of certain solid tumors such as metastatic melanoma. Commonly reported adverse effects include nausea and vomiting, constipation, headache, fatigue and myelosuppression. Cutaneous hypersensitivity reactions are rare and include an urticarial hypersensitivity reaction, alopecia, and Stevens–Johnson syndrome. To our knowledge, there are minimal reports of temozolomide-induced DRESS syndrome. Case Report We present a 54-year-old man with glioblastoma multiforme who presented with a fever, diarrhea and progressively worsening rash 6 weeks after starting temozolomide. Management & Outcome The patient was diagnosed recurrent DRESS syndrome and restarted on a gradual prednisone taper with resolution over the following weeks. Unfortunately, the patient was unable to be followed long-term due to relocation to a different state. Discussion To our knowledge, there are minimal reports of temozolomide-induced DRESS syndrome. The diagnosis can be life-threatening, which makes management of patients with GBM and no alternative treatment option challenging. The use of de-sensitization therapy to temozolomide has been proposed for the management of severe adverse cutaneous reactions.

A Possible Type IV Hypersensitivity Reaction to Older Antiepileptic Drugs During and After Recovery from COVID-19 Infection

To the EditorNearly two years after the onset of the coronavirus disease 2019 (COVID-19) pandemic, healthcare workers face new and unexpected complications. Although accelerating the vaccination process in recent months has reduced the incidence and mortality of the COVID-19 infection, the general population (particularly vulnerable groups) remains at risk of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Over the last two months, Iran has encountered the fifth wave of the COVID-19 pandemic, i. e., the B.1.617.2 (Delta) variant of the SARS-CoV-2, with faster infectiousness and higher severity and mortality among hospitalized patients 1. Although fever, cough, and expectoration are the most common clinical features of COVID-19, recent studies have indicated an increasing number of skin manifestation reports in the disease. Besides, there is growing evidence that underlying SARS-CoV-2 infection may increase the risk of adverse drug reactions 2. However, the enduring concern in our medical centers in recent days is a raised incidence of Stevens-Johnson syndrome (SJS) in recovered COVID-19 patients following monotherapy with older antiepileptic drugs (0.004 vs. 0.0008% – i. e., 5 times higher than the pre-COVID-19 period) 3. It is worth noting that these patients did not have any history of SJS/toxic epidermal necrolysis (TEN) or additional etiopathogenic factors, including infections, genetic factors (particularly HLA-B*1502 allele), and malignancy. Furthermore, for many years before developing the COVID-19 and recovering from it, they had been treated with the above drugs without showing any cutaneous hypersensitivity reactions. These observational findings raise two important questions: (i) Could a history of the COVID-19 infection be a potential risk factor for type IV hypersensitivity reactions to older antiepileptic drugs? (ii) If so, what are its mechanisms of action?

Interleukin-6 induces spatially dependent whole-body hypersensitivity in rats: implications for extracephalic hypersensitivity in migraine

Background Migraine is a complex neurological disorder that is characterized by throbbing head pain, increased sensitivity to light, sound, and touch, as well as nausea and fatigue. It is one of the most common and most disabling disorders globally but mechanisms causing migraine are poorly understood. While head pain is a typical feature of attacks, they also often present with cutaneous hypersensitivity in the rest of the body. In contrast, primary pain conditions in the lower parts of the body are less commonly associated with cephalic hypersensitivity. Previous studies indicate that application of stimuli to the meninges of rodents causes cutaneous facial as well as hindpaw hypersensitivity. In the present study, we asked whether widespread hypersensitivity is a unique feature of dural stimulation or whether body-wide responses occur similarly when the same stimulus is given in other locations. Methods Rats were given the same dose of IL-6 either via dural, intraplantar, subcutaneous, intramuscular, intracisternal, or intrathecal injection. Cutaneous facial and hindpaw allodynia was assessed using Von Frey following injection into each location. Results Hindpaw allodynia was observed following dural and intraplantar injection of IL-6 in both males and females. Hindpaw allodynia was only observed in females following intracisternal and intrathecal IL-6 injections. In contrast, facial allodynia was only observed in either sex following dural and intracisternal injections, which would activate meningeal afferents and the trigeminal nucleus caudalis (TNC), respectively. Conclusions Here we show that while stimulation of upper body regions with IL-6 including the meninges and brainstem can cause widespread hypersensitivity spreading to the paws, similar stimulation of the lower body does not cause the spread of hypersensitivity into the head. These data are consistent with the observations that whole body hypersensitivity is specific to conditions such as migraine where pain is present in the head and they may provide insight into co-morbid pain states associated with migraine.

MPLA and AddaVax® Adjuvants Fail to Promote Intramuscular LaAg Vaccine Protectiveness against Experimental Cutaneous Leishmaniasis

There is so far no vaccine approved for human leishmaniasis, mainly because of the lack of appropriate adjuvants. This study aimed to evaluate in mice the capacity of a mixture of monophosphoryl lipid A (MPLA) and AddaVax® adjuvants in enhancing the efficacy of a Leishvacin®-like vaccine comprised of Leishmania amazonensis whole antigens (LaAg). For that, mice were immunized with LaAg plus MPLA/AddaVax® by the intramuscular route (i.m.) prior to challenge with 2 × 105 and 2 × 106 living parasites. Immunization with LaAg alone reduced the lesion growth of the 2 × 105-challenged mice only in the peak of infection, but that was not accompanied by reduced parasite load, and thus not considered protective. Mice given a 2 × 106 -challenge were not protected by LaAg. The association of LaAg with MPLA/AddaVax® was able to enhance the cutaneous hypersensitivity response compared with LaAg alone. Despite this, there was no difference in proliferative cell response to antigen ex vivo. Moreover, regardless of the parasite challenge, association of LaAg with MPL/AddaVax® did not significantly enhance protection in comparison with LaAg alone. This work demonstrated that MPL/AddaVax® is not effective in improving the efficacy of i.m. LaAg vaccine against cutaneous leishmaniasis.

Delayed Cutaneous Hypersensitivity Reaction to Vaxzevria (ChAdOx1-S) Vaccine against SARS-CoV-2

Recently, an increasing number of cases with delayed large cutaneous reaction after immunisation with mRNA-based vaccines have been reported. This adverse reaction – which is considered a delayed-type or T-cell mediated hypersensitivity reaction – has been described primarily for the Moderna (mRNA-1273) vaccine and to a lesser extent for Comirnaty (Pfizer/BioNTech, BNT162b2).We describe a delayed large cutaneous reaction in a patient who received the viral vector vaccine Vaxzevria (ChAdOx1-S). The time course and clinical symptoms of delayed major skin reaction after vaccination with Moderna or Pfizer/BioNTech have a similar pattern that we recognized in our patient after Vaxzevria vaccination. In contrast to the Moderna vaccine trials, this phenomenon has not been described in the Vaxzevria clinical trials and is to the best of our knowledge the first report of this adverse reaction to a vector-based vaccine against SARS-CoV-2.With this, we hope to raise awareness about delayed injection site reactions that also occur after viral vector vaccines and to encourage additional reporting and patient education regarding the cutaneous reactions after COVID-19 vaccination.

CONCEPTUAL STUDY OF DENGUE FEVER ON THE BASIS OF AYURVED

Dengue fever is one of arthropod born and epidemiological disease caused by Arbovirus carried by vector Aedes aegypti. Dengue is the most rapidly spreading mosquito borne viral disease in the world.lifestyle changes and deficient water management including improper water storage practices in urban, peri urban The survey findings indicated that 49% of country's population had been previously infected with DENV. Due to rapid urbanization, and rural areas, leading to proliferation of mosquito breeding sites. Dengue fever has a seasonal pattern, the cases peak after monsoon not uniformly disrtibuted throughout the year. Incubation period of 2-7 days. Fever, malaise, retro-orbital pain, headache, arthralgia, petechiae, itching are common features. Thrombocytopenia is common. Macular rash may occur on first day. Illness may last a week with additional symptoms such as nausea, vomiting, anorexia, marked cutaneous hypersensitivity. Maculopapular rash begins on the trunk spreading to extremities and face. Leucocytes and platelets numbers decreases. Serum aminotransferase level may rise. IgM ELISA or paired serology test should be done at the phase of recovery. Antigen detection ELISA or RT-PCR during acute phase should be done. Due to Jwara Nidan, Pachakagni produces Doshakar Dravya which imbalances Tridosha. Ushma is necessary for Jwalan (burning) of this Doshkar Dravyas. Doshkar Dravya causes Kshobh to Vata Dosha and particularly Saman Vayu, causes more Agni Prajwalan and increases Ushma. Excessive increase in Ushma leads to Ojasthana Hriday Dushti, Tarpak Kapha in Shira Dushti, Shirashta Indriyadushti, Pranasthana Dushti. According to Samhita study, dengue fever can be correlated to Agantu Jwara, Sannipatik Jwara, Dandak Jwara and Vishamjwara. Keywords: Doshakar Dravya, Jwara Nidan, Pachakagni, Tridosha, Ushma

Interleukin-6 induces spatially dependent whole-body hypersensitivity in rats: implications for extracephalic hypersensitivity in migraine

Background: Migraine is a complex neurological disorder that is characterized by throbbing head pain, increased sensitivity to light, sound, and touch, as well as nausea and fatigue. It is one of the most common and most disabling disorders globally but mechanisms causing migraine are poorly understood. While head pain is a typical feature of attacks, they also often present with cutaneous hypersensitivity in the rest of the body. In contrast, pain conditions in the lower parts of the body do not generally lead to cutaneous hypersensitivity in the head. Previous studies indicate that application of stimuli to the meninges of rodents causes cutaneous facial as well as hindpaw hypersensitivity. In the present study, we asked whether widespread hypersensitivity is a unique feature of dural stimulation or whether body-wide responses occur similarly when the same stimulus is given in other locations.Methods: Rats were given the same dose of IL-6 either via dural, intraplantar, subcutaneous, intramuscular, intracisternal, or intrathecal injection. Cutaneous facial and hindpaw allodynia was assessed using Von Frey following injection into each location. Results: Hindpaw allodynia was observed following dural and intraplantar injection of IL-6 in both males and females. Hindpaw allodynia was only observed in females following intracisternal and intrathecal IL-6 injections. In contrast, facial allodynia was only observed in either sex following dural and intracisternal injections, which would activate meningeal afferents and the trigeminal nucleus caudalis (TNC), respectively. Conclusions : Here we show that while stimulation of upper body regions with IL-6 including the meninges and brainstem can cause widespread hypersensitivity spreading to the paws, similar stimulation of the lower body does not cause the spread of hypersensitivity into the head. These data are consistent with the observations that whole body hypersensitivity is specific to conditions such as migraine where pain is present in the head and they may provide insight into co-morbid pain states associated with migraine.

Immediate reaction to ibrutinib amenable to oral desensitization

Introduction Although up to half of patients receiving chemotherapeutic agents develop hypersensitivity reactions to the same, desensitization protocols can induce temporary tolerance to allow patients to continue to receive first-line treatment. Approximately 25% of patients develop cutaneous hypersensitivity reactions to ibrutinib, but there are no published management guidelines. Case report We describe the case of a 71-year-old woman with chronic lymphocytic leukemia who developed a delayed maculopapular rash with lip tingling and swelling following ibrutinib therapy. Management and outcome We performed a novel 11-step desensitization procedure to ibrutinib allowing us to successfully induce tolerance against IgE-mediated symptoms in this patient. Discussion As indications for ibrutinib use expand and more patients present with IgE-mediated symptoms, we expect that this protocol will provide benefit for many such patients.