History of the KSHV Inflammatory Cytokine Syndrome (KICS)
- - INCLUSION CRITERIA: - Age greater than or equal to18 Years. - Any HIV status. - At least two manifestations drawn from at least two of the categories (clinical symptoms, laboratory abnormalities and radiographic abnormalities), which are at least possibly attributable to KICS and are not readily explicable from known medical conditions in the patient: - Clinical symptoms (each at least grade 1 by CTCAE definitions) - Fever (>38 degrees C), chills or rigors - Fatigue or lethargy - Cachexia or edema - Cough, dyspnea, airway hyperreactivity, or nasal inflammation - Nausea, anorexia, abdominal pain or altered bowel habit - Athralgia or myalgia - Altered mental state - Neuropathy with or without pain - Laboratory abnormalities - Anemia (hemoglobin<12.0g/dL) - Thrombocytopenia (platelets<100,000 cells/microL) - Leukopenia (white cell count<4,000 cells/microL) - Hypoalbuminemia (albumin<3.5g/dL) - Hyponatremia (sodium<135mmol/L) - Coagulopathy (PT or PTT >1.5 times upper limit of normal) - Radiographic Abnormalities - Pathologic lymphadenopathy (at least five discrete nodes each >1cm in their longest dimension) - Splenomegaly (>12 cm in the longest dimension) - Hepatomegaly (>17cm in the longest dimension) - Body cavity effusions not caused by primary effusion lymphoma nor chylous effusions directly related to lymphatic infiltration by KS -. C-reactive protein >3mg/L. - Exposure risk for KSHV infection (including being a first or second generation immigrant from an endemic area, or male-to-male sexual activity) or evidence of KSHV infection demonstrated by one of: - Molecular evidence of KSHV in whole blood, confirmed by testing at Focus Laboratories, CA (HHV-8 Quantitative PCR, Focus Unit Code 45700). - Immunohistochemical evidence of KSHV in tissues (for example by staining for LANA or vIL-6). Confirmed in the Laboratory of Pathology, CCR, NCI. - Presence of KS or PEL (KSHV-associated malignancies), confirmed in the Laboratory of Pathology, CCR, NCI. EXCLUSION CRITERIA: - Biopsy proven KSHV-associated MCD, confirmed in the Laboratory of Pathology, CCR, NCI. - Pregnancy - Any abnormality that would be scored as NCI CTC Grade 4 toxicity that is unrelated to HIV, its treatment, or to KICS that would preclude the use of all of the study treatments or the ability to monitor the natural history of KICS untreated. - Any condition or set of circumstances that in the opinion of the investigators would make participation in this study unsafe or otherwise inappropriate for a given individual.
KSHV inflammatory cytokine syndrome (KICS) is a newly recognized syndrome caused by Kaposi
sarcoma-associated herpesvirus (KSHV). It is characterized by severe inflammatory symptoms
including fevers, wasting, cytopenias, hypoalbuminemia, and hyponatremia, associated in some
cases with lymphadenopathy or effusions, without pathological evidence of MCD. Patients with
KICS exhibit elevated KSHV viral loads and cytokine dysregulation, with elevations of IL-6,
IL-10, and a KSHV-encoded IL-6 homolog, viral IL-6.
The primary study objective is to enable intensive study and description of the natural
history of KICS.
Adults of any HIV status with:
- At least two symptoms, laboratory or radiographic abnormalities which are at least
possibly attributable to KICS (including fever, fatigue, cachexia, edema, respiratory or
gastrointestinal symptoms, hematologic cytopenias, hypoalbuminemia, hyponatremia,
- C-reactive protein >3mg/L.
- Evidence of KSHV infection or a risk exposure for KSHV infection
- No evidence of KSHV-associated multicentric Castleman disease
Patients with these characteristics will be further evaluated to identify those whose
clinical and laboratory features are consistent with the working KICS working case definition
to be followed in the natural history phase of the study.
This is a single center natural history cohort with an observation arm and two nested open
label pilot treatment arms, and an accrual ceiling of 40 patients to the overall natural
history arm. Natural history patients will undergo clinical, laboratory and correlative
assessment every 3 months until sustained resolution. Patients with clinical and laboratory
manifestations of KICS, elevated inflammatory markers and KSHV viral load will be eligible
for therapy with high dose zidovudine/valganciclovir or, if they have intercurrent KS
requiring cytotoxic therapy, rituximab/liposomal doxorubicin. Each treatment arm uses a two
stage design, with interim analysis at 8 patients in each arm and potential accrual of 14 per
arm. Patients on the treatment arm who have not responded to the pilot treatments or for whom
such treatment would not be suitable may also be treated with best available therapy.
Trial Phase Phase II
Trial Type Treatment
National Cancer Institute
- Primary ID 110220
- Secondary IDs NCI-2019-00208, 11-C-0220, NCI-2013-01499
- Clinicaltrials.gov ID NCT01419561