Natural History Study of the KSHV Inflammatory Cytokine Syndrome (KICS)

May 29, 2026 updated by: National Cancer Institute (NCI)

Background:

- KSHV inflammatory cytokine syndrome (KICS) is a newly recognized disease caused by Kaposi sarcoma-associated herpesvirus (KSHV). This virus can cause cancer. People with KICS can have severe symptoms. They include fever, weight loss, and fluid in the legs or abdomen. People with KICS may also be at risk of getting other cancers associated with KSHV. These cancers include Kaposi sarcoma and lymphoma. Because KICS is a newly identified disease, more information is needed on how the disease works and what can be done to treat it.

Objectives:

- To collect genetic and medical information from people with KSHV inflammatory cytokine syndrome.

Eligibility:

- Individuals at least 18 years of age who have Kaposi sarcoma herpes virus and symptoms that resemble those caused by KICS.

Design:

  • Participants will have regular study visits. The schedule will be determined by the study researchers.
  • Participants will provide a complete medical history and have a full physical exam. Blood and urine samples will be collected as well.
  • People with KICS that requires treatment may get new experimental treatments. These treatments may include antiviral drugs and chemotherapy drugs, depending on the nature of the disease.
  • Participants will have imaging studies, such as chest x-rays and computed tomography scans, to study the tumors.
  • Bone marrow and lymph node biopsies may be done to collect tissue samples for study.
  • Participants who have Kaposi sarcoma will have photographs taken of their lesions.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Background

-Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly recognized syndrome caused by 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.

Objective

-Assessment of the natural history of KSHV inflammatory cytokine syndrome (KICS), including the spectrum of clinical, laboratory and radiographic abnormalities seen in affected participants.

Eligibility

  • 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, lymphadenopathy, organomegaly, effusions)
    • C-reactive protein >3mg/L
    • Evidence of KSHV infection or a risk exposure for KSHV infection
    • No evidence of KSHV-associated multicentric Castleman disease
  • Participants with these characteristics will be further evaluated to identify those whose clinical and laboratory features are consistent with the KICS working case definition to be followed in the natural history phase of the study.

Design

-This is a single center natural history study with a cohort of up to 120 evaluable participants. Participants who meet the criteria for KICS will go onto a natural history arm, which permits observation for KICS with or without other concurrent KSHV-associated disorders. Participants who require KS and/or primary effusion lymphoma (PEL) treatment along with a KICS diagnosis will receive rational therapies for these conditions or be treated for their KS and/or PEL on a separate protocol while still followed on this study.

Study Type

Interventional

Enrollment (Estimated)

140

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • Recruiting
        • National Institutes of Health Clinical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

  • 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/or radiographic abnormalities), which are at least possibly attributable to KICS and are not readily explicable from known medical conditions in the participant:
  • 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 (CRP) >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, or KSHV VL levels within circulating PBMCs as determined by the Whitby laboratory
    • Immunohistochemical evidence of KSHV in tissues (for example by staining for LANA or vIL-6) confirmed in the Laboratory of Pathology (LP), CCR, NCI.
    • Presence of KS or PEL (KSHV-associated malignancies), confirmed in the LP, CCR, NCI.
  • Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and after treatment (if received), according to drug requirements. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

EXCLUSION CRITERIA:

- Biopsy proven KSHV-associated MCD, confirmed in the LP, CCR, NCI.

Note: In collaboration with LP, we have recently found that some participants with KICS but without a lymph node or splenic diagnosis of MCD have MCD-like cells in their effusions or circulating blood. This may in fact represent a newly recognized form of KSHV-MCD, but our analysis continues. While certain of these participants were historically included in this study, given this new understanding, they will not be entered on this protocol and removed if liquid MCD is diagnosed.

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: 1
Evaluation for Alternative Causes of KICS Symptoms (inactive)
No Intervention: 2
Natural history/Observation arm (inactive)
Experimental: 3
High dose zidovudine + valganciclovir (inactive)
Drug: Zidovudine
Zidovudine 600 mg will be administered orally 4 times a day or i.v. at 300 mg every 6 hours for 14 days for cycle 1 and for 7 days (up to additional 7 days if ongoing symptoms) for following cycles.
Drug: Valganiclovir
Valganciclovir (900mg) will be administered orally twice/day or Ganciclovir (5 mg/kg) will be administered i.v. over 1 hour for 14 days for cycle 1 and for 7 days (up to additional 7 days if ongoing symptoms) for following cycles.
Experimental: 4
Rituximab with or without liposomal doxorubicin (inactive)
Drug: Liposomal Doxorubicin
Liposomal doxorubicin (20 mg/m2) will be administered i.v. over 1 hour at day 1 of each cycle
Drug: Rituximab

Rituximab (375 mg/m2) will be admnistered i.v. at 50 mg/hr up to 100 mg/hr at day 1 of the first cycle and at 100mg/hr up to 400 mg

/hr at day 1 of following cycles.
Other: 5
Standard and alternative rational therapies (inactive)
Other: Standard Therapies
Standard of Care drugs
Other: 6
Natural history
Other: Cohort 1
Participants who are infected with KSHV who meet criteria for inflammatory cytokine syndrome (KICS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Natural history of KICS
Time Frame: one year
Description of the natural history of KICS, including the spectrum of clinical, laboratory and radiographic abnormalities seen in affected patients
one year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Participants with KICS
Time Frame: one year
Evaluate the survival of participants with KICS and of KICS with primary effusion lymphoma (PEL)
one year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Robert Yarchoan, M.D., National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 8, 2011

Primary Completion (Estimated)

December 31, 2028

Study Completion (Estimated)

December 31, 2028

Study Registration Dates

First Submitted

August 17, 2011

First Submitted That Met QC Criteria

August 17, 2011

First Posted (Estimated)

August 18, 2011

Study Record Updates

Last Update Posted (Actual)

June 1, 2026

Last Update Submitted That Met QC Criteria

May 29, 2026

Last Verified

May 28, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 110220
  • 11-C-0220

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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