Defining and treating KICS: experience from the largest cohort yet Open Access

In this issue of Blood Advances, Ramaswami et al¹ present the largest prospective cohort to date of Kaposi sarcoma herpesvirus (KSHV)–associated inflammatory cytokine syndrome (KICS), a severe complication of KSHV infection. Over 11 years, they identified 35 patients using a refined case definition that distinguishes KICS from other KSHV-related disorders such as multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). Their treatment approach, directed at the viral replication and inflammation driving KICS, improved survival vs earlier cohorts and set the stage for defining optimal therapy and expanding care to global settings where their work may have greatest impact.

KICS is a rapidly progressive and often fatal syndrome that arises most often in severely immunocompromised patients with poorly-controlled HIV and advanced KS. Its diagnosis is challenging because it overlaps clinically with other KSHV-related disorders characterized by systemic inflammation. A patient with newly-diagnosed HIV and KS may present with fever, lymphadenopathy, hepatosplenomegaly, and pleural effusions—a differential that may include KICS, MCD, PEL, immune reconstitution inflammatory syndrome (IRIS), or infections.

The diagnostic approach developed by Ramaswami et al helps narrow this differential by combining clinical, laboratory, and radiographic findings, elevated inflammatory markers, and circulating KSHV to screen patients. MCD and PEL are then excluded by pathology, whereas IRIS is distinguished by recent antiretroviral therapy initiation with rising CD4 counts and worsening KS.² Of 73 patients suspected of having KICS, over half were reclassified as MCD, PEL, or IRIS, underscoring the importance of careful exclusion.

Ramaswami et al also demonstrate a unique cytokine signature for KICS compared with MCD and PEL. Although KSHV viral load was elevated in KICS, it was lower than in MCD; cytokine levels showed a distinct pattern of increased interleukin 6 (IL-6), IL-10, and IL-1β compared with KS alone. These findings support KICS as a biologically-distinct syndrome and highlight the need for accurate diagnosis.

Historical reports of KICS were marked by poor survival.^3,4 In its original description, 3 of 6 patients died early, and in a later cohort, 6 of 10 patients died with a median survival of only 14 months.^3,4 Treatment strategies were heterogeneous, largely consisting of KS-directed chemotherapy with liposomal doxorubicin ± valganciclovir, with dismal outcomes.

Building on experience from KSHV-associated MCD, rituximab was proposed as therapy for KICS with the rationale that depleting B cells could reduce viral IL-6 production and systemic inflammation. In this cohort, reductions in KSHV viral load were observed following rituximab, supporting its role as a useful adjunct to KS-directed therapy. These findings are notable as rituximab is likely ineffective in reducing KSHV production of viral IL-6 in CD20-negative endothelial cells driving KS lesions.

The ideal therapy for KICS remains uncertain, but the median survival of 5.7 years in this cohort, extending well beyond earlier reports, is encouraging. Outcomes were variable; overall survival among rituximab recipients was lower than the cohort as a whole, but interpretation of rituximab’s effect on survival is limited by small numbers and possible selection bias for sicker patients. One patient achieved a complete response to the IL-6 receptor antagonist tocilizumab, whereas another treated with valganciclovir was lost to follow-up. The remaining 22 patients received KS-directed therapy alone. Together, these data suggest that rituximab- and cytokine-directed regimens may yield meaningful clinical improvement, but they are not universally effective, and their precise role remains to be defined.

What is next for KICS? As Ramaswami et al note, future studies will be needed to establish optimal therapy, and given the rarity of KICS, this will require large, multi-institutional studies. Their updated case definition offers a foundation for such work and a benchmark against which future strategies can be measured.

Importantly, this diagnostic and therapeutic approach may also be expanded to the low- and middle-income countries (LMICs) where most patients with HIV-KSHV coinfection live.⁵ High population prevalence of both viruses in Africa results in the highest global incidence of KSHV-associated disease, including over 70% of adult KS cases and virtually all pediatric KS cases.^6,7 Although the epidemiology of KICS is undescribed in Africa, its incidence is likely highest in this region of the world where its identification and treatment are most challenging, and survival is poorest.

Identifying KICS in LMICs requires a tailored approach. In Malawi, Kumwenda et al⁸ recently proposed an adapted definition based on the original KICS case definition developed by Uldrick et al.³ Similarly, it uses clinical, basic laboratory, and radiographic abnormalities to identify patients with KICS, requiring only confirmation of KS and exclusion of disseminated tuberculosis infection to exclude other etiologies. In their working definition, KSHV viremia and histologic exclusion of MCD are optional due to limited laboratory capacity for these tests in low-resource settings.

A pediatric case definition developed in Malawi similarly omits KSHV viral load and histopathologic diagnosis, instead relying on persistent fevers, bulky lymphadenopathy, severe thrombocytopenia, and massive hepatosplenomegaly in a child with KS. KSHV viremia is likely unnecessary for a highly specific pediatric case definition as viral loads are often elevated in the lymphadenopathic variant of KS, the most common phenotype in children, among whom the majority do not have KICS.⁷ Additionally, other KSHV-associated diseases, particularly MCD and PEL, are very rare in children.

Treatment will also require adaptation and study in LMICs, where agents such as rituximab and tocilizumab are frequently unavailable or prohibitively expensive. Corticosteroids have been used with some success in small case series of adults and children with KICS in Africa, but their potential to worsen KS or precipitate IRIS requires caution and further study.^8-10 Fortunately, rituximab’s availability is increasing in Africa as it is incorporated into treatment for non-Hodgkin lymphoma, potentially allowing for inclusion in follow-up studies building on its potential effectiveness for KICS described here.

To conclude, Ramaswami et al have provided the most comprehensive description of KICS to date, clarifying its distinction from related syndromes with underlying systemic inflammation and demonstrating that outcomes can improve with targeted therapy. The next step is to build on this remarkable progress through collaborative studies that refine therapy and adapt diagnostic and treatment strategies across the spectrum of settings where KICS occurs.

Conflict-of-interest disclosure: The authors declare no competing financial interests.