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1250 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1251

of whom received rituximab, the overall median survival was longer and multicentric Castleman disease patients, and much higher than in
than 12 years with therapy; this is much improved in comparison to 20 patients with isolated Kaposi sarcoma. Whether KICS represents a form
years ago when Castleman disease was rapidly fatal. fruste of multicentric Castleman disease, part of the clinical spectrum of
Incipient flares of Castleman disease may be heralded by cytope- Castleman disease, or a distinct clinical syndrome requires more inves-
nias, increased C-reactive protein, or by increased levels of HHV8 in the tigation. There is scant information on treatment of KICS.
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blood. Serial studies of 52 HIV+ patients with multicentric Castleman
disease showed that approximately 75 percent had elevated C-reactive HUMAN IMMUNODEFICIENCY
protein and 90 percent had detectable plasma HHV8 during a flare, with VIRUS–ASSOCIATED HEMOPHAGOCYTIC
a median HHV8 viral load of 27,000 copies/mL. HHV8 was detectable
in 38 percent of patients during remission. If relapse occurs, patients can SYNDROME
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safely be retreated with rituximab. Up to 20 percent of HIV+ patients Hemophagocytic syndrome is a rare and potentially fatal disorder char-
with Castleman disease will develop lymphoma, 208,214 often primary acterized by excess immune activation that occurs with increased fre-
effusion lymphoma, plasmablastic lymphoma, or diffuse large B-cell quency in people living with HIV. An autopsy study in the pre-ART
lymphoma, but occasionally Hodgkin lymphoma, so it is important era identified hemophagocytosis in 20 percent of 56 patients who died
to consider this during followup. Use of rituximab to treat Castleman of AIDS. The pathogenesis of the hemophagocytic syndrome results
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disease may decrease the risk of subsequent NHL. In HIV+ patients from failure to regulate the immune response, resulting in excess acti-
with both Castleman disease and Kaposi sarcoma, Kaposi sarcoma vation of T lymphocytes, increased cytokine secretion, and hyperac-
may progress following treatment with rituximab. 218,219,222 When Kaposi tivation of macrophages. There are primary and secondary forms of
sarcoma involves a key clinical location such as the lungs, where pro- hemophagocytic syndrome. Secondary forms can occur in the setting
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gression might result in significant respiratory compromise, a regimen of infection, hematologic malignancy, or autoimmune disease. In
of rituximab plus liposomal doxorubicin can be considered to address HIV+ patients, the hemophagocytic syndrome is usually secondary to
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both the Castleman disease flare and Kaposi sarcoma. R-CHOP or a viral infection, either HIV itself or, more commonly, a member of the
other multiagent systemic chemotherapy has also been used to treat herpes virus family (EBV, CMV, HHV8), but can also occur in patients
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Castleman disease, but given the excellent response to rituximab alone, with Hodgkin lymphoma, NHL, or Castleman disease. A study of 58
R-CHOP is usually not necessary. An alternative therapeutic approach HIV+ patients with hemophagocytic syndrome performed in the ART
234
focuses on the central role of IL-6. A multiinstitution, randomized, era showed that the median duration of HIV at the time of diagnosis
placebo-controlled clinical trial of an anti–IL-6 monoclonal antibody was 4 years. Most patients were on ART, and the median CD4 count was
siltuximab in 79 HIV– patients with Castleman disease showed a 34 91 cells/μL, demonstrating advanced HIV disease. Patients with hemo-
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percent response rate. Siltuximab was given IV every 3 weeks and can phagocytic syndrome are typically very ill: greater than 40 percent of
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be administered long-term (up to 60 months). Siltuximab is FDA- the patients in this series required ICU care and 31 percent died within
approved for treatment of Castleman disease in HIV– patients but not a year of diagnosis. The clinical features of hemophagocytic syndrome
in HIV+ patients. Tocilizumab, an anti–IL-6 receptor monoclonal anti- in HIV+ patients include fever, hepatosplenomegaly, and cytopenias.
body has been FDA-approved for use in rheumatoid arthritis. Tocili- Patients often have a markedly elevated ferritin (greater than 10-fold the
zumab had short-term effects in two HIV+ patients with Castleman upper range of normal), coagulopathy, and increased triglycerides. 234
disease, but both patients relapsed within 6 months and required sub- The differential diagnosis of hemophagocytic syndrome in HIV+
sequent treatment with rituximab. Tocilizumab is not FDA-approved patients includes a Castleman disease flare or KICS, and the clinical
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for treatment of Castleman disease. Another approach to treatment features of these syndromes may overlap. Table 81–8 shows the diag-
of Castleman disease is to use antiviral therapy, such as ganciclovir, nostic criteria for hemophagocytic syndrome . If an underlying trigger
valganciclovir, foscarnet, cidofovir, or zidovudine, to suppress HHV8 for the hemophagocytic syndrome is identified, specific therapy should
replication. 227,228 When 14 HIV+ patients with Castleman disease were be directed at the trigger. Treatment for hemophagocytic syndrome is
treated with high-dose zidovudine plus valganciclovir, the C-reactive standardized using the Histiocytosis Society 1994 protocol or the
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protein level, human IL-6 levels and HHV8 viral load improved. The
median progression-free period was 6 months and the major toxicity TABLE 81–8. Diagnostic Criteria for Secondary
was marrow suppression. However, until additional information is Hemophagocytic Syndrome*
available from clinical trials, the data at this time most strongly support
the use of rituximab as the backbone of treatment of Castleman disease. 1. Fever ≥38.5°C
2. Splenomegaly
KAPOSI SARCOMA–ASSOCIATED 3. Cytopenias in at least 2 of 3 lineages (hemoglobin <9 g/dL,
platelets <100,000/μL, neutrophils <1000/μL)
HERPESVIRUS–ASSOCIATED INFLAMMATORY 4. Hypertriglyceridemia (fasting >265 mg/dL) and/or low
CYTOKINE SYNDROME fibrinogen (<150 mg/dL)
A new syndrome termed Kaposi sarcoma-associated herpesvirus 5. Hemophagocytosis found on biopsy of the marrow, spleen,
(KSHV)-associated inflammatory cytokine syndrome (KICS) is char- lymph nodes, or liver
acterized by an inflammatory illness similar to a flare of Castleman dis- 6. Low or absent natural killer cell activity
ease, but without the pathologic diagnosis of Castleman disease. 229–231 7. Ferritin >500 mg/mL
Patients present with fever, sweating, anorexia, leukopenia, anemia,
thrombocytopenia, hypoalbuminemia, and hyponatremia, and may also 8. Elevated soluble CD25
have dyspnea or abdominal pain. Four of the six patients in the original *Presence of 5 of these 8 criteria is required for diagnosis of hemo-
report also had severe manifestations of Kaposi sarcoma. Patients with phagocytic syndrome.
KICS have a very high HHV8 viral load, similar to that seen in patients Adapted with permission from Henter JI, Horne A, Arico M, et al:
during a flare of multicentric Castleman disease. Levels of other cytok- HLH-2004: Diagnostic and therapeutic guidelines for hemophago-
ines, including human IL-6, viral IL-6, and IL-10, are similar in KICS cytic lymphohistiocytosis. Pediatr Blood Cancer 48(2):124–131, 2007.

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