The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman’s disease

The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman's disease

Dieases caused by HHV-8 infection include Kaposi sarcoma (KS), multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL), which occur primarily in patients with HIV infection. Recent studies have shown that upon reactivation, HHV-8 expresses factors that downregulate major histocompatibility class I proteins and coactivation molecules and that may enable productively infected cells to escape cytotoxic T lymphocytes and natural killer cell responses. Pulmonary symptoms were present in all patients and were frequently life threatening. Thoracic and abdominal computed tomography showed enlarged mediastinal, axillary, paracardiac, paraaortic, celiac, mesenteric, obturator and inguinal lymph nodes concomitant with enlarged liver and spleen. Two patients experienced a reduction in the frequency of episodic flares of MCD and detectable HHV-8 DNA with intravenous or oral ganciclovir, whereas the third patient recovered from an acute episode of renal and respiratory failure with intravenous ganciclovir therapy. Therefore, HHV8 and CMV DNA measured in the blood of AIDS patients, are each related mainly to the associated disease, and have no additional predictive value in these patients. PEL is usually extremely aggressive and dissemination of lymphoma to distant sites, opportunistic infections and HIV-related complications are often fatal.

It is not known if SYLVANT® will harm your unborn baby. Discontinue SYLVANT® if the patient does not tolerate the infusion following these interventions. Females who are able to become pregnant should use effective birth control during treatment with SYLVANT® and for 3 months after stopping treatment. After 13 months, follow-up computed tomography and gallium scintigraphy revealed focal hepatic and bone marrow involvement without clinical symptoms except for slight anemia. He completed his dissertation on the epidemiology of HHV-8 and has since published several studies about the virus. As Director of this alliance, based at the Fred Hutchinson Cancer Research Center, he established a translational clinical research site in Kampala. Clinically, patients with virus-associated secondary HPS present with similar sign and symptoms to multi-centric Castleman’s disease (MCD)[6].

In addition, both have been related aetiologically to infection with the γ-herpesviridae, Epstein–Barr virus (EBV) and human herpesvirus-8 (HHV-8) (also known as Kaposi’s sarcoma-associated herpesvirus, KSHV) [7–9]. SYLVANT® may lower your ability to fight infections. We describe HPS in the setting of human immunodeficiency virus (HIV)-MCD, the largest case series in this setting to the best of our knowledge [8,12,13]. Generally speaking, the more suppressed the immune system becomes, the more likely it is that new lesions will occur. The Chelsea and Westminster HIV cohort is one of the largest in Europe and we have collected clinical data prospectively on all HIV seropositive patients with histologically confirmed MCD at our organization. This extensive data set, that now contains 42 individuals, includes four patients who presented with HPS, as defined in accordance with the diagnostic criteria [10,11]. Fifteen serum cytokines were measured at the time of diagnosis of HPS and during follow-up in three separate panels; proinflammatory inflammatory cytokines, interleukin (IL)-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α, granulocyte–macrophage colony-stimulating factor (GM-CSF); T helper type 1 (Th1)/Th2 cytokines, IL-2, IL-4, IL-5, IL-10, interferon (IFN)-γ and immunostimulatory cytokines, IFN-α, IL-12p40/p70, IL-13, IL-15 and IL-17, using FIDIS™ cytokine-coated beads (Biomedical Diagnostics, Oosterhout, the Netherlands).

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. For Permissions, please e-mail: journals.permissions{at}oup.com. Subsequent steps involved washes interspersed by the addition of biotinylated detector antibody and later streptavidin–R-phycoerythrin solution. Although the etiology of HHV-8–unrelated PEL-like lymphoma is still unclear, aging is thought to be a factor, given that the vast majority of patients are elderly, with a median age older than 60 years, in contrast to a median age of 44 years for PEL.2 EBV infection is also suspected to be a factor, although the majority of patients do not demonstrate it.3 EBV is known to be associated with a number of malignancies, and patients with immunodeficiency have an increased risk of EBV-associated lymphomas, which are of B-cell lineage in nearly all instances.8 EBV-associated lymphomas are generally caused by uncontrolled B-cell proliferation that is induced by EBV infection in the setting of immunosuppression, particularly when a patient has pharmacologically impaired EBV-specific T-cell immunity, such as that induced by high-dose cyclosporine administration.9 The current WHO classification recognizes the occurrence of EBV-driven B-cell lymphoma related to immunologic deterioration or senescence that is part of the aging process without any known immunodeficiency.10 Although this possibility was excluded in our patient, it is conceivable that age-related reduction of immune function and EBV infection may have been associated with tumorigenesis. STarStation software was used for data acquisition and analysis. Standard curves were generated for each analyte, and the mean fluorescence intensity value of each analyte in each well was converted into a concentration using the standard curve. Four months before admission, the patient had had multiple cutaneous nodules with normal overlying skin on her trunk, legs, and left hand (Panel C); seven months later, 17 typical KS nodules appeared on her left arm (Panel D).

The former group lived mainly in urban contexts showing sedentary habits, whereas, the latter owned to a nomadic community which was moving throughout Karamoja region to feed livestock. Three months after diagnosis, biopsy showed A1B0 rejection, treated with intravenous methylprednisolone alone. Isolated cases of pulmonary failure in immunocompetent patients have been attributed to HHV-6 when no other pathogens have been isolated; however, such cases are not common, and no causal relation has been established. Typical histopathology of hyaline vascular and plasma cell variants of castleman disease (original magnification × 40). Second, ganciclovir, cidofovir, and foscarnet inhibit the production of HHV-8 from latently infected cell lines upon stimulation, whereas antiviral medications such as acyclovir have been shown to have little or no activity against HHV-8 [8 12]. Polyclonal hypergammaglobulinaemia was present in all patients and none had a detectable plasma paraprotein; all were hypoalbuminaemic (mean 17 g/l) and had raised serum ferritin levels (mean 11 413 µg/l), three of four had raised triglyceride levels (mean 3·3 mmol/l) and two of three had raised fibrinogen levels (mean 4·9 g/l). None of the patients had a previous acquired immune deficiency syndrome (AIDS)-defining illness, two were established on protease inhibitor-based highly active antiretroviral therapy (HAART) with undetectable plasma HIV viral loads and the remaining two individuals were not on HAART and had significant HIV viraemia ().

AIDS-associated Kaposi’s sarcoma occurs particularly in homosexual males. Gene-expression profiling has identified molecular signatures in EBV-positive and EBV-negative cases of PEL. The durable tumor and symptom response rate was 34% on the siltuximab arm compared to no response on the placebo arm, a result that was statistically and clinically significant. In two cases the white pulp showed follicles with features of MCD. It is generally accepted that the HHV8-specific immune control is not dramatically suppressed in both MCD and PEL occurring in HIV-positive or elderly patients,85,86 compared with AIDS-KS or iatrogenic KS onset.82⇓–84,87 However, in our clinical practice, we have recently observed 1 renal transplant patient with MCD and 1 liver recipient with PEL, who have both shown almost undetectable HHV8-specific T-cell responses at the time of disease diagnosis. A clinical attack of MCD was present at 45 visits, whereas chemotherapy-induced clinical remission was noted in 50 visits. genetic, immunosuppressants) enables HHV-8 to escape control by the immune system, replicate in lymph nodes, and signal the release of an excess of inflammatory chemicals (or cytokines), such as Interleukin-6 (IL-6).

In addition there was a prominent histiocytic component within the sinusoids and these histiocytes showed active phagocytosis of red blood cells and other haemopoietic cells. Histiocytes with foamy cytoplasm and less obvious phagocytosis were seen in one case. The phagocytic histiocytes expressed CD68R. An HHV-8-latent nuclear-1 (LNA1) immunostain identified plasmablasts in both white and red pulp (). In addition, these cells expressed CD79a, multiple myeloma 1, B cell lymphoma 2 (BCL2), immunoglobulin (Ig)M and lambda light chains. They were focally positive for CD30, negative for IgD, kappa light chains, CD20, CD138, BCL6, T cell markers and cytomegalovirus. In situ hybridization for EBV (using an EBER probe) was negative.

The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman's disease
1c). There was no evidence of monoclonal B cell expansion. The atypical cells had a moderate amount of eosinophilic cytoplasm and round to oval nuclei with one or more prominent nucleoli (). Severe hypercytokinemia and organ failure may not respond sufficiently to anti–IL-6 targeting monoclonal antibodies, and they require combination chemotherapy or consideration of experimental treatment. The phagocytic histiocytes are seen expressing CD68R and the plasmablasts … Splenic hilar lymph nodes showed small follicles that had features of MCD. As HHV-8 encodes at least one highly mannosylated glycoprotein (gB) (Baghian et al., 2000) and the virus is known to bind to DC-SIGN (Rappocciolo, Jenkins, Hensler, Piazza, Jais, Borowski, Watkins, & Rinaldo, Jr., 2006;Rappocciolo et al., 2008), it is plausible that DC-SIGN binding to virus is at least partly responsible for the dampened immune responses previously observed in HHV-8 infected DC.

Medullary cords were rich in differentiated plasma cells, and larger lymphoid cells with features of plasmablasts were seen in two cases. Even if continuous HHV-8 lytic replication is important for the persistence of KS tumors, it is possible that once KS has developed these drugs may not suppress HHV-8 replication effectively enough to have clinical benefits. Immunohistochemistry was similar to the spleen itself. In one case, the sinusoidal endothelial cells both within the lymph node and the lymphatics surrounding the lymph node demonstrated positivity for HHV-8-LNA1, possibly representing a forme-fruste of Kaposi’s sarcoma. The three bone marrow trephine biopsies were highly oedematous. Two cases showed myeloid predominance and two cases demonstrated focal megaloblastic erythropoiesis. Histiocytes were increased and prominent in two cases and less so in the other case.

These cells showed phagocytosis of nucleated haemopoietic cells, apoptotic debris and expressed CD68R; there were no granulomas. The plasma cells were increased in numbers and amounted to 10–20% of the total marrow cellularity, and there was no evidence of light chain restriction. Occasional HHV-8-LNA1-positive large plasmacytoid cells (plasmablasts) were seen in two cases (both with prominent phagocytosis) (). It was not possible to document Ig light chain or IgM expression specifically in the HHV-8-positive plasmablasts. Moriyama, MD, for providing DNA from Kaposi sarcomas in patients with acquired immunodeficiency syndrome. The reticulin was increased (grades 1–2). The stainable iron was moderately increased.

Section of a cellular bone marrow shows increased numbers of histiocytic cells amidst other haemopoietic lineage cells. The phagocytic histiocytes are seen expressing CD68R and there are occasional human herpesvirus-8-latent nuclear-1 (HHV-8-LNA1) plasmablasts … The HHV-8 levels were raised markedly in all four individuals (median 3 840 000 copies/ml, range 30 000–90 000 000 copies/ml) at presentation with one of the patients having one of the highest HHV-8 viraemias we have ever observed. This compared with the median plasma HHV-8 level of 12 800 copies/ml in 34 patients with HIV-associated MCD without HPS. HHV-8 viraemia decreased in all four patients during the course of therapy (). Of the 15 cytokines measured, only IL-8 and IFN-γ were elevated in all the individuals at baseline and follow-up. IL-4, IL-6 and IL-10 were elevated in three of four patients and IL-1β, IL-2, IL-15, GM-CSF, TNF-α and IFN-α were normal at baseline ().

Follow-up measurements were similar to those obtained at baseline. Only differences in IL-10, which was increased in one of four patients at follow-up versus three of four at baseline, and IL-17, which was increased in three of four patients at follow-up and one of four individuals at baseline, were observed in more than one patient comparing baseline with follow-up. Plasma cytokine measurements at the time of diagnosis and during the follow-up of haemophagocytic syndrome (HPS) in all four patients. The first follow-up sample time-point was 4–6 weeks following the baseline sample, which corresponded to the … The HPS, a rare condition, was associated with HIV-MCD in four (9%) cases of our cohort including 44 patients. At present, there is little diagnostic or treatment consensus for secondary HPS which is dealt with generally on a case-by-case basis, depending on the associated infection(s) identified. Here, treatment with etoposide-based chemotherapy and rituximab was successful in all cases thus far, with all patients in remission after a median of 12 months’ follow-up.

Indeed, the morphologic changes were consistent with the presence of an atypical immunoproliferative disorder characterized by reactive, nonspecific paracortical hyperplasia, which can occur in response to viral infections18 but to our knowledge has not previously been described in a patient with HHV-8 infection. Since 1999, several genetic loci related to the activity of perforin and granzyme granules have been associated with genetic HPS, thus explaining the impaired or absent function of natural killer cells and cytotoxic T cells characteristic of the disease [17], although such findings cannot necessarily be extrapolated to reactive HPS. We demonstrate for the first time a partial response of pulmonary KS to reduced immunosuppression and the initiation of sirolimus. an increase in CD14/CD16 expression) [19]. VEGF has been found to specifically promote the growth of endothelial cells and is capable of controlling blood vessel formation. Sixteen (62%) of 26 participants were HIV-positive, with a median CD4 T cell count of 434 cells/mm3 (range, 49 936 cells/mm3) and a mean HIV RNA plasma level of log10 3.8 copies/mL (range, 2.25.3 copies/mL). However, it is considered that an exaggerated inflammatory response is responsible for necrosis and organ failure and results in uncontrolled proliferation and phagocytic activity of histiocytes [1].

Despite this increasing literature concerning immune dysregulation in HPS, the majority of cytokines we measured were not elevated in all the patients. This is particularly surprising considering the ‘extreme’ HHV-8 viraemia we observed, including levels of more than 7 million copies/ml in two cases. Similarly, the International Prognostic Index, while demonstrating prognostic value in large series of NHL [49] and ARL [50], has never been validated in a cohort of patients with PEL. In one previous study in the literature, the cytokine profile in fatal HIV–tuberculosis–EBV-associated HPS showed increases in the plasma Th1 cytokine IFN-γ, the Th1-related chemokine monokine induced by IFN-γ (MIG)/CXCL9, IFN-induced protein 10 (IP-10)/CXCL10, IL-8/CXCL8 and IL-6, the last group of which increased during therapy with foscarent [21]. The authors of that high-profile case report concluded by stating that immunosuppressive agents (i.e. steroids and anti-cytokine antibodies) may be beneficial in such severe HPS cases and demonstrated that cytokine profiling enhances the understanding and management of immune-mediated diseases. While we have not measured chemokines, our cytokine data derived from four patients with HHV-8-associated HPS suggest that their approach should be treated with caution.

Chemotherapy using dexamethasone, cyclosporine and etoposide (adopted by the Histiocyte Society in 1994 and updated more recently [11,22]) is recommended for severe HPS, including familial and EBV-associated cases. Use of bone marrow transplants has also been reported and the HLH-94 study in 113 children showed a 56% 3-year survival [23]. These data are unlikely to be directly relevant to HIV-1 seropositive adults with HHV-8-driven HPS. We consider that etoposide-based chemotherapy is appropriate treatment here and that rituximab should also be added to the list of potentially useful therapies. The cytokine data we have shown is notable for the lack of heterogeneity which normally afflicts plasma measurements during the course of disease; data at follow-up were remarkably similar to baseline values. The most prominent change in plasma cytokine concentration was seen with IL-10 (decreases), which is produced by HHV-8-infected and HIV-tat-induced cell lines and has been linked to B cell activation and polyclonal hypergammaglobulinaemia in HIV-1 infection [24–26]; other data in HHV-8-driven disease suggest that it is a better marker of disease activity than IL-6. The role of IL-10 in the control of immune hyperactivation observed in one patient with HPS has been reported previously [27].

There are no studies on the role of IL-17 in HHV-8-associated diseases (to the best of our knowledge), but its role in immunoregulation is consistent with the increased levels we observed at follow-up [28]. We have demonstrated recently that the incidence of HIV-MCD in our cohort of over 10 000 patients measures 4·3/10 000 patient-years [95% confidence interval (CI): 2·7–6·4] (Bower et al., in press). We have not calculated the incidence of HPS here as, because of small numbers, 95% CIs would be extremely wide. We thank Dr. We would like to thank the patients who took part in this study and are grateful for the care provided by the nurses and doctors at TMAC ward and Kobler Day Care, Chelsea and Westminster Hospital. The authors acknowledge the technical support provided by Ms Sally Clark and Ms Hannah Poulson at Imperial College. The study was funded by the St Stephen’s AIDS Trust.

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