Hemophagocytic lymphohistiocytosis (HLH) is a result of an abnormal activation of immune cells (T lymphocytes, natural killer cells, and macrophages) resulting in cytokine overproduction and immune destruction of cells, eventually resulting in multiorgan failure. Genetic causes are responsible for primary hemophagocytosis, but malignancies, infections, and autoimmunity underlie most of the secondary cases. We present an unusual case of a patient with AIDS and disseminated Kaposi sarcoma who was commenced on highly active antiretroviral therapy (HAART) but developed HLH secondary to immune reconstitution inflammatory syndrome (IRIS). We report this case to highlight the difficulty in managing this patient given the complex interplay of immunosuppression due to AIDS, immune reconstitution following initiation of HAART, and immune overdrive manifesting as HLH.
Hemophagocytic lymphohistiocytosis (HLH) is a result of an abnormal activation of immune cells (T lymphocytes, natural killer cells, and macrophages) resulting in cytokine overproduction and immune destruction of cells, eventually resulting in multiorgan failure. Primary HLH is due to genetic defects and usually presents in childhood and very rarely in adults. However, secondary HLH can be triggered by a number of conditions including infections (viral, bacterial, fungal, and parasitic infections), malignancies (particularly lymphomas), immunodeficiencies, and autoimmune conditions.
Kaposi sarcoma is an AIDS-defining illness, and the cornerstone of AIDS-related Kaposi sarcoma treatment is highly active antiretroviral therapy (HAART).
We present a case of a patient with disseminated Kaposi sarcoma who was commenced on HAART but developed fatal hemophagocytosis secondary to immune reconstitution inflammatory syndrome (IRIS). We report this case to highlight the difficulty in managing this patient given the complex interplay of immunosuppression due to AIDS, immune reconstitution following initiation of HAART, and immune overdrive manifesting as HLH.
A 59-year-old female with a past medical history of hypothyroidism presented with a rash involving her scalp, neck, torso, and vagina. She denied taking any new medication and had been on levothyroxine replacement for about 12 years: she had no known allergies. There was no significant family history; she was an ex-cigarette smoker with a 20-pack-year smoking history. Physical examination was significant for diffuse purplish plaques over the torso. Human immunodeficiency virus (HIV) viral load was 196,000 copies/ml with CD4 count 76/
She re-presented two weeks later with fever. Physical examination revealed a maximum temperature of 38.8°C and tachycardia (pulse rate 108/min), and previously noted cutaneous Kaposi lesions were still present. She was worked up with appropriate cultures and serological testing, but no opportunistic infection was found. Further workup of her Kaposi sarcoma including upper gastrointestinal endoscopy and CT scan of her thorax, abdomen, and pelvis revealed no visceral involvement, but splenomegaly was present (Figure
CT scan of the abdomen and pelvis. Abdominal CT scan showing splenomegaly. The spleen was enlarged and was 14 cm in length (white arrow pointing to the enlarged spleen).
She again presented 1 month from AIDS diagnosis with severe fatigue and diarrhea to another hospital. She was found to be hypotensive (systolic blood pressure 80 mmHg), necessitating intravenous fluids and a brief course of vasopressors before she was transferred to our institution. Initial labs showed pancytopenia (platelet count 6,000/
Bone marrow aspirate smear. The Wright Giemsa stain of the patient’s bone marrow aspirate with an arrow highlighting a macrophage phagocytizing red blood cells, lymphocytes, and neutrophils (arrow pointing to the macrophage).
Hemophagocytic lymphohistiocytosis (HLH) is a fulminant disorder resulting in unbridled activation of immune cells, resulting in death if untreated [
Although she had a high HIV viremia and HHV8 (Kaposi-associated herpesvirus) infection at diagnosis, hemophagocytosis was not manifest until 6 weeks after HAART was initiated: the temporal association between HAART and hemophagocytosis makes immune reconstitution inflammatory syndrome (IRIS) the most probable trigger of her hemophagocytosis.
IRIS is the restoration of the immune response to pathogen-specific antigens, resulting in unmasking of previously subclinical opportunistic infections and nonpathogen-specific response manifesting as autoimmune conditions such as Graves’ disease [
Patients with IRIS manifest clinical worsening despite improvement in their immune function as evidenced by improving HIV viremia and/or CD4 count. Our patient responded to HAART as evidenced by a reduction in her viremia from 196,000 RNA/mL to 670 RNA/mL, signifying a recovery of her immune system. In our patient, she already had clinically apparent extensive cutaneous Kaposi sarcoma before the initiation of HAART, and there was no clinical worsening of her skin lesions after the commencing HAART. Her clinical deterioration was secondary to hemophagocytosis.
In the medical literature, HLH is not described as part of the spectrum of immune reconstitution in the setting of HIV/AIDS. There have however been a few case reports suggesting that hemophagocytosis secondary to IRIS can occur. Two cases of hemophagocytosis secondary to IRIS in AIDS patients with lymphoma as well as an additional 2 cases of IRIS-associated hemophagocytosis in the absence of lymphoma have been reported [
Treatment modalities in HLH include immunosuppressants such as high-dose steroids, intravenous immunoglobulin, chemotherapeutic agents such as etoposide, and allogeneic hemopoietic stem cell transplant [
Given the heterogeneity of the clinical manifestations of IRIS, treatment strategies also vary and are usually aimed at the underlying infection or autoimmune condition. If patients have multiple risk factors for the development of IRIS following initiation of HAART, clinicians sometimes commence treatment for the underlying opportunistic infection first with a lag period before initiating HAART [
In a consensus guideline issued by members of the adult HLH working group of the Histiocyte Society, etoposide is recommended for treating adult HLH, but the duration and intensity of treatment should be tailored to the severity of HLH on a case-by-case basis. In refractory HLH, combination chemotherapy and allogenic stem cell transplantation is recommended [
Furthermore, due to the rarity of IRIS-associated HLH, affected patients may not be diagnosed early enough. With the benefit of hindsight, our patient had bicytopenia, fever, and splenomegaly at her prior presentation, and an earlier bone marrow biopsy might have been warranted. Although there are certain criteria that must be met to diagnose HLH, patients may not develop all these features at once, and this may lead to a delay in diagnosis and treatment. One of such criteria is elevated soluble interleukin-2 receptor (sIL-2r), also referred to as soluble CD 25 (sCD 25). Although sIL-2r of at least 2400 U/mL has a high sensitivity for HLH, it was only 63% specific in the adult cohort studied by Hayden et al. [
The commonly used criteria were developed by the HLH-2004 study group who only studied the pediatric population [
There remains the need to conduct a prospective study to evaluate the efficacy of the various treatment modalities for HLH in adults.
Clinicians need to maintain a high index of suspicion for HLH in the appropriate clinical setting. This is because an early diagnosis will aid the prompt initiation of treatment, and this can improve patient outcomes. Regarding our patient presented here, the most challenging aspect of her care was how to manage her as there are currently no treatment guidelines for IRIS-associated HLH in the setting of AIDS.
Future efforts need to be directed primarily towards conducting prospective studies to evaluate the efficacy of the various treatment modalities for HLH in adults. The specific subset of adults with IRIS, AIDS, and HLH can then be studied secondarily. We believe that by reporting this case, clinicians will be more aware of the possibility of HLH developing after initiating HAART in AIDS patients.
The authors have no conflicts of interest to declare regarding the authorship of this case report.
The authors acknowledge the contribution of Dr Jody Borgman (HIV medicine specialist, Einstein Medical Center) and Dr Manju Balasubramanian (Chief of the Department of Pathology and Laboratory Medicine, Einstein Medical Center) in the care of the patient.