Infections associated with haemophagocytic syndrome

Lancet Infect Dis 2007; 7: 814–22

97/2/28 報告人： R1 林軒名

Content

Introduction Case presentation Definition Classification Pathophysiology Diagnosis Treatment Virus-associated haemophagocytic syndrome Bacteria, parasite, and fungi-associated haemophag

ocytic syndrome

Case presentation

20-year-old white woman presented with a 2 week history of fever, fatigue, and 3 kg weight loss.

Occasional headaches without neck stiffness or photophobia, some shortness of breath on exertion, and occasional nausea.

Case presentation

Past medical history: Holt-Oram syndrome, autosomal-dominant, congenital cardiac and forelimb anomalies. s/p operation 2 m/o

Both her mother and brother had Holt-Oram syndrome.

Case presentation

A year before : Primary EBV infection diagnosed with positive

serologies and a positive EBV PCR assay. Severe pancytopenia, bone marrow biopsy done

at that time was non-diagnostic No history of recurrent infections after that epi

sode A college student who abstained from sexual

activity, tobacco, alcohol, and illicit drug use. No recent travel or tick bites.

Case presentation

Physical examination No acute distress BT: 38·5°C, HR: 96/min, BP: 106/65 mm Hg. Supple neck A grade 3/6 systolic murmur at the left upper stern

al border, unchanged from previous examinations.

Case presentation

truncated upper extremities and was missing digits on both hands from her congenital syndrome

Case presentation

A total leuckocyte count of 500 cells/uL with 40% band forms,16% neutrophils, 40% lymphocytes, and 4% monocytes, normocytic anaemia (hematocrit 25%) and platelet count 102000/μL)

PT/INR and aPTT ratio were normal. LDH was 575 IU/L with normal GOT/GPT, bili

rubin, and haptoglobin levels.

Case presentation

Mycobacteria, fungi, HIV-1, HIV-2, hepatitis B and C, cytomegalovirus, parvovirus, and ehrlichia were negative.

Toxoplasma IgG antibodies(+), IgM(-). Serum cryptococcal antigen test (-) urine histoplasma antigen test (-)

Case presentation

EBV capsid IgG antibodies and EBV nuclear antigen were positive. EBV capsid antigen IgM antibodies were negative.

the EBV serum PCR result was 36 800 copies/mL (cut off value: 300 copies/ml)

The bone marrow biopsy on admission showed dysplasia in all cell lines with some fibrosis, but cytogenetics were normal.

Case presentation

P’t received ceftazidime (2 g intravenously three times a day)

The fever persisted and progressive hepato-splenomegaly and generalised tender lymphadenopathy.

CT scan on hospital day10 revealed three new lung nodules, with diffuse neck adenopathy and hepato-splenomegaly.

Case presentation

Bronchoscopy and lavage showed active hemorrhage.

Pneumocystis jirovecii, fungal infection, acid fast bacilli, cytomegalovirus, and herpes simplex virus (HSV) were negative.

Lung biopsy of the nodules revealed acute and organising pneumonia with nuclear debris suggesting the possibility of viral origin.

Immunoperoxidase stains for CMV, HSV, EBV, adenovirus and fungal stains were all negative.

Case presentation

Transjugular liver biopsy showed centrizonal hepatocyte dropout and damage with sinusoidal histiocytic infiltrate and all stains were again negative.

Case presentation

On hospital day 15, the patient had increasing respiratory distress followed by altered mental status and multiorgan failure.

Leukocyte count of 0·5 cells/μL, Hct 16·8%, and a platelet count of 8000/μL.

Cr:3·2 mg/dL, requiring H/D. AST: 2132 IU/L ,total bilirubin:16 mg/dL, Ferritin level :4800 ng/mL; TG: 381 mg/dL.

Case presentation

Disseminated intravascular coagulation developed (D-dimer 4456 ng/mL, INR 8·3, aPTT 152 s, fibrinogen less than 60 mg/dL).

The EBV PCR continued to increase from 443000 copies/mL to 974000 copies/mL

High dose steroids were given. She was then transferred to the intensive c

are unit and died on hospital day19

Case presentation

Autopsy: proliferation of macrophages and hemophagocytosis in the bone marrow, lymph nodes, and spleen with positive immunohistochemistry for EBV.

The patient met the criteria for EBV-associated haemophagocytic syndrome, including persistent fever, splenomegaly, severe pancytopenia, liver test abnormalities, elevated ferritin, and histological evidence of haemophagocytosis.

(A) Haematoxylin-eosin stain of bone marrow sample obtained on autopsy showing rare phagocytic cells with engulfed haematopoietic elements (arrows). (B) CD68 (macrophage marker) staining by immuno-histochemistry showing presence of abundant macrophages within lymph nodes. (C) EBV staining by immuno-histochemistry showing numerous infected cells (arrows) within lymph node.

Haemophagocytic syndrome

An impaired or absent function of NK cells and cytotoxic T cells.

Results in uncontrolled and ineffective immune activation leading to cellular damage and multiorgan dysfunction as well as proliferation and activation of benign macrophages with haemophagocytosis throughout the reticuloendothelial system causing pancytopenia, hepatosplenomegaly, and lymph-adenopathy.

Classification

Primary or genetic Can occur at any age Underlying genetic mutation in only 40% patients both primary and secondary syndromes can be

precipitated by an infection. some secondary cases carry a higher mortality.

Secondary or reactive haemophagocytic syndrome

Genetic haemophagocytic syndrome Occur in one out of 30000–50000 births. Manifest in the first year of life in 70–80% of cases. Related with Immune deficiency syndromes: Chedia

k-Higashi syndrome, Griscelli syndrome, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, Severe combined immunodeficiency, Lysinuric protein intolerance, Hermansky-Pudlak syndrome

Holt-Oram syndrome is not associated with any immune deficiency state and does not result in increased susceptibility to infections.

Reactive haemophagocytic syndrome Most patients in subsequent reports had no k

nown genetic or acquired immunodeficiency. Classification

Infection associated Malignancy-associated Lymphohistiocytosis (especially lymphoma-associ

ated ) Macrophage activation syndrome (associated wit

h autoimmune diseases)

infection-associated hemophagocytic syndrome A review of the published cases by Janka an

d colleagues showed that of 219 children diagnosed with infection-associated haemophagocytic syndrome before 1996,

More than half were from east Asia. Overall mortality was 52% (103 of 198 childre

n died) but was higher in patients with EBV-associated disease (72 [73%] of 99 children with EBV died). EBV was the triggering virus in 121 (74%) of 163 children.

Infection associated haemophagocytic syndrome Virus-associated haemophagocytic syndrome

Herpes virus infection (herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, human herpesvirus 8)

HIV Other viruses: adenovirus, hepatitis viruses, parvovirus, infl

uenza Other infections associated with haemophagocytic s

yndrome Bacteria including mycobacteria and spirochaetes Parasites Fungi

Pathophysiology

The pathophysiology is not fully understood. The deficiency in cytolytic activity results in p

ersistent activation of lymphocytes and histiocytes.

Uncontrolled immune response leads to hypersecretion of pro-inflammatory cytokines. an upregulation of adhesion molecules and MHC I and II molecules on mono-macrophages, and an expansion of inflammatory monocytes

Pathophysiology

This exaggerated inflammatory response is responsible for necrosis and organ failure and results in uncontrolled proliferation and phagocytic activity of histiocytes. s

Diagnosis A molecular diagnosis consistent with haemophagocytic

syndrome (eg, PRF mutations, SAP mutations, MUNC13-4 mutations)

Having 5/8 of the following Fever Splenomegaly Cytopenia (affecting more than two cell lineages, haemoglobin ≤9

g/dL, <100 000 platelets/μL, neutrophils <1000 cells/μL) Hypertriglyceridaemia (triglycerides ≥265 mg/dL) and/or hypofibri

nogenaemia (fibrinogen ≤150mg/dL) Haemophagocytosis in the bone marrow, spleen, or lymph nodes

without evidence of malignancy Low or absent natural killer cell cytotoxicity Hyperferritinaemia (ferritin ≥500 ng/mL) Elevated soluble CD25 (interleukin-2Rα chain ≥2400 IU/mL)

Diagnosis

Diagnosis

Diagnosis

Two highly diagnostic parameters: increased plasma concentration of the alpha chai

n of the interleukin-2 receptor (sCD25) impaired NK-cell activity.

The elevation of interleukin-2 receptor suggests the activation of T lymphocytes and correlates with prognosis.

The haemophagocytosis can be seen in any organ, particularly in the bone marrow, lymph nodes, liver, and spleen.

Diagnosis

Once a diagnosis of haemophagocytic syndrome is established, searches for an underlying genetic, rheumatological, or malignant disease and a possible infectious trigger should be undertaken.

Treatment

No randomised controlled clinical trials testing potential treatments have been done.

Suppressed the increased inflammatory response and control cell proliferation with immunosuppressive or immunomodulatory agents and cytotoxic drugs.

Pathogen-direct therapy + supportive therapy Other than EBV infection, treatment of the un

derlying infection alone is associated with recovery in 60–70% of patients.

Treatment

Chemotherapy using dexamethasone, cyclosporin, and etoposide ( severe or familial and EBV-associated case)

Bone marrow transplantation (genetic haemophagocytic syndrome and severe or refractory haemophagocytic syndrome)

Monoclonal antibodies (anti-CD20 [rituximab] and anti-interleukin-2Rαreceptor daclizumab) (heumatic disease or malignancy associated case)

Treatment

Intravenous immunoglobulin, ? Intravenous immunoglobulin + steroids is infe

rior to an etoposide-containing regimen. Granulocyte-colony stimulating factor or

GM-CSF can exacerbate haemophagocytic syndrome

EBV-associated hemophagocytic syndrome Mainly occur in

immunocompetent children and adolescents immune deficiencies patient Infectious mononucleosis, chronic active EBV i

nfection,28 and lymphoproliferative disorders EBV : high incidence in Asian countries

EBV-associated hemophagocytic syndrome EBV typically infects and replicates in B cells,

EBV-specific cytotoxic T cells are usually required to regulate the infected B cells and produce memory cells.

EBV infects primary CD8+ cells with a failure to produce a sufficient number of EBV-specific cytotoxic T cells, suggesting a NK T-cell dysfunction.

EBV viral load (EBV nucleic acid by PCR), to make diagnosis and prognosis

EBV-associated hemophagocytic syndrome EBV viral load is higher in EBV-associated he

mophagocytic syndrome compare with infectious mononucleosis.

The quantitative analysis of cell-free EBV genome copy number at 4 months after therapy can assess the response to treatment and carries prognostic value.

Genetic testing needs to be done to rule out or confirm an underlying immunodeficiency

EBV-associated hemophagocytic syndrome EBV-associated syndrome carries the wors

t prognosis in all virus associated syndrome. EBV responds poorly to aciclovir Etoposide-containing regimens : Reduce mor

tality in group receive etoposide within 4 weeks after diagnosis.

Bone marrow transplantation: necessary for genetic immunodefficiency, chronic active EBV infection, and refractory disease.

Herpes viruses-associated hemophagocytic syndrome Cytomegalovirus

Cytomegalovirus immunoglobulin, foscarnet, and ganciclovir, is curative.

HHV8-associated haemophagocytic syndrome an etoposide-containing regimen or ganciclovir an

d foscarnet.

HIV-associated haemophagocytic syndrome Around 10% of bone marrow biopsies in HIV

patients before initiation of highly active antiretroviral therapy (HAART) showed haemophagocytosis.

In one autopsy study, hemophagocytosis was found in 20% of HIV patients.

HIV

Influuenza

Parvovirus

Bacteria-associated haemophagocytic syndrome and Mycobacteria spp

Parasites-associated haemophagocytic syndrome

Fungi-associated haemophagocytic syndrome