European Journal of Internal Medicine 22 (2011) e155–e157
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European Journal of Internal Medicine
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Letter to the Editor
Favourable outcome of life-threatening infectious-related
haemophagocytic syndrome after combination treatment with
corticosteroids and intravenous immunoglobulin infusions
Keywords:
Haemophagocytic syndrome
EBV infection
Infective endocarditis
Intravenous immunoglobulin therapy
Secondary haemophagocytic syndrome (HPS) is an infrequent,
life-threatening condition with an unfavourable outcome in terms of
mortality as it is often underdiagnosed [1]. The syndrome can be
induced by numerous triggering factors namely, malignancies, in-
fections, several autoimmune diseases or lymphoproliferative disor-
ders and is characterised by an impaired or absent function of NK cells
and cytotoxic T-cells [1–3]. The final result is an uncontrolled and
ineffective immune activation leading to cellular damage, multi-organ
dysfunction and proliferation of macrophages with haemophagocy-
tosis throughout the reticuloendothelial system [1–3].
Recently, diagnostic and therapeutic guidelines for HPS have been
proposed [4]. Since HPS is a highly fatal disease the immediate aim of
therapy should be the suppression of the increased inflammatory
response using immunosuppressive or immunomodulatory and
cytotoxic drugs including dexamethasone, etoposide and cyclosporine
as adopted by the Histiocyte Society in 1994 and updated in 2004 [4].
However, since HPS is rare, no randomised controlled clinical trials
testing potential treatments are available. Accordingly, we present
herein three patients who fulfilled the diagnostic revised criteria of
HPS due to infectious agents treated all efficiently with combination of
corticosteroids and intravenous immunoglobulin.
1. Patient A
A severely ill 28-year-old Caucasian male farmer was admitted to our
department because of high fever accompanied by chills, generalised
malaise and cough of 8 days duration. Physical examination revealed
tachypnoea (24/min), conjuctival injection, hepatosplenomegaly and
cervical and axillary lymphadenopathy. His family and past history were
unrevealing.
Laboratory tests showed anaemia, thrombocytopenia, elevation of
liver function tests (LFTs), erythrocyte sedimentation rate (ESR),
triglycerides and ferritin levels accompanied by hypofibriginaemia
(Table 1). ECG, bone marrow aspiration and cerebrospinal fluid (CSF)
analysis were unrevealing. On hospital day 2, the patient deteriorated
and was supported by high oxygen mixtures (FiO2 50%) and
intravenous ceftriaxone (4 g/day) with no improvement. Clinical
and extensive laboratory examinations using conventional and
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2011.07.010
molecular techniques [5] ruled out several infectious diseases
including streptococcal infections, human immunodeficiency virus
(HIV), herpes simplex virus, cytomegalovirus, adenovirus, H1N1
influenza virus, Hantaan virus, Echo and Coxsackie viruses, brucello-
sis, leptospirosis, leishmaniasis and tuberculosis.
However, serum IgM antibodies against Epstein-bar virus (EBV)
capsid antigen tested high positive along with positive EBV-PCR in
CSF. The patient considered to suffer from EBV-induced HPS since
fulfilled 5 out of 8 criteria for HPS [4] (Table 1). He was managed by
combination of intravenous corticosteroids (daily pulses of 1 g
methylprednisolone for 3 days followed by 1 mg/kg/day of prednis-
olone with appropriate rapid tapering of 10 mg every fourth day) and
intravenous immunoglobulin (0.4 mg/kg per day for 5 days) which
resulted in an immediate remission of all symptoms and laboratory
abnormalities. The patient was discharged after 10 days of treatment
in very good health and he is still completely healthy after 15 months
of follow-up though he has been without any treatment for the last
14 months.
2. Patient B
A 53-year-old Caucasian female patient was referred to our
department because of high fever, chills, skin rash, generalised fatigue
and disturbance of consciousness during the last 5 days. She suffered
from diabetes mellitus type-2 and chronic atrial fibrillation and she
had undergone surgery for prosthetic mitroid valve 5 years ago. The
patient was on acenocoumarol but brain computed tomography (CT)
and CSF analysis had no abnormal findings.
On clinical examination she was critically ill as attested by the
presence of hypotension, tachypnoea (25/min) and high fever. Liver
and spleen were palpable, while significant systolic murmur (3/6) at
the apex of heart and Osler nodes on the palms were obvious.
Fundoscopy revealed Roth spots while multiple blood cultures proved
positive for methicillin-sensitive Staphylococcus aureus (MSSA). Trans-
oesophageal echocardiography confirmed the clinical diagnosis of
infective endocarditis by the presence of prosthetic valve vegetations.
However, due to the significant anaemia and thrombocytopenia of the
patient along with the considerable elevation of triglycerides and
ferritin levels accompanied by hypofibriginaemia and haemophago-
cytosis in bone marrow biopsy (Table 1), HPS due to MSSA-related
infective endocarditis was considered since the patient fulfilled 6 out
of 8 HPS criteria (Table 1). She received combination of specific
treatment against MSSA infective endocarditis (intravenous cloxacil-
lin 12 g/day for 6 weeks) with intravenous pulses of 1 g methylpred-
nisolone for the first 2 days and intravenous immunoglobulin
(0.4 mg/kg per day) for 5 days for the MSSA-related HPS. Immediate
stabilisation of her condition was noted namely, no fever or
tachypnoea, normal blood pressure after 2 days of treatment and
improvement of all haematological and biochemical laboratory
parameters after 5 days of treatment. However, due to hemodynamic
disturbances of the prosthetic valve a surgical replacement was
decided which was performed successfully at the 8th week of
e156 Letter to the Editor

Table 1 health after 15 days of combination treatment. He is still in good

Demographic, clinical and laboratory characteristics, the diagnostic criteria for HPS, and health after 10 months of follow-up though he has been without any
the management and outcome of the three HPS patients of the study.
treatment for the last 8.5 months.
Characteristics Patient A Patient B Patient C The main clinical and laboratory findings of HPS include fever,
Sex (M/F) M F M splenomegaly, hepatomegaly, lymphadenopathy, rash, cytopenias,
Age (years) 28 53 36 characteristic elevated ferritin and triglyceride levels and hypofrino-
White blood cells 14.6 9.5 19.2 genaemia [1–4]. Haemophagocytosis is typically seen in any organ,
(×103/mm3)
particularly in the bone marrow, lymph nodes, liver and spleen
INR 1.01 1.41 1.21
aPTT (s) 30.3 39.7 25.3 although it could be absent in an initial biopsy specimen. Almost all
AST (IU/L) 241 130 31 the abovementioned clinical and laboratory characteristics of HPS
ALT (IU/L) 336 73 42 were profound in our cases making the diagnosis of HPS definite. Once
LDH (IU/L) 974 533 370 a diagnosis of acquired HPS is established, investigation for an
ESR (mm) 50 95 76
underlying rheumatological or malignant disease and a possible
Criteria for HPS Diagnosis
1. Fever 40 °C 40 °C 39.5 °C infectious trigger should be undertaken [1–4]. In terms of infectious
2. Splenomegaly Yes Yes Yes agents, HPS has been associated with a variety of viral, bacterial,
3. Cytopenias (≥2 cell Hb: 8.2/Ht: 26 Hb: 8.0/Ht: 26 Hb: 7.2/Ht: 24 fungal, and parasitic infections [2]. Among viruses, EBV is thought to
lineages, b105 PLTs/mm3 PLTs: PLTs: 0.38 × 105 PLTs:
be the most common triggering agent, as also confirmed in our first
Hb b 9 g/dL, b103 0.76 × 105 0.95 × 105
neutrophils/mm3) case [2]. The inability to identify a causative infectious agent in our
4. Triglycerides 432 530 484 third case besides the extensive investigation is not surprising as no
(≥ 265 mg/dL) and/or 125 140 128 other disease such as malignancies, several autoimmune diseases and
fibrinogen (≤150 mg/dL) lymphoproliferative disorders could be identified and therefore, we
5. Haemophagocytosis No Yes Yes
supposed the presence of an undefined infectious trigger as the most
6. Reduced natural killer NA NA Yes
cell toxicity probable cause of HPS taking into account the whole clinical picture
7. Ferritin ≥500 ng/mL 12.000 7600 1247 and the preceding flu-like syndrome of the patient. It should be noted,
8. Elevated interleukin-2Rα NA NA NA however, that although infections have an important role in HPS
chain (≥2400 IU/mL)
aetiology, no data exist on the precise incidence and prevalence of
Definite diagnosis of HPS 5/8 6/8 7/8
(≥ 5 out of 8 above)
infection-associated HPS.
Infectious agent EBV MSSA Undefined In the absence of randomised controlled trials HPS treatment has
Treatment Corticosteroids Pulse methyl- Corticosteroids in principle two aims. The first is to suppress the severe hyperin-
plus IVIG prednisolone plus IVIG flammation and the second is to identify – if possible – the underlying
plus cloxacillin
trigger and in the case of an infectious agent to try killing the
plus IVIG
Outcome Alive Alive Alive pathogen-infected antigen-presenting cells and thus remove the
Follow-up (months)a 15 12 10 stimulus of the ongoing but ineffective activation of T-cells. It has to be
Abbreviations are same as in text. M=male; F=female; Hb=haemoglobin; Ht= specifically emphasised that pathogen directed therapy is usually not
haematocrit; PLTs=platelets; INR=international normalised ratio; aPTT=activated partial sufficient to control hyperinflammation with the potential exception
thromboplastin time; AST=aspartate aminotransferase; ALT=alanine aminotransferase; of visceral leishmaniasis-associated HPS [6]. Hyperinflammation can
LDH=lactate dehydrogenase; IVIG=intravenous immunoglobulin; NA=not available. be treated with corticosteroids, cyclosporin and etoposide-containing
a
Free of symptoms.
regimens which are cytotoxic for lymphocytes and inhibit the
expression of cytokines and differentiation of dendritic cells, while
hospitalisation; the patient was discharged in good health at week 10. preventing T-lymphocyte activation [4].
She is still in an excellent healthy condition (12 months of follow-up). Nevertheless, in our three HPS cases we used corticosteroids and
intravenous immunoglobulin infusions in an attempt to stop the
3. Patient C hyperinflammation stage of the syndrome in association with specific
antibiotic treatment (cloxacillin) in the second case with MSSA-
A 36-year-old Caucasian male patient was admitted to our related infective endocarditis and HPS. To the best of our knowledge,
department because of high fever accompanied by flu-like symptoms this is the fourth case of infective endocarditis associated with HPS in
of 6 days duration. Physical examination revealed confusion, con- the literature [7–9]. Of note, similar treatment (corticosteroids plus
juctival injection, and hepatosplenomegaly. His family and past intravenous immunoglobulin plus specific antibiotic regimen) with
history were not contributory. Laboratory tests revealed anaemia, favourable outcome in case of infective endocarditis-related HPS has
thrombocytopenia and elevation of ESR, triglycerides and ferritin been reported previously in a patient with Abiotrophia defectiva
levels and hypofibriginaemia (Table 1). ECG, CT of the brain, chest, endocarditis and HPS [7]. The role, however, of the use of
upper and lower abdomen, autoimmune serology and CSF analysis immunoglobulin infusions for treating HPS is not fully understood.
were normal. As in Case A, clinical and laboratory investigations using Intravenous immunoglobulin enhances immune homeostasis by
conventional and molecular techniques [5] ruled out several infec- interfering with costimulatory molecules and the activation of
tious diseases. complement, providing anti-idiotypic antibodies or suppressing the
Empirical treatment with intravenous antibiotics including ceftri- antibody production, and modulating the expression and function of
axone, vancomycin, cotrimoxazole and acyclovir was started without Fc receptors on macrophages, suppression of cytokines, chemokines,
improvement. On hospital day 4, worsening of the respiratory and adhesion molecules and altering the activation, differentiation,
function was evident in chest-X-ray with bilateral infiltration of the and effector functions of T-cells. These mechanisms may explain the
lungs, while bone marrow aspiration showed considerable haemo- effectiveness of intravenous immunoglobulin in HPS. Additionally,
phagocytosis. Moreover, low NK cell activity was confirmed. As the perhaps the early recognition and early treatment of the syndrome
patient fulfilled 7 out of 8 diagnostic criteria for HPS (Table 1), during the disease process as was done in our cases could be the key
antibiotics stopped and combination of corticosteroids and intrave- for the favourable outcome when intravenous immunoglobulin is
nous immunoglobulin at the same doses as in Case A was started. used as the treatment schedule of HPS. This indeed appears to be the
Immediate response of all symptoms and laboratory abnormalities case in patients with adult-onset Still disease-associated HPS treated
was profound after 2 days and he was discharged in a very good early with intravenous immunoglobulin and corticosteroids [10].
 Letter to the Editor
Conclusively, our cases of critically ill HPS patients indicate that
early recognition of acquired HPS is of outmost importance for the
final outcome of the patients since it leads to a rapid decision of
treatment initiation. This early treatment could include corticoste-
roids and immunoglobulin infusions which at least in our hands,
proved sufficient to control hyperinflammation and to reverse the
clinical and laboratory symptoms of HPS, while avoiding the use of
[10] Hot A, Toh ML, Coppere B, Perard L, Madoux MH, Mausservey C, et al. Reactive
cytotoxic agents like cyclosporine and etoposide in critically ill
patients, and therefore, all of the potential subsequent detrimental
complications of chemotherapy.
Conflict of interest
The authors state that they have no conflicts of interest.
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Catherine K. Argyraki 1
Stella Gabeta 1
Kalliopi Zachou 1
Maria Boulbou
Asterios Polyzos
George N. Dalekos⁎
Department of Medicine, Medical School, University of Thessaly, 41110
Larissa, Thessaly, Greece
⁎Corresponding author at: Department of Medicine and Research
Laboratory of Internal Medicine, University of Thessaly,
School of Medicine, Biopolis, Larissa, 41110 Larissa, Greece.
Tel.: +30 241350 2285; fax: + 30 241350 1557.
E-mail address: dalekos@med.uth.gr (G.N. Dalekos).
14 January 2011
1
These authors contributed equally to this article.