Analytic Review

Journal of Intensive Care Medicine

1-10
Management of Hemophagocytic ª The Author(s) 2018
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Lympho-Histiocytosis in Critically Ill Patients DOI: 10.1177/0885066618810403
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Virginie Lemiale, MD1, Sandrine Valade, MD1, Laure Calvet, MD1,

and Eric Mariotte, MD1

Abstract
Hemophagocytic syndrome remains a rare but life-threatening complication and is associated with intensive care unit (ICU)
admission. The pathophysiology is based on a defect of cytotoxicity in T cells that results in a state of hyperinflammation in the
presence of a trigger. As a consequence, patients may develop multiorgan failure. The diagnosis of hemophagocytic syndrome
(HS) remains difficult and relies on persistant high-grade fevers in the absence of infection and on constellation of laboratory
parameters. However, prompt diagnosis and treatment (supportive care and specific treatment) are associated with improved
outcome. Interaction with other specialists (hematologist, internist) may improve the diagnosis and treatment strategy.
This article describes diagnostic tools, organ failures associated with HS, main etiologies, and management.

Keywords
immunosuppression, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, ICU

Introduction hypertension with perindopril, and for gastric ulcer with

Hemophagocytic lympho-histiocytosis (HLH) or hemophago-
cytic syndrome (HS) is a rare life-threatening syndrome usually
resulting from an impairment of T cells and natural killer cell
functions1,2 leading to massive pro-inflammatory cytokines
production in response to a trigger. The initial immune defect
may be inherited in primary HS1 (related to a genetic anomaly,
usually involving the perforin pathway) or acquired in second-
ary HS3 (related to an underlying condition4 involving various
cytotoxicity defects or spontaneous cytokines overproduction).
The onset of HS usually requires an additional trigger that is
responsible for the uncontrolled expansion and macrophage
activation of T cells, leading to a cytokine storm and acute
organ failures.
Causes (underlying condition and/or trigger) and conse-
quences of HS (diagnostic features and/or organ failures) may
share the same symptoms, resulting in diagnostic hardships.
Some patients may develop life-threatening organ failures
and intensive care unit (ICU) admission related to HS compli-
cation is not rare. 5 Intensivists should be aware of this
syndrome.6
The aims of this review are to describe HS diagnosis and
treatment in the setting of ICU.
lansoprazole.
She had never traveled outside of France.
Approximately 1 month before ER admission, she devel-
oped asthenia and 1 week before admission was presented with
cough, fever, and muscle pain. She received clarithromycin for
4 days for presumed bacterial bronchitis but her symptoms did
not improve.
At the emergency department, she had neither hemody-
namic instability nor respiratory failure. Clinical examination
revealed splenomegaly and purpura. Laboratory data showed
thrombopenia (45 000/mm3), anemia (7.3 g/dL), neutropenia
(900/mm3), and acute hepatic dysfunction (2N) associated with
cholestasis (2N). Thoraco-abdominal computed tomography
(CT) scan only revealed splenic infarcts (no sign of active
inflammatory bowel disease, no pneumonia, or other lesion).
She was hospitalized on a medical ward and received empirical
antibiotherapy with cefotaxime, teicoplanine, and gentamicin
for suspected infective endocarditis. The lack of valvular lesion
1
Medical ICU, AP_HP Saint Louis hospital, Paris, France

Received May 10, 2018. Received revised October 11, 2018. Accepted
October 11, 2018.
Case Report
Corresponding Author:
A 68-year-old woman was admitted to the emergency depart- Virginie Lemiale, Réanimation médicale, Hôpital Saint Louis, Paris 75010,
ment for suspected sepsis. Previously, she had been treated for France.
ulcerative colitis with azathioprine for more than 3 years, for Email: virginie.lemiale@aphp.fr
2 Journal of Intensive Care Medicine XX(X)
Figure 1. Computed tomography scan. Thoracic CT showed diffuse bilateral ground glass opacities, consolidative changes in the lower lobes,
and splenomegaly with splenic infarct.
on transthoracic echocardiography and negative blood cultures
ruled out the diagnosis of endocarditis.
The patient did not improve on antibiotics. Within the first
days of hospitalization, she developed dyspnea associated with
crackles. She required ICU transfer 3 days after hospital admis-
sion for acute respiratory failure. She received furosemide for
presumed pulmonary edema without effect. A fiberoptic
bronchoscopy with broncho-alveolar lavage (BAL) was per-
formed and macroscopic bronchial inflammation and purulent
mucus were observed. Antibiotherapy was modified to
piperacillin-tazobactam, gentamicin, and linezolid. No infec-
tious pathogen was found in the BAL.
The patient’s state worsened with multiple organ failures:
intubation with mechanical ventilation was required and vaso-
pressors were introduced 3 days after ICU admission. Liver
failure and pancytopenia appeared. There was no kidney fail-
ure. A new CT scan showed diffuse bilateral ground glass
opacities, consolidative changes in the lower lobes, and sple-
nomegaly with splenic infarct. (Figure 1).
Hemophagocytic syndrome was suspected on the association
of pancytopenia, splenomegaly, fever, and immunosuppressed
state (ulcerative colitis treated by azathioprine). Ferritin level
was 9000 mg/L (range 13-150 mg/L) and triglycerides 1.7 g/L
(range 0.45-1.3 g/L). A bone marrow smear was performed that
revealed cytologic aspects of hemophagocytic macrophages.
Because of the severity of HS and lack of evidence of hema-
tologic malignant disease, the patient received high-dose intra-
venous infusions of immunoglobulins (2 g/kg) and high-dose
intravenous steroids. She failed to improve after 3 days of this
treatment. She then received intravenous etoposide (150 mg/
m2). Within 2 days, pyrexia and organ failure resolved.
Several tests were performed to find a trigger for secondary HS,
including viral polymerase chain reaction (PCR) in the blood and/or
BAL (Epstein Barr virus [EBV], cytomegalovirus [CMV], Herpes
simplex Virus [HSV], Varicela Zoster Virus [VZV], human herpes-
virus [HHV6], HHV8, Human T-Lymphotropic Virus [HTLV],
parvovirus B19), viral serologies for human immunodeficiency
virus (HIV) and hepatitis, mycobacteria tests in the sputum, protein
electrophoresis, antinuclear antibodies, and blood lymphocyte
immunophenotyping.
The results revealed a CMV PCR at 4.02 log in the blood,
5 log in the BAL, and 3.93 log in the bone marrow aspiration.
Cytomegalovirus serology was positive for (immunoglobulin)
IgM and IgG. Epstein Barr virus blood PCR was 2.47 log.
Final diagnosis was HS related to disseminated CMV infec-
tion in a patient with ulcerative colitis treated by azathioprin.
She was started on intravenous ganciclovir and improved
slowly. She was discharged from the ICU after 15 days.
When Should I Think of HS in an ICU Patient?
The prevalence of HS is low, but not precisely known and possi-
bly undervalued. As clinical and biological symptoms of HS are
neither specific7 nor sensitive, a high level of suspicion should be
maintained for patients with long-term unexplained symptoms.
The hallmark of diagnosis is the association of a high fever
(39 C-40 C) and pan/bicytopenia (varying from 92%-100% in
the studies8-10).
Although the first diagnosis associated with fever is an evolu-
tive bacterial infection, persistent fever (1-4 weeks) when infec-
tion has been ruled out should alert the clinician. Similarly, HS
should be considered as a possible diagnosis for patients admitted
to the ICU with septic shock11 and preexisting fever and asthenia
for several weeks.12-14 Asthenia is usually associated.9
Nonregenerative anemia is the most frequent hematological
sign (90%-100%). Thrombopenia occurs in 80% to 90% (usually
mild) and leucopenia (even moderate leucopenia and mostly in
the late phase of the syndrome) is found in 70% of the cases.9 In
case of multiple organ failure, cytologic anomalies can be diffi-
cult to distinguish from those found during septic shock. The
unusually long duration of cytopenias before the onset of septic
shock or after shock resolution should alert clinicians.12
Splenomegaly occurs for 60% to 75% of cases9 and remains
an important sign of HS, but is not mandatory for the diagnosis.
Abdominal sonogram may be required9 when physical exam-
ination is difficult. Hepatomegaly (60%-70%)9 and adenome-
galies (30%-40%)9 may also be present at clinical examination
or on radiological workup.
Biochemical anomalies must then be sought, especially high
ferritin and triglycerides levels. High levels of ferritin can
Lemiale et al
Figure 2. Lymphohistiocytosis figure on bone marrow aspiration after hematoxylin-eosin stain. In figure A and B, erythrocytes and platelets are
inside the macrophage cells.8
obviously be related to more frequent differential diagnosis
(sepsis, blood transfusions, hepatitis), but the intensity of ferritin
level elevation is usually high (over 2000 g)15 and the associa-
tion with other symptoms must increase the suspicion of HS.16
Clinicians should always consider an immunosuppressive
factor leading to a defect in Natural Killer [NK] or T-cell
cytotoxicity in the diagnostic workup of HS. Sometimes the
underlying immunosuppression is known before HS diagnosis,
but it is not rare to diagnose it at the same time as HS. This
remains the most difficult part of the diagnosis.8,13,14
When there is a clinical and biological suspicion of HS,
clinicians should perform bone marrow aspiration. Hemopha-
gocytic figures are very frequent (Figure 2) but not constant.
The lack of hemophagocytic figures does not preclude the
diagnosis of HS.5,17 Moreover, for ICU patients with multiple
organ failure and/or sepsis and/or blood transfusions, hemopha-
gocytic figures can be observed without any HS.18,19
All the symptoms are neither sensitive nor specific and
should be considered with caution (Figure 3).
Some diagnostic criteria have been described in the setting
of primary HS in pediatric patients.20 The HLH 2004 criteria
and the more recently developed HScore are now commonly
used for the diagnosis of secondary HS in adult popula-
tion9,21,22 (Tables 1 and 2). One biological marker, soluble
CD25 level, seems to be quite specific and may be associated
with hemophagocytic activity, but it is not routinely
available.23,24
Hemophagocytic syndrome must be promptly diagnosed to
avoid an increased risk of multiorgan failure,5,25 clinicians may
have to treat HS empirically while waiting for the results of con-
firmatory tests such as CD25 level and/or bone marrow studies.
What Etiological Workup Should I Perform
Once I Have Diagnosed HS?
In the adult setting, the development of HS usually requires the
association of a predisposing condition (underlying disease)
and a trigger (« second hit » condition for HS occurrence). The
3
etiological workup of HS should focus on the research of both.
Sometimes, the underlying condition and the trigger may be the
same disease (eg, T-lineage lymphoid neoplasms, adult onset
Still Disease [AOSD] . . . ).
Underlying disease
In adult patients, secondary or reactive HS is more frequent
than in pediatric patients. Genetic risk factor and underlying
disease associated with primary HS in pediatric setting are not
the subject of this review. In secondary HS, treatment of the
underlying condition is essential to cure, and in some cases,
sufficient to improve the symptoms of HS.17
For patients without known immunodepression, the under-
lying condition leading to immunodeficiency can be diag-
nosed26 through targeted questions about infections during
childhood and about a family history of predisposing factor
as well as a careful clinical examination.
These underlying diseases can be related to infection, malig-
nancy or other less frequent conditions27 (Table 3 and Figure 4).
Trigger
Infections25,28,9
Virus. Although the epidemiology of HS related to infectious
diseases is variable according to country and exposition to
various predisposing factors,9 viral infections remain the most
frequent trigger of HS, particularly viruses from the herpes
group (50% to 62% of HS etiology). Among herpes viruses,
EBV is most frequently associated with HS, particularly for
patients with genetic disorders.29 Epstein Barr virus infection
is an ubiquitary, usually benign infection. Severe EBV primo
infection manifesting as HS occurs mainly in younger
patients.17,29 Epstein Barr virus reactivations usually associ-
ated with T-cells lymphoma or for patient with solid organ
transplant are observed in older patients.9,29,30
Another frequent virus associated with HS is CMV. Primo
infection can be associated with severe HS in case of predis-
posing factors, as a genetic predisposition in young adults or an
4 Journal of Intensive Care Medicine XX(X)

Figure 3. Diagnostic strategy of HS.

Table 1. HS Criteria From HLH 2004: 5 of the Criteria are Manda- Table 2. HScore Criteria.22
tory for Diagnosis. Criteria in Italics are not Performed Routinely in an
Adult Setting.20 Parameter Number of Points

Fever > 38.5 C Known inderlying immunosupression 0 if not present

Splenomegaly (HIV or immunosuppressive 18 if present
Cytopenia (at 2 of 3 cell lineages) treatment)
Hemoglobin < 9 g/dL Temperature 0 if temperature <38.4 C
Platelets < 100  109/mm3 33 if temperature 38.4 C
Neutrophils < 1  109/mm3 and 39.4 C
Hypertriglyceridemia (>3 mmol/L) and hypofibrinogenemia 49 if temperature >39.4 C
<1.5 g/L or both Number of cytopenia 0 if 1 lineage
Haemophagocytosis on bone marrow aspiration, spleen, lymph Leucopenia < 5000/mm3 24 if 2 lineages
nodes, or liver Platelets < 110 000/mm3 34 if 3 lineages
Low or absent natural killer cell activity Hb < 9.2 g/dL
Ferritin level > 500 mg/L Ferritin (ng/mL) 0 if <2000
Increased soluble CD5 level 35 if 2000 and 6000
50 if >6000
Triglyceride (mmol/L) 0 if >1.5
immunosuppressive therapy in patients with solid organ
44 if 1.5 and 4
transplantation.8,9 64 if >4
Other herpes viruses, parvovirus B1931 and influenzae virus Fibrinogen (mg/L) 0 if >2.5
have also been associated with HS in case reports.8 30 if 2.5
During HIV infection, HS have been reported in patients Serum glutamic oxaloacetic 0 if <30
with or without opportunistic infection, more frequently in the transaminase (UI/L) 19 if 30
presence of multicentric Castleman disease related to HHV8 Hemophagocytosis features on bone 0 if not present
marrow aspiration 35 if present
infection.32 Emphasis must be made on the fact that HIV by
itself is rarely a cause of HS, but more often the cause of T-cell Abbreviation: HIV, human immunodeficiency virus.
immunosuppression. An additional trigger must always be
thoroughly sought. Bacteria. Mycobacterium tuberculosis is the most frequent
Other chronic viral infections such as Hepatitis B or C have intracellular bacteria responsible for HS. Tuberculosis may
also been rarely associated with HS. then be occurring on an immunocompromized state (HIV
Lemiale et al 5

Table 3. Diseases Associated With HS. Red Etiologies Could be Legionnella, Brucella, Borrelia) have also been associated with
Underlying Disease as Risk Factor of HS and Trigger of HS in the HS.9 Although HS have been described in severe infections due
Same Time. to pyogenic bacteria, differentiating between symptoms related
Infectious Malignancy Other Diseases to sepsis from those related to a possible HS is challenging. In
particular, cytologic features of macrophage activation on bone
Viral Hematological Solid organ marrow smear have been described in multiorgan failure ICU
malignancy tranplantation patients without criteria of HS.18
EBV, CMV, HSV, VZV, parvovirus T-cell Still disease
B19, HTLV, HHV6, HHV8 lymphoma Fungal or parasitic infection. Fungal or parasitic pathogens
HIV NKT Lupus leading to HS are usually Leishmania, Histoplasma, Toxo-
lymphoma plasma, and, rarely Plasmodium.8,9,25 History of travel in ende-
Influenzae B cell Auto immune
mic regions and clinical examination may help the diagnosis.
lymphoma disease
Bacteria Leukemia Castleman Specific PCR can be performed.
disease
M. tuberculosis, Rickettsia Solid tumor Drugs Malignancies. Malignant diseases can be both the predisposing
Staphylococcus, E coli Diabetes factor and the trigger of HS.
Fungus Pregnancy
HS can be associated with several hematological neoplasms
Histoplasma Hemodialysis
Parasitic and seems to be present in 1% of patients with hematological
Leishmania, toxoplasma, malignancies.2,5,9 However, some types of lymphomas such as
plasmodium, B cells intravacular lymphoma, NK and T-cell lymphomas are
more frequently associated with HS. Diagnosis of these lym-
Abbreviations: CMV, cytomegalovirus; EBV, Epstein Barr virus; HIV, Human
Immunodeficiency Virus; HS, hemophagocytic syndrome; HSV, Herpes simplex
phomas can be difficult as they may present exclusively with
Virus; HTLV, Human T-Lymphotropic Virus; NKT, Natural Killer T cell; VZV, extra-nodal involvement.
Varicela Zoster Virus. Some cases of solid tumors have also been described.

Systemic Rheumatic diseases. Several systemic diseases can be

infection, solid organ transplantation . . . ) and often displays
associated with HS.33,34 Although severe bouts of the autoim-
extra-pulmonary localizations. Mortality is high, about 50%,
mune disease can by themselves lead to HS, a trigger must
irrespective of whether or not specific treatment for HS is
always be ruled out (eg, infection, malignancy . . . ). In that
introduced. Other intracellular bacteria (as Rickettsie,
setting, HLH treatment depends on the presence or the absence

Figure 4. Etiology of HS. Hemophagocytic syndrome occurs when underlying disease (risk factor) and trigger are present at the same time.
Some underlying diseases are also triggered by HS.
6 Journal of Intensive Care Medicine XX(X)
Table 4. Biological Screening of Trigger During HS Without Diagno-
sis (Adapted From Saint Louis hospital) According to Suspicions.
Hematological Blood cells count
Lymphocytes immunophenotyping
Bone marrow aspiration
Biochemistry Beta HCG
Protein electrophoresis
Urinary ionogram and urinary protein
Fungus/ Toxoplasmosis serology or PCR
parasites Histoplasmosis serology
Leishmania PCR
Malaria
Virology HIV, B hepatitis, C hepatitis, EBV, CMV serologies
EBV, CMV, HSV, VZV, HHV6, HHV8, parvovirus B19,
(HTLV) PCR
Microbiology Blood cultures
Mycobacteria test (sputum, biopsies if needed)
Urinary bacteriologic culture
Immunology Antinuclear antibodies
Abbreviations: CMV, cytomegalovirus; EBV, Epstein Barr virus; HHV6, human
herpesvirus; HSV, Herpes simplex Virus; HTLV, Human T-Lymphotropic Virus;
VZV, Varicela Zoster Virus.
of a trigger, and may consist of an increase in immunosuppres-
sion in case of an acute SRD bout, or a decrease in immuno-
suppressive treatments along with anti-infectious drugs in case
of infection. Hemophagocytic syndrome associated with
AOSD e is more frequently caused by a flare-up of the dis-
ease.35 In those cases, HS could be severe and fatal.36
Other diseases. Some case reports have described HS in patients
with diabetes, pregnancy or chronic kidney or liver diseases.
However, an infectious or hematological cause of HS may have
been underdiagnosed in these case reports.37
Undetermined etiology. For patients with HS and no evidence of
underlying disease, a broad exploration should be performed
(Table 4). Undetermined etiology after exhaustive diagnostic
workup occurs in 10% of cases.38 These patients should be
carefully monitored for HS relapse. Any relapse of HS should
lead to new broad explorations.
What are the Organ Dysfunctions
Associated With HS?
Without treatment, HS can lead to organ failures requiring ICU
admission.5,8,14 Only few studies described in detail the organ
failures in patients admitted to ICU with suspicion of HS. One
retrospective study described 75 patients who fulfilled HS cri-
teria and were admitted to the ICU.5 The main reasons of
admission were acute respiratory failure (30%), neurological
failure (21%), shock (18%), acute kidney failure (16%), fulmi-
nant liver failure (7%), and bleeding (5%). Sepsis-related
Organ Failure Assessment at admission was 6.5 (4-8) and most
patients had at least 2 organ failures.
Cardiovascular
Hemodynamic instability from the cytokine storm, may be one
of the reasons of ICU admission for patients with severe HS.10
More than half of ICU patients with HS require vasoactive
drugs.5 As it may be impossible to exclude an ongoing severe
sepsis/septic shock associated with or secondary to HS, empiri-
cal wide spectrum antibiotic therapy aiming at nosocomial
organisms is warranted in case of hemodynamic failure in
patients with possible/proven HS.
Cardiac dysfunction has been described in up to 15% of
patients with severe HS requiring ICU admission.25,39 Intra-
myocardial images of hemophagocytosis have been documen-
ted in patients with fulminant myocarditis.31
Neurological
Neurological abnormalities may be present in 25% of patients
with HS.40
In children with hereditary forms of HS, brain biopsies may
show an infiltration of leptomeninges and brain parenchyma by
monocytes and activated lymphocytes. Myelin pallor, neuronal
loss, infarction, and cavitation may occur in the most severe
forms.20 In adults with reactive HS, the mechanism of neuro-
logical involvement is more loosely established.
Clinical features are nonspecific, including meningeal syn-
drome, coma, seizures, brain stem symptoms, and psychiatric
changes.9,40,41
Cerebrospinal fluid examination may find moderate lym-
phocytic pleiocytosis with elevated proteinorachy. Brain mag-
netic resonance imaging usually shows white matter T2
hypersignals.42
Cerebrospinal fluid examination and central nervous system
imaging may also be able to search for signs of complications
of the predisposing condition and/or of the trigger of the HS
(eg, cerebral lymphoma, tuberculous meningoencephalitis . . . ).
Liver
The liver is the first organ involved in HS with hepatomegaly
present in more than 60% of patients.8 Liver function abnorm-
alities are seen in more than 70% of the cases. Elevated con-
jugated bilirubin level is the most frequent finding. A moderate
increase in transaminases level has been also described. How-
ever, when transaminases increase over 10N, HSV infection
should be ruled out. Although liver histology could be useful
for the diagnosis of HS and the underlying disease, percuta-
neous liver biopsy is rarely performed because of coagulation
disorders and thrombopenia, but transjugular biopsy can be
attempted under image-guidance.
Few studies described liver lesions associated with HS. One
study included 30 patients with HS associated with hepatitis for
whom liver biopsy was performed.43 Interestingly, the authors
found Kupffer cell hyperplasia and sinusoidal dilatation with-
out compression in all cases. Moreover, proliferation of acti-
vated macrophages was always present. The authors conclude
Lemiale et al
that inflammation related to HS was responsible of endothelial
cells dysfunction. Although liver biopsy is not always possible,
it can be useful for the diagnosis of the trigger of HS (in this
study, lymphoma (n ¼ 22) and tuberculosis (n ¼ 1)).
Coagulation
Hemostasis disorders are commonly described in patients with
HS, constituting nearly 60% of the patients according to the
literature.1,9,30,44 The most frequent abnormality reported is an
isolated decrease in fibrinogen level.45 It is important to
emphasize that the alteration of hemostasis parameters is not
only observed in onco-hematological patients, but also occurs
during HS related to an infectious or auto-immune etiology.
The pathophysiology of hemostasis disorders is not fully
explained, but it could be linked to disseminated intravascular
coagulation or primary hyperfibrinolysis. 9,45,46 Another
hypothesis supports that hypofibrinogenemia is related to the
“cytokine storm,” with an increased secretion of plasminogen
by activated macrophages. Interestingly, in a retrospective
study in ICU, the authors found that patients with hypofibrino-
genemia had higher ferritin levels, more frequent cytologic
pictures of hemophagocytosis, and required organ supports
more often, as the result of an increased intensity of HS.44
Moreover, several studies demonstrated that hypofibrino-
genemia (<1.5 or 2 g/L) is correlated with adverse outcome
(particularly hemorrhagic complications) and higher
mortality.47,48
Lung
Although acute respiratory failure (ARF) remains one of the
most frequent reasons of ICU admission for patients with HS,
pulmonary involvement has not been well-described.49 Acute
respiratory distress syndrome (ARDS) can be one of the first
manifestations of HS.14 In a retrospective study of 72 patients
with HS admitted to ICU, mechanical ventilation was required
for 58% of the patients.5 Another study described 219 patients
with HS and 118 (54%) had lung involvement.39 Acute respira-
tory failure was mostly related to the underlying disease (most
frequently lymphoma), comorbidities (cardiogenic edema), or
infection associated with HS. Lung involvement was associ-
ated with higher mortality in this study.39
Pulmonary involvement could be related to parenchymal
lesions (infectious as tuberculosis), pleural lesions (pleural
effusion related to lymphoma), or mediastinal adenopathies
(lymphoma). Chest X ray or CT scan are useful for HS etiolo-
gical diagnosis and should be performed quickly in case of HS
with respiratory symptoms.
In patients with HS, lung involvement and particularly ARF
is associated with higher mortality.8,39
Skin
Skin involvement directly linked to HS is usually not associ-
ated with ICU admission. A nonspecific skin rash seems to be
7
frequent (30%-39% of patients).5,50 Skin examination should
then be performed carefully and skin biopsies should be per-
formed for all suspect lesions. Skin lesion can reveal infectious
disease or intravascular lymphoma. In a recent study including
69 patients with HS mainly related to T or B-cells lymphoma,
46% of patients had cutaneaous symptoms.51 Three categories
of dermatologic lesions were found: cutaneous lesions related
to underlying disease (lymphoma), cutaneous lesions related to
thrombopenia and specific rash.14 Although skin biopsy was
not performed for all patients in this study, it may be interesting
for diagnosis of underlying disease, particularly in case of T-
cell lymphoma.
Kidney
Acute kidney failure (AKF) associated with HS is present in
8% to 62% of patients. This discrepancy seems to be related to
different studied populations, kidney failure definitions, and
severity of HS. In a recent study from our group,50 AKF was
related mainly to nephrotoxic agents, tumor lysis syndrome
(77% of patients had hematological malignancy), hypoperfu-
sion, and acute tubular necrosis. In most cases (78%), etiolo-
gies of AKF were numerous. In this study, few kidney biopsies
were performed. In another small study including 11 patients
with HS and AKF, the authors described collapsing glomerulo-
pathy in 5 patients, minimal change glomerulopathy in 4
patients, and thrombotic microangiopathy with abnormal podo-
cytes in 2 patients.52 A case report showed membranoprolifera-
tive glomerulonephritis and interstitial nephritis in a young
man with HS related to EBV.53 Kidney biopsy did not yield
etiological diagnosis in the different studies and biopsy of other
organs (as lymph node or liver) should be preferred.
Acute kidney failure was associated with higher mortality
particularly when patients were discharged from ICU with the
need to continue renal remplacement therapy (RRT).
How should I Treat HS in my ICU Patient?
Management of HS requires the involvement of physicians
accustomed to the condition, usually hemato-oncologists,
immunologists, and internists.
Supportive care
Severely ill patients should be treated as any ICU patient with
organ failures. Best supportive care with mechanical ventila-
tion or RRT should be started for patients with ARF or AKF. In
a recent study with 56 patients admitted to the ICU for HS,
mechanical ventilation was required in 58% of cases, vasoac-
tive drugs in 54%, and RRT in 33%.5
Coagulation disorders should be carefully assessed. 44
Patients may need platelet and plasma transfusions. Particular
attention is required when biopsies have to be performed in this
setting. Admission to ICU can be required for coagulation
abnormalities and risk of bleeding.
8 Journal of Intensive Care Medicine XX(X)
As the symptoms of HS may be indistinguishable from those
of septic shock, broad spectrum antibiotics and/or antifungal
drugs must be started at the time of presentation.25,8
Decrease the cytokine storm
The mainstay of treatment is to decrease cytokine levels
responsible for hyperinflammation54 and organ failures. Ster-
oids can be used but etoposide seems to be more effective.55
Etoposide depletes activated T cells, which represent the
source of macrophage activation. For patients without autoim-
mune disease, etoposide is considered the first line of treatment
and protocols include dosages of 150 to 200 mg/m (a reduced
dose is warranted in case of kidney and/or liver dysfunc-
tion).2,56 Neutropenia induced by etoposide should lead to con-
sideration for secondary infection in case of fever relapse. Also,
etoposide could lead to an increased risk of secondary cancers.
For HS related to infectious diseases, high-dose intravenous
polyvalent immunoglobulins may improve the symptoms,
especially in the case of viral infections. However, steroids are
often an integral component of the treatment.8,25
For HS related to SRD, steroids are the treatment of choice,
but etoposide may be required in severe cases. In case of severe
bouts of SRD disease or when HS is related to AOSD, cyclos-
porine could be useful.8,9,57
Treatment should be started as promptly as possible after
symptoms onset. Untreated HS can lead to multiorgan failure
and death. However, for patients with less severe forms of HS,
diagnostic investigations can be performed. In that case,
patients must be carefully monitored because a rapid onset of
cytokines levels can occur at any time.8,9
Specific treatment adapted to the underlying disease
In HS associated to hematological malignancies, chemotherapy
is usually required with therapeutic protocols including etopo-
side.58 In the absence of specific treatment of the underlying
lymphoma, HS treated with steroids and etoposide would
relapse in days or weeks following symptomatic treatment.
Mortality
Patients should be monitored carefully in the first days after
ICU admission. Response to treatment generally occurs within
24 to 48 hours after etoposide or steroid infusion.57
Reported HS mortality is high, about 40%, depending on
underlying disease and severity of HS. Prognostic factors asso-
ciated with early mortality include age, severe thrombopenia,
liver disease, and underlying etiology (T-cell lymphoma is
associated with 80% mortality).39,17,9,47,8 Mortality is higher
within the first months of diagnosis and for hematology-
oncology patients.17,47 Moreover, for the same underlying
disease, patients with HS have higher mortality than patients
without HS.
Early mortality could be related to uncontrolled underlying
disease but also to early infectious complications.11
Conclusion
Hemophagocytic syndrome remains a rare but life-threatening
condition. Intensivists should be aware of this syndrome
because of its high potential for inducing multiple organ fail-
ures and its high mortality rate. Definitive diagnosis of HS is a
medical challenge, particularly in the context of critical illness
and must account for the underlying disease. Diagnosis of trig-
ger and/or underlying disease is a mandatory step to improve
the prognosis, to adapt the specific treatments, and to avoid
relapse of HS. Coagulation disorders should not be an obstacle
to biopsy if indicated.
Therapeutic strategy should always be discussed with teams
of clinicians familiar with the management of patients with HS.
Etoposide should be used in the frontline in the majority of
severe cases with organ failures, even if an infectious trigger
is suspected. Although some patients will not have severe
organ failure, ICU monitoring should be discussed because the
cytokine storm may become suddenly overwhelming and
because coagulation abnormalities can lead to severe hemor-
rhagic complications.
Acknowledgment
The authors would like to thank Enago (www.enago.com) for the
English language review.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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