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2019, Volume 35, Number 3, Page(s) 207-212
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DOI: 10.5146/tjpath.2018.01456 |
Case Series of Hemophagocytic Lymphohistiocytosis from a Tertiary Care Centre: An Underdiagnosed Entity |
Vijay KUMAR, Bhavna SHARMA, Abhay S. NIGAM |
Department of Pathology, PGIMER, Dr. Ram Manohar Lohia Hospital, NEW DELHI, INDIA |
Keywords: Hemophagocytosis, Lymphohistiocytosis, Hyperferritinemia, Pancytopenia |
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Objective: Hemophagocytic Lymphohistiocytosis (HLH) is an uncommon, life-threatening hyperinflammatory syndrome, caused by severe
hypercytokinemia, due to an overstimulated but ineffective immune process. The presenting features of HLH are non-specific, mimicking many
other diseases, and hence its early recognition still remains a challenge. It requires a high index of suspicion and detailed analysis of clinical and
laboratory findings to arrive at a conclusive diagnosis. The objective of this study is to present detailed clinical and laboratory features of a series
of HLH cases.
Material and Method: A retrospective study was conducted wherein all the bone marrow aspirate smears diagnosed as HLH between January
2015 to June 2018 were reviewed. Detailed correlation of clinical and laboratory criteria was done with the bone marrow findings.
Results: A total of twelve cases were diagnosed as HLH from January 2015 to June 2018. Ten patients fulfilled 5 out of 8 clinical and lab diagnostic
criteria of HLH (2004). After correlating clinical and laboratory criteria along with bone marrow findings the diagnosis of HLH was suggested.
Conclusion: We present a series of twelve cases of Hemophagocytic Lymphohistiocytosis from a tertiary care hospital in New Delhi which will
add not only to the understanding of this rare life threatening disease but also to the early diagnosis and intervention. |
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The first case of hemophagocytic lymphohistiocytosis
(HLH) was reported in 1952 by Farquhar and Claireaux,
who named it familial hemophagocyticreticulosis 1. HLH
represents a hyperinflammatory, uncontrolled immune
response caused by various stimuli 2. The disease
primarily affects pediatric age group but adults are also
commonly involved 3. It is of two types- genetic and
acquired. The basic defect in both genetic and acquired
cases lies in the NK/T cell cytotoxic pathway. This leads to
inability of NK/T cells to kill activated macrophages, which
in turn leads to uncontrolled proliferation of activated
macrophages 3. Genetic cases can be further divided into
familial and those associated with an immunodeficiency
syndrome 4. Familial HLH is of five types with mutations
in various proteins involved in packaging, transport and
release of cytolytic granules, namely Perforin 1, UNC13D,
STX11 and STXB2. The common immunodeficiency
syndromes associated with HLH are Chediak Higashi
syndrome, Griscelli syndrome, Hermansky Pudlak
syndrome and X linked lymphoproliferative syndrome
4. Acquired cases can be broadly secondary to infections/
malignancy/ rheumatologic causes 4. Macrophage activation syndrome (MAS) is usually associated with
rheumatologic diseases like systemic-onset juvenile
idiopathic arthritis (SOJIA), adult-onset Still disease, and
systemic lupus erythematosus 5,6.
Diagnostic criteria for HLH were proposed in 1991 and
updated in 2004 7,8. The 2004 criteria are as follows. The
diagnosis requires the presence of either criterion A or 5
out of 8 of criterion B.
Diagnostic criteria for HLH (2004)
A. Familial disease/known genetic defect
OR
B. Clinical/laboratory criteria
1. Fever,
2. Splenomegaly,
3. Cytopenia (at least 2 cell lines)
HGB < 9 gram/dL,
PLT< 100,000/microL,
ANC< 1000/microL
4. Hypertryglyceridemia and/or hypofibrinogenemia,
Fasting triglyceride> 265 mg/dL, Fibrinogen < 150 mg/L,
5. Hyperferritinemia, Ferritin>500ug/l
6. Hemophagocytosis in bone marrow, CSF, or lymph
nodes,
7. Decreased/absent NK cell activity
8. Soluble CD25 > 2400 U/ml. |
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Abstract
Introduction
Methods
Results
Disscussion
References
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We conducted a retrospective study in the department of
pathology, PGIMER, Dr. Ram Manohar Lohia Hospital,
Delhi. All the bone marrow aspirate smears diagnosed as
HLH between January 2015 to June 2018 were reviewed.
The requisition forms of the same were reviewed to get
all relevant clinical and laboratory details. Bone marrow
smear findings were correlated with clinical and laboratory
findings. |
Top
Abstract
Introduction
Methods
Results
Disscussion
References
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A total of twelve cases were diagnosed as HLH from January
2015 to June 2018. The clinical features and laboratory
findings of patients are summarized in Table I and II.
All bone marrow smears, except one, showed increased
number of histiocytes, with features of hemophagocytosis
(Figure 1A-D). The age of the patients ranged from 3
months to 65 years (male: female= 2:1). All patients
presented with fever and cytopenia, one had pancytopenia,
eight had bicytopenia, one had only anemia and two did not have any cytopenia. The etiological spectrum primarily
included infections and autoimmune disease. None of the
cases was malignancy related. Four patients had history of
systemic onset juvenile idiopathic arthritis (out of which
one was positive for both parvovirus and rickettsia), two
had undifferentiated connective tissue disease (out of
which one had tuberculosis and the other one had past
history of macrophage activation syndrome), one was a
known case of SLE, one was hepatitis B +ve , one typhidot positive, one CMV positive and one was a suspected case
of dengue. Ten patients fulfilled 5 out of 8 clinical and
lab diagnostic criteria of HLH (2004). The two patients
who did not fulfill five criteria were diagnosed as HLH
because of strong clinical suspicion. One of these had
past history of MAS with present bone marrow showing
prominent hemophagocytosis and the other one also
similarly demonstrated extensive hemophagocytosis on
bone marrow biopsy (Figure 2). After correlating clinical and laboratory criteria along with bone marrow findings,
the diagnosis of HLH was suggested.
Click Here to Zoom |
Figure 1: A) Bone marrow aspirate showing two histiocytes with phagocytosed debris in cytoplasm (Giemsa; x200). B) High power view
of histiocyte in bone marrow aspirate with phagocytosed hematopoetic cells in cytoplasm (Giemsa; x1000). C) Bone marrow aspirate
with histiocyte showing phagocytosed neutrophils in cytoplasm (Giemsa; x1000). D) Bone marrow aspirate with histiocyte showing
phagocytosed erythroid series cells in cytoplasm (Giemsa; x1000). |
Click Here to Zoom |
Figure 2: A) Bone marrow biopsy showing many foamy histiocytes with hemophagocytosis (H&E; x100). B) High power view of
hemophagocytosis in bone marrow biopsy showing histiocytes with phagocytosed hemopoietic cells in the cytoplasm (H&E; x200). |
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Top
Abstract
Introduction
Methods
Results
Disscussion
References
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The knowledge about the profile of HLH in the Indian
subcontinent is limited despite the disease being life
threatening, and is available in the form of few case series
9-14. The age range in our series varied from 3 months
to 65 years (mean age 14 years). This is similar to the series
of five cases reported by Reddy et al. (mean age 17 years)
9. The male to female ratio in the present series was 2:1.
Reddy et al. similarly found a male preponderance (M:F
4:1) whereas Joshi et al. found a female preponderance
(M:F 1:4) 9,11. The most frequent presenting symptom
was fever with cytopenia and hepatosplenomegaly. Joshi et
al. in their case series from Mumbai also concluded that
HLH should be suspected in any patient experiencing
unresolving fever with cytopenia and hepatosplenomegaly
11. Similarly Ramachandran et al. also found fever and
hepatosplenomegaly as the most common presenting
complaint in their case series of 33 pediatric patients
12. Only one patient presented acutely with neurologic
symptoms in the form of abnormal body movements
and shock. This was a 7-year-old female, a known case
of SOJIA, and was diagnosed as MAS. We found CNS
involvement in only one patient (8%) which is in contrast
to Joshi et al. (30%), Ramachandaran et al. (36%), and
Reddy et al. (80%) 9,11,12. Ferritin levels were available at
the time of diagnosis in 6/12 patients, LDH in 8/12, serum
triglycerides in 9/12 and serum fibrinogen in 3/12 patients.
Hyperferritenemia, raised LDH and raised triglycerides
(according to the HLH 2004 criteria ) were found in all these patients. However, low fibrinogen was observed in
2/3 patients only.
We could determine the underlying etiology in 11/12
patients. An infectious cause was found in 6/12 patients
(50%) [1-CMV, 1 -Dengue, 1- hepatitis B, 1- Typhoid,
1-TB, 1- Rickettsia]. Ramachandran et al. similarly found
an infectious cause in 42% of the pediatric patients and Joshi
et al. in 30% of the patients 11,12. Out of the infectious
causes, the most commonly responsible ones are viral{EBV,
CMV, parvovirus] followed by bacterial [Brucella, TB],
parasitic [Leishmaniasis] and fungal infections 15,16.
One of the patient in the present series was a suspected
case of uncomplicated dengue fever who presented with
fever and macular rash on the abdomen [third day of fever]
along with anemia and thrombocytopenia. Dengue virus is
a very uncommon cause of HLH with most of the reported
cases being associated with complicated hemorrhagic cases
17-19. However, our case was of uncomplicated dengue
as has been previously reported once 20. This patient had
very high levels of ferritin, LDH, triglycerides and was thus
diagnosed to have HLH, even though the bone marrow
failed to reveal hemophagocytosis. Hemophagocytosis may
not be evident in very early stages of HLH, and thus its
absence does not negate the diagnosis of HLH 21. The
incidence of bone marrow involvement varies between
25% and 100% 22. This implies that the diagnosis of
HLH requires a comprehensive clinical, biochemical and
hematological approach.
HLH is a diagnostic challenge to clinicians as its presenting
signs and symptoms are non specific and thus portend a
wide array of differential diagnoses. The presenting signs involve multiple organs and hence multiorgan disorders
like sepsis, MODS, etc. come into close differentials. It has
been found that cytopenias and extremely high ferritin
levels are most helpful in diagnosing HLH 3. The closest
differential in pediatric patients is sepsis. Palazzi et al.
in their series of pediatric PUO patients found that very
high levels of ferritin and LDH were highly suggestive
of HLH 23. Other differentials include multiple organ
dysfunction syndrome [MODS], liver failure, and
encephalitis. Again increasing levels of ferritin, high LDH
and cytopenias accompanied by evidence of bone marrow
hemophagocytosis help in clinching the diagnosis 3.
For familial HLH the only confirmatory test is genetic
testing for mutations, the most common being mutations
in the perforin gene 3. However, this is available in only
limited laboratories. Recently, flow cytometry for perforin
expression has been introduced for screening of HLH.
It can prove to be useful as it is economical and readily
available 24.
is difficult to establish a preset diagnostic approach
for reaching the right diagnosis. Most of the patients
are seriously ill and present with signs and symptoms
pertaining to multiple organs, i.e. central nervous system
abnormalities, liver function dysfunction, bone marrow
insufficiency, immune dysfunction, etc. Sometimes all the
criteria for HLH are not met but a high index of suspicion
is required for the diagnosis of such cases in the initial
stages. All patients with prolonged fever and cytopenias
must be evaluated for HLH by obtaining a detailed history,
performing a detailed physical examination and by using the
relevant biochemical tests. The history should aim at finding
out the underlying etiology, so the patient should be asked
about pre-existing viral illness, fever to rule out infectious
causes, history of fever with joint pains to rule out underlying
autoimmune joint disease and history of significant weight
loss and any other symptoms for underlying malignancy.
The physical examination should include detailed search
for lymphadenopathy, hepatosplenomegaly, and complete
examination of all the organ systems. In addition laboratory
tests should be ordered to confirm the suspected etiology
like complete blood count and blood, urine, CSF culture
to establish infective cause, and CT neck, abdomen, etc.
to rule out malignant etiology, etc. Additional tests like
ferritin, triglycerides, LDH and fibrinogen will confirm
the diagnosis. Bone marrow examination should be done
and diligently searched for hemophagocytosis. Cr release
assays to measure NK cell activity and measurement of
sCD25 are also helpful to arrive at the diagnosis; however,
these tests are not readily available and hence cannot be relied upon. It is imperative to differentiate genetic HLH
from secondary HLH as the latter is treatable by finding
the underlying cause. Management of secondary HLH
cases includes antiviral agents for virus associated cases,
antibiotics, antiparasitic drugs, and antifungal agents for
bacterial, parasitic and fungus associated cases respectively.
For genetic HLH, stem cell transplantation is the only
effective therapy.
The 2004 HLH treatment protocol by the Histiocyte
Society recommends use of 8 weeks of induction therapy of
cyclosporine, etoposide and corticosteroids (25). Permanent
cure is possible only with stem cell transplantation but
treatment of the underlying cause is indicated for acquired
HLH. In the present series, all the patients diagnosed
as HLH were treated with corticosteroids. In addition,
antiviral agents were given in the cases found to be positive
for CMV and Parvovirus, and ceftriaxone was given to the
case found to be typhidot positive. All the patients were
followed for a period of two months following which all
showed improvement and were ultimately discharged.
The prognosis of genetic HLH is dismal 25. The prognosis
of acquired HLH is variable depending on the underlying
cause, with malignancy associated cases having the worst
outcome 26.
In conclusion, HLH is an uncommon, fatal but
underdiagnosed disease. The symptoms of the disease
are non specific, mimicking many conditions and
hence requires a high index of suspicion for making a
timely diagnosis. In view of the paucity of data from the
Indian subcontinent, this study is an attempt for better
understanding and early diagnosis of the disease as it will
pave the way for better management of the patients.
CONFLICT of INTEREST
The authors declare no conflict of interest.
FUNDING
None |
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Abstract
Introduction
Methods
Results
Discussion
References
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Abstract
Introduction
Methods
Results
Discussion
References
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