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Fever of Multiple Possible Origins: Acquired
Hemophagocytic Lymphohistiocytosis in the Context
of Pyelonephritis, Newly Diagnosed Systemic Lupus
Erythematosus, and an Ulcer of the Aortic Arch
David Spillane, MDCM
1,2
, Jeffrey Wiseman, MD, Med
1,2
1
McGill University Health Center, Montreal, QC, Canada;
2
McGill University, Montreal, QC, Canada
Author for correspondance: Jeffrey Wiseman: jeffrey.wiseman@mcgill.ca
Received:
13 February 2020; Accepted after revision: 27 April 2020; Published: 21 June 2021
DOI:
https://doi.org/10.22374/cjgim.v16i2.461
Abstract
A 60-year-old man presented with 1 week of fever despite broad-spectrum antibiotics for presumed
pyelonephritis based on extended spectrum bacteriuria, recent bladder catheterization, and a
negative search for other infections. He developed a maculopapular truncal rash, and pancytopenia
with persistent fevers and worsening inflammatory markers despite modifying then stopping
antibiotics. The non-specific clinical features at presentation and absence of hemophagocytosis
on the initial bone marrow aspirate confounded multiple subspecialists and delayed the final
diagnosis of hemophagocytic lymphohistiocytosis (HLH). Once this syndrome was elucidated,
he responded well to dexamethasone and etoposide. An underlying diagnosis of systemic lupus
erythematosus with aortic vasculitis was made, which in combination with pyelonephritis likely
precipitated HLH. We summarize current concepts, pitfalls, and lessons learned in the diagnosis
and management of HLH.
Résumé
Un homme de 60ans se présente à l’hôpital à la suite dune semaine de fièvre malgré la prise
dantibiotiques à large spectre pour traiter une pyélonéphrite soupçonnée, fondée sur une
bactériurie à spectre étendu, un cathétérisme vésical récent et une recherche infructueuse dautres
infections. Il a développé une éruption cutanée maculopapulaire sur le tronc et une pancytopénie
accompagnée d’une fièvre persistante et dune augmentation des marqueurs de linflammation
malgré la modification, puis larrêt des antibiotiques. Les manifestations cliniques non spécifiques
à la présentation et l’absence d’hémophagocytose lors de la ponction médullaire initiale ont
confondu de multiples surspécialistes et retardé le diagnostic définitif de lymphohistiocytose
hémophagocytaire (LHH). Une fois que ce syndrome a été élucidé, le patient a bien répondu au
traitement par la dexaméthasone et létoposide. Un diagnostic sous-jacent de lupus érythémateux
systémique accompagné dune vascularite de laorte a été posé qui, combiné à la pyélonéphrite,
a probablement précipité la LHH. Nous résumons les concepts actuels, les pièges et les leçons
apprises dans le diagnostic et la prise en charge de la LHH.
C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 1 6 , I s s u e 2 , 2 0 2 1 43
Case Reports and Clinical Images
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Case Report
A 60-year-old man, who immigrated to Canada from Punjab
30 years prior, presented to another hospital with abdominal
pain. He was known for a history of hypertension, non-alcoholic
steatohepatitis, and obstructive sleep apnea. He was noted to be
in urinary retention and was discharged home with an indwelling
Foley catheter.
At home, he experienced recurrent fevers over the following
week, and presented to a second hospital. Urine cultures grew
extended-spectrum beta lactamase-producing E. coli. He was
treated for presumed acute pyelonephritis with Piperacillin-
Tazobactam and the urinary catheter was removed. Subsequently,
an erythematous maculopapular facial and truncal rash appeared
along with progressive leukopenia and thrombocytopenia, with
mild anemia. Antibiotics were stopped given concern for a drug
reaction, and he was transferred to our tertiary care institution
for further work-up.
At presentation, he was afebrile and vitally stable. He was
noted to have facial edema with a maculopapular rash affecting
his face and trunk. There were several oral ulcers. His abdomen
was benign, without hepatosplenomegaly. There was no
lymphadenopathy. Cardiorespiratory exam was unremarkable.
He was noted to have a leukocyte count of 1.2 × 10
9
cell/L,
neutrophil count of 0.51 × 10
9
cell/L, platelet count of 43 × 10
9
cell/L, triglyceride level of 3.44 mmol/L, ferritin level of 2408 g/L,
and a fibrinogen level of 2.90 g/L. Blood cultures were sterile.
Computed tomography (CT) scans of the chest and abdomen
revealed small areas of consolidation in the right upper and
middle lobes and a small lung nodule, with slightly enlarged
axillary, supraclavicular, mediastinal, and hilar nodes. There were
traces of retroperitoneal fluid around the pancreas. The spleen
was 13.5 cm. A subsequent positron emission tomography (PET)
scan showed no significant fluorodeoxyglucose (FDG) avidity
in the lymph nodes and lung nodule. Skin biopsy showed mild,
non-specific inflammatory changes, without evidence of drug
reaction with eosinophilia and systemic symptoms (DRESS).
Lymph node biopsy was non-diagnostic, and bone marrow
biopsy was unremarkable. Multiple induced sputa were negative
for acid-fast bacilli.
The patients fevers soon recurred despite starting meropenem.
He became increasingly delerious without focal features on
neurologic examination, and without meningismus. An MRI of
the head was normal. Repeat cultures were still sterile. In light
of his worsening condition, a consensus decision between the
involved subspecialty services was made to start pulse steroids
(solumedrol 100 mg IV q12 h). At this time, the presence of
tuberculosis had not been ruled out, so he was started on quadruple
Figure 1. Bone marrow aspirate showing hemophagocytosis. Activated histiocyte
engulfing erythrocytes, platelets (A). Early erythroid precursor undergoing
phagocytosis (B). Erythrocyte undergoing phagocytosis (C). Platelets undergoing
phagocytosis (D).
therapy with rifampin, INH, pyrazinamide, and ethambutol to
prevent TB activation.
Despite an initial improvement with steroids, he again
deteriorated, requiring ICU admission and intubation for
distributive shock secondary to his severe inflammatory state. At
this time, his laboratory parameters had worsened: triglyceride
peak of 7.08 mmol/L, ferritin peak of 16,115 g/L. He now met
4/8 clinical criteria for hemophagocytic lymphohistiocytosis
(HLH), but had an HScore of 212 (93–96% probability of HLH),
so a diagnosis of HLH was favored. Steroids were switched to
dexamethasone, and etoposide was started. Quadruple therapy
was switched to INH given interaction between etoposide and
the other tuberculosis (TB) drugs and a lower suspicion of
tuberculosis at that time. A second bone marrow biopsy was
performed and showed hemophagocytosis (Figure 1).
Work-up for predisposing conditions was notable for positive
anti-nuclear antibodies, anti-double stranded DNA antibodies,
and anti-histone antibodies, consistent with underlying systemic
lupus erythematosus in the context of his rash and oral ulcers. He
was eventually transitioned to steroid-sparing drugs mycophenolic
acid and hydroxychloroquine.
The patients condition improved and he was discharged
to a rehabilitation facility. He returned 2 days after discharge
following a fall without change in consciousness. A CT angiogram
of the chest, done to rule out pulmonary embolism, revealed a
44 V o l u m e 1 6 , I s s u e 2 , 2 0 2 1 C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e
Fever of multiple possible origins
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non-penetrating ulcer of the aortic isthmus which was felt to
be secondary to lupus vasculitis. Serial CT scans have shown
ulcer stability. The patient is now well and has returned to his
previous activities.
Discussion
HLH is a clinical syndrome characterized by an exaggerated
systemic inflammatory response secondary to unregulated
activation of cytotoxic T lymphocytes and natural killer cells.
HLH is classified as primary (aka genetic) HLH, or secondary
(aka acquired) HLH.
Primary HLH is predominantly a pediatric disease but has
been described in adults. Secondary HLH is usually seen in adults,
and may be precipitated by infection, malignancy, or rheumatic
disease. In infection-associated HLH, responsible for 50% of
secondary HLH,
1
the most commonly identified organisms are
viral, particularly EBV, HIV, and CMV.
1,2
Malignancy-associated
HLH, 48% of cases,
1
occurs mostly in T-cell lymphomas and
leukemias, but may occur with other hematologic or even solid
malignancies, and in the context of chemotherapy (especially if the
treatment course is complicated by infection).
1,3
HLH associated
with rheumatologic conditions is rare but may arise in systemic
lupus erythematosus, adult onset Still’s disease, systemic onset
juvenile idiopathic arthritis and other autoimmune disorders.
1
HLH that is due to rheumatologic conditions is commonly called
macrophage activation syndrome (MAS).
HLH is associated with significant patient mortality, ranging
from 20 to 88%.
4
Therefore, it is important for clinicians to
consider this diagnosis, particularly in patients with evidence
of systemic inflammation not responding to other therapy such
as broad-spectrum antibiotics or tumor-specific chemotherapy.
Diagnostic criteria for HLH were developed by the Histiocyte
Society in the HLH-1994 clinical trial.
5
The criteria were refined
for the HLH-2004 clinical trial (Table 1).
6
Five of the eight
clinical features are needed for diagnosis of acquired HLH: fever
>38.5 C, splenomegaly, cytopenias affecting ≥2 of 3 lineages
(hemoglobin <90 g/L, platelets < 100 × 10
9
cells/L, neutrophils
<1.0 × 10
9
cells/L), hypertriglyceridemia (2.0 mmol/L), and/or
hypofibrinogenemia (1.5 g/L), hemophagocytosis, ferritin >500
mcg/L, low/absent NK cell activity, and soluble CD25 elevation.
Alternatively, familial HLH may be diagnosed with molecular
studies demonstrating mutation in one of seven known HLH-
associated genes: PRF1, UNC13D, STXBP1, RAB27A, STX11,
SH2D1A, or XIAP.
Notably, these diagnostic criteria were established in pediatric
patients. In addition, their use is limited by the lack of weighted
importance for each criterion, and the difficulty in measuring
certain parameters such as NK cell activity and IL-2R levels.
To assist in the diagnosis of HLH in adults, clinicians may
use the HScore, an HLH probability calculator.
7
It calculates
the probability of HLH based on several weighted clinical
parameters, most of which are diagnostic criteria from HLH-
2004 (Table 2). The HScore was found to have a sensitivity of
93% and specificity of 86% when the optimal cutoff value of
169 is used.
7
The HScore is more reliable that the HLH-2004
criteria in diagnosing HLH in both pediatric and adult patients.
8
Use of the HScore can also facilitate diagnosis in critically ill
patients, in whom the HLH-2004 criteria are less sensitive.
9
Further confusing matters, critically ill patients are more likely
to have hemophagocytosis in the absence of HLH.
9
As well,
hemophagocytosis is not required for diagnosis of HLH, and is
absent in 30–40% of cases.
10,11
Therefore, hemophagocytosis is
neither sufficient nor required for diagnosis of HLH.
Treatment protocols are based on the HLH-94 guidelines
for treatment of primary HLH in children.
5
According to this
protocol, dexamethasone is given daily and tapered every week.
Etoposide is given twice weekly, then at gradually increasing
intervals. Cyclosporin treatment begins as early as Week
3. Intrathecal methotrexate is given for select patients with
neurological symptoms not responsive to steroids, etoposide, and
cyclosporin. Earlier administration of cyclosporin was assessed
in the HLH-2004 trial, but outcomes were not significantly
different.
6
Many pediatric patients will benefit from subsequent
allogeneic stem cell transplant.
These protocols were developed for use in children, in
whom HLH is almost always primary. There have been no
large-scale clinical trials establishing the optimal treatment for
adults. Therefore, management recommendations for HLH in
adults are provided by the HLH in adults working group of the
Histiocyte Society based on consensus expert opinion.
12
These recommendations suggest that the HLH-94 protocol is
highly effective for adults but may result in unnecessary toxicities
in older individuals with other comorbidities. Individualized
treatment protocols should thus be considered, such as dose
reductions and shorter treatment durations. Depending on
the underlying precipitant, different treatment protocols are
suggested (Table 3).
The treatment differs most substantially for MAS, where
high-dose pulse corticosteroids are the mainstay, and cyclosporin,
interleukin-1 antagonists and interleukin-6 antagonists may
be considered. Dexamethasone and etoposide are reserved for
severe or refractory cases.
C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 1 6 , I s s u e 2 , 2 0 2 1 45
Spillane D et al.
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A. Molecular diagnostic criteria for HLH
Mutation in any familial HLH-associated genes:
PRF1, UNC13D, STXBP1, RAB27A, STX11, SH2D1A, XIAP
B. Five out of eight clinical criteria for HLH
Fever > 38.5C
Splenomegaly
Cytopenias affecting 2 of 3 lineages (hemoglobin < 90 g/L, platelets <
100 × 10
9
cells/L, neutrophils < 1.0 × 10
9
cells/L)
Hypertriglyceridemia (2.0 mmol/L) AND/OR hypofibrinogenemia (1.5 g/L)
Hemophagocytosis
Ferritin > 500 mcg/L
Low/absent NK cell activity
Soluble CD25 elevation
Fulfillment of either A) or B) is required for diagnosis of HLH. Adapted from Henter et al.
6
Table 2. The HScore
Clinical feature HScore points Probability of HLH
Known underlying immunosuppression
No = 0 pts
Yes = 18 pts
90 pts = <1%
100 pts = 1%
110 pts = 3%
120 pts = 5%
130 pts = 9%
140 pts = 16%
150 pts = 25%
160 pts = 40%
170 pts = 54%
180 pts = 70%
190 pts = 80%
200 pts = 88%
210 pts = 93%
220 pts = 96%
230 pts = 98%
240 pts = 99%
250 pts = >99%
Temperature (Celsius)
<38.4 = 0 pts
38.4–39.4 = 33 pts
>39.4 = 49 pts
Number of cytopenias
1 lineage = 0 pts
2 lineages = 24 pts
3 lineages = 34 pts
Ferritin (ng/L)
<2000 = 0 pts
2000–6000 = 35 pts
>6000 = 50 pts
Triglyceride (nmol/L)
<1.5 = 0 pts
1.5–4 = 44 pts
>4 = 64 pts
Fibrinogen (g/L)
>2.5 = 0 pts
≤ 2.5 = 30 pts
Serum aspartate transaminase (IU/L)
<30 = 0 pts
≥30 = 19 pts
Hemophagocytosis features on bone marrow aspirate
No = 0 pts
Yes = 35 pts
Weighted scores for clinical features of HLH and the probability of HLH based on total points. Adapted from Fardet et al.
7
Often, HLH patients will require supportive management in
the intensive care unit. This can be necessitated due to multiple
organ failures, including vasoplegia,
13,14
acute respiratory
distress syndrome,
13,15
neurological symptoms such as coma
and seizures,
1,13,16
liver failure,
13
coagulopathies particularly
as a result of hypofibrinogenemia,
13,17
and kidney failure.
13,18
This case highlights the importance of including HLH in
the differential diagnosis of patients presenting with fever or
cytokine storm particularly if sepsis or malignancy is suspected
and the patient is not responding to appropriate therapy.
Application of the HLH-2004 clinical criteria and HScore can
be useful in diagnosing this uncommon condition. Importantly,
the absence of hemophagocytosis should not deter treatment if
HLH is suspected, as it is not required for diagnosis. Treatment
in adults should be highly individualized and based on the
HLH-94 protocol.
46 V o l u m e 1 6 , I s s u e 2 , 2 0 2 1 C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e
Fever of multiple possible origins
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Table 1. HLH-2004 Diagnostic Criteria
Table 3. Summary of Treatment Protocols for Secondary HLH in Adults
Steroids/IVIG Etoposide CNS agents Stem cell transplant Other comments
Malignancy-
associated HLH
Triggered by
malignancy
First-line
corticosteroids ± IVIG
prior to tumor-specific
treatment
May be
given prior to
tumor-specific
treatment
or added to
tumor-specific
treatments such
as CHOP
Consider if
evidence of CNS
involvement
Autologous or allogeneic
SCT considered for those
eligible for treatment
intensification and in
young patients with HLH
and EBV-driven lymphoma
who may have HLH-
associated mutations on
germline genetic testing
Consider germline
genetic testing for HLH
mutations in younger
patients with HLH and
lymphoma, particularly
EBV-driven lymphoma
Associated with
chemotherapy
First-line
corticosteroids ± IVIG
Avoid use
if possible,
to allow for
bone marrow
recovery
Consider this diagnosis
when cytopenias are
prolonged, persistent
fevers despite
antimicrobial therapy,
other HLH features
Also need to consider
recurrent/refractory
malignancy as the
trigger
Infection-
associated HLH
Triggered by
EBV
First-line
corticosteroids ± IVIG
Use if rapid
clinical
deterioration or
severe disease
SCT may be considered for
those with increasing or
persistently high EBV DNA
May consider
rituximab to target EBV
replication in B cells
Triggered by HIV
First-line
corticosteroids ± IVIG
May be given
for severe
disease
Consider HIV directed
therapy
Triggered by
other infections
Generally not required
Generally not
required
Treatment of underlying
infection is usually
sufficient.
Rheumatic
HLH (aka MAS)
First-line
corticosteroids with
high-dose pulse
methylprednisolone
Reserved
for patients
with severe
disease or CNS
involvement
despite steroids,
cyclosporin
or interleukin
antagonists
MAS treatment differs
from other HLH
treatment. A highly
personalized treatment
approach is suggested,
with high-dose steroids
as the mainstay of
treatment.
Cyclosporin,
interleukin-1 or
-6 antagonists
(eg. Anakinra
and tocilizumab,
respectively) can be
added in refractory
cases
Adapted from La Rosee et al.
12
C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 1 6 , I s s u e 2 , 2 0 2 1 47
Spillane D et al.
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Acknowledgements
We would like to thank Dr. Gizelle Popradi for providing
information and assisting with the labelling of Figure 1.
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