To the Editor,
Both hemophagocytic lymphohistiocytosis (HLH) and multi-inflammatory
syndrome in children (MIS-C) are treated with high dose corticosteroids
[1, 2]
which may put patients at risk for neurological abnormalities via the
development of posterior reversible encephalopathy syndrome (PRES)
[3].
HLH itself may also cause central nervous system (CNS) effects, either
directly, or as an independent risk-factor for PRES
[3].
Here, we present a patient initially diagnosed with MIS-C and HLH who
develops PRES following the administration of high dose corticosteroids.
A previously healthy 6-year-old female presented with a 2-month history
of relapsing and remitting fevers and lethargy following SARS-CoV-2
infection. At presentation, the patient was tachycardic and hypotensive
with cracked, erythematous lips and a full body, pruritic rash. She was
moaning and minimally verbally responsive. Intravenous fluid
resuscitation, ceftriaxone, and vancomycin were administered in the
emergency department. Within twelve hours, the patient developed a fever
of 40° C, signs of multi-organ dysfunction, and shock requiring
norepinephrine.
Laboratory tests revealed a mild leukocytosis, anemia, thrombocytopenia,
elevated creatinine, and transaminitis. Additionally, there were
elevations in C-reactive protein (CRP) (33 mg/dL), procalcitonin (32.99
ng/mL), ferritin (>20 000 ng/mL), prothrombin time (18.3),
and d-dimer (37 178 ng/mL). Fibrinogen was low at 129 mg/dL. Abdominal
ultrasound revealed hepatomegaly and borderline splenomegaly. Initial
lab tests and imaging were not concerning for cardiomyopathy or
pneumonia.
After meeting criteria for MIS-C (Table 1) the patient received two
corticosteroid loading doses of 250 mg methylprednisolone on day one,
followed by 60 mg on days two and three. On treatment day two,
intravenous immunoglobulin (IVIG) therapy via was initiated.
With fever, splenomegaly, anemia, thrombocytopenia, hypofibrinogenemia,
and hyperferritinemia, the patient also met criteria for HLH (Table 1)
with an H-score suggesting a 99%-likelihood of HLH
[4].
Cerebrospinal fluid (CSF) cell counts showed histiocytes within normal
limits.
By the end of day two, the patient’s blood pressure stabilized, and
norepinephrine was discontinued. The patient defervesced, and creatinine
returned to age-appropriate levels.
Despite these improvements, the patient’s worsening fibrinogenemia,
anemia, and transfusion-resistant thrombocytopenia raised concern for
worsening HLH. Soluble interleukin-2 receptor (sIL-2R), natural killer
cell activity, and bone marrow biopsy were pending, as were the results
of CSF cytology.
On treatment day 3, the patient experienced a mean blood pressure
elevation to the 99th-percentile of her
age/height-adjusted range (95 mmHg). This was followed by brief oxygen
desaturation, tonic-clonic movements, and altered mental status. She
received hydralazine, levetiracetam, midazolam, and lorazepam and was
placed on a nicardipine drip and continuous hemodynamic monitoring.
Methylprednisolone was changed to dexamethasone, and anakinra was
started. An initial head computed topography (CT) scan without contrast
showed no acute pathology, while follow-up magnetic resonance imaging
(MRI) findings were consistent with PRES (Fig. 1).
On treatment day five, the patient self-extubated. She began speaking in
short sentences, blood pressure was maintained at age/height-adjusted
norms with amlodipine, and ferritin levels continued to downtrend. The
patient’s neurologic status and ferritin levels returned to baseline
over the following week, and she was discharged home with hematology
follow up.
Her sIL-2R level eventually resulted, showing a value of 38 463.6 pg/mL
on day two of treatment. HLH genetic tests showed two equivocal results:
(1) a heterozygous variant (c.402>T, p.Ser134er) in exon 5
of the AP3B1 gene
[5]
and (2) a heterozygous variant (c.912C>T, p.Ser134er) in
exon 7 of the LAMP1 gene
[6][7].
This case highlights several complications that may arise in children
following SARS-CoV-2 infection. For example, the development of MIS-C
symptoms may mask an underlying HLH (Table 1)
[1].
In such cases, the presence of hyperferritinemia, anemia, and
splenomegaly are more specific to HLH
[8].
Additionally, Fardet’s HScore
[4]
may aid in predicting the likelihood of HLH while awaiting the results
of confirmatory labs such as sIL-2R.
Mortality is as high as 80% in untreated HLH, and involvement of the
CNS portends particularly poor outcomes
[9].
Symptoms vary in CNS HLH, but include seizures, ataxia, and
encephalopathic mental status changes
similar to those found in PRES
[10]
Theoretically, CSF analysis should assist in differentiating these
diagnoses. However, as in this case, confirmatory cytology may be slow
to return, inciting the need for prompt CNS imaging. Radiographically,
PRES often presents with signs of bilateral posterior hemisphere edema
on CT or MRI, whereas CNS HLH may show meningeal signs or
periventricular hypodense lesions
[9, 11].
If PRES is confirmed, treatment includes anti-epileptics and hemodynamic
control
[3].
The diagnosis and management of PRES during the treatment of
SARS-CoV-2-related-HLH is a novel issue that presented several
challenges. We considered three diagnostic possibilities following our
patient’s seizure: (1) Direct CNS HLH, (2) HLH-triggered-PRES, and (3)
treatment-triggered PRES. MRI findings (figure 1) confirmed PRES, and
CSF cytology eventually ruled out CNS HLH involvement
[9][10].
The mechanism of HLH-associated PRES in our patient is likely
multifactorial, involving an HLH-induced pro-inflammatory state
exacerbated by steroid neurotoxicity as previously described
[3].
An algorithm to avoid steroid-induced neurotoxic hypertension is
well-outlined in the treatment of acute lymphoblastic leukemia
[12],
but such considerations may not yet be highlighted in institutional
treatment guidelines for MIS-C and HLH
[1].
As this case suggests, increased attention to hemodynamic monitoring may
prevent steroid-associated PRES during the treatment of
hyperinflammatory syndromes.
Conflict of Interest Statement: We have no conflicts of interest to
disclose.
Acknowledgements: A special thank you to the patient and her family, who
endured much.
References
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Legends List:
Table 1 Title
TABLE 1 Multisystem inflammatory syndrome in children vs. hemophagocytic
lymphohistiocytosis diagnostic criteria
Table 1 Legend
TABLE 1 A comparison of the diagnostic criteria for multisystem
inflammatory syndrome in children
[1]
and hemophagocytic lymphohistiocytosis
[2].
MIS-C, multisystem inflammatory response in children; HLH,
hemophagocytic lymphohistiocytosis; CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate; IL-6, interleukin-6; SARS-CoV-2, severe
acute respiratory syndrome coronavirus 2; NK cell activity, natural
killer cell activity; sIL-2R, soluble interleukin-2 receptor.
a Systems include: Cardiac, renal, respiratory,
hematologic, gastrointestinal, dermatological, neurological.
b At least five of the eight criteria marked
with “b ” are required for diagnosis of HLH
[2].
Figure 1 Title
FIGURE 1 CT & MRI radiographs in a patient presenting with PRES
Figure 1 Legend
FIGURE 1 Following seizure-like activity, an initial CT without contrast
(A) showed no acute pathology. A follow-up MRI under sedation (B, C, D)
revealed abnormal, symmetrical signal hyperintensities in the cortex and
subcortical white matter of the parietal and occipital lobes on
T2-weighted-Fluid-Attenuated Inversion Recovery consistent with PRES.