SARS-CoV-2-Triggered Hemophagocytic Lymphohistiocytosis with Complications of Posterior Reversible Encephalopathy Syndrome

In this article, we describe a novel case of SARS-CoV-2-associated-hemophagocytic lymphohistiocytosis (HLH) complicated by posterior reversible encephalopathy syndrome (PRES). Initially diagnosed with multisystem inflammatory response in children (MIS-C), the patient received a large corticosteroid dose days before the onset of neurological symptoms. After developing PRES, the patient was treated with antihypertensives, antiepileptics, dexamethasone, and anakinra, leading to neurologic normalization. We propose that given the challenging diagnostic picture of PRES developing in patients with HLH or MIS-C, institutionalized standards for blood pressure management during corticosteroid induction may significantly improve outcomes in patients being treated for hyperinflammatory syndromes who develop neurological symptoms.


Introduction
Te severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has increased hospital admissions for pediatric hyperinfammatory syndromes including multisystem infammatory syndrome in children (MIS-C) and, even more rarely, hemophagocytic lymphohistiocytosis (HLH) [1].High dose corticosteroids, a mainstay of treatment for both HLH and MIS-C [1,2], may induce hypertensive urgency; therefore, increasing the risk of posterior reversible encephalopathy syndrome (PRES), a transient clinicoradiographic syndrome is thought to be secondary to dysregulation of cerebral blood fow [3].
We present this case as evidence that during the treatment for MIS-C, the clinical picture may rapidly evolve to HLH and even PRES and prompt pharmacological adjustments may minimize morbidity in patients who develop central nervous system (CNS) symptoms.

Case Description.
Te patient is a fully immunized, previously healthy 6-year-old female who presented with a 2-month history of relapsing and remitting fevers and lethargy following a PCR-confrmed SARS-CoV-2 infection.On initial evaluation, the patient was afebrile, tachycardic, and hypotensive.Physical exam revealed cracked, erythematous lips and a full body, pruritic rash.She was moaning and minimally verbally responsive.Her hands were cold and pale with delayed capillary refll.Intravenous fuid resuscitation, ceftriaxone, and vancomycin were administered in the emergency department.Within twelve hours, the patient developed a fever of 40 °C, signs of multiorgan dysfunction, and fuid-refractory shock requiring norepinephrine.
Meeting criteria for moderate-severe MIS-C (Table 1), the patient began corticosteroid induction therapy.Per institutional standards, she received two doses of 250 mg of methylprednisolone on day one of treatment, followed by 60 mg on days two and three.On treatment day two, intravenous immunoglobulin (IVIG) therapy via was initiated.
On treatment day two, the patient's blood pressure stabilized, and norepinephrine was weaned and discontinued.By this time, the patient had defervesced and creatinine had returned to age-appropriate levels.
Despite these improvements, the patient's worsening fbrinogenemia, anemia, and transfusion-resistant thrombocytopenia raised concern for worsening HLH, prompting strong consideration of anakinra.Confrmatory HLH labs such as 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 99 th -percentile of her age/ height-adjusted range (95 mmHg).Tis was followed by brief hemodynamic desaturation, tonic-clonic movements, and altered mental status.She received hydralazine, levetiracetam, midazolam, and lorazepam and was placed on a nicardipine drip with continuous arterial pressure monitoring via arterial line.Given the concern for CNS HLH, 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) fndings were consistent with PRES (Figure 1).
On treatment day fve, the patient self-extubated after a sedative wean.Her neurologic status improved to the point of speaking in short sentences, blood pressure was maintained at age/height-adjusted norms with amlodipine, and ferritin levels continued to downtrend.Te patient's neurologic status and ferritin levels returned to the baseline over the following week, and she was discharged home with outpatient hematology follow-up.
Her sIL-2R level eventually resulted, showing a value of 384.636IU/L from day two of treatment that decreased to 0.8719 IU/L three months later.HLH genetic tests showed two equivocal results: (1) a heterozygous variant in exon 5 of the AP3B1 gene [5] and (2) a heterozygous variant of unknown signifcance in exon 7 of the LAMP1 gene [6,7].

Discussion
Tis report describes the diagnosis, management, and complications that arose in a case of SARS-CoV-2-triggered-HLH in a previously healthy 6-year-old female with equivocal genetic HLH markers.Te patient developed seizure-like activity during the frst week of treatment and was diagnosed with PRES via MRI.She quickly returned to neurologic and physiologic baseline after initiation of antiepileptics, antihypertensives, and anakinra.
Her 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].While both syndromes can present with fever, shock, elevated CRP, neutropenia, and thrombocytopenia, the presence of hyperferritinemia, anemia, and splenomegaly are more specifc to HLH [8].Henter et al.'s HLH-2004 guidelines may assist in the diagnosis of HLH [2] (Table 1), while Fardet's HScore [4] may aid in predicting the likelihood of HLH while awaiting the results of confrmatory labs such as sIL-2R (Fardet's HScore was originally validated for the diagnosis of "primary HLH."However, the North American Consortium of Histiocytosis (NACHO) has since recognized that the use of "primary" and "secondary" HLH is an unnecessary and confusing distinction that fails to delineate the diference between "HLH disease" and "HLH disease mimics" [17].Terefore, we have chosen to omit any discussion of primary and secondary HLH from the current case report).Treatment for MIS-C and HLH involves high-dose corticosteroids and sometimes IVIG [1].For HLH, early initiation of etoposide, a CD8+ cytotoxic chemotherapy, has been the standard of care [4].However, recent evidence suggests anakinra, an IL-1 antagonist, is a viable, less chemotoxic alternative that may better attenuate the hyperinfammatory cascade underlying HLH pathophysiology [9].
Mortality is as high as 80% in untreated HLH, and involvement of the CNS portends particularly poor outcomes [10].Symptoms vary in CNS HLH, but they include seizures, ataxia, and encephalopathic mental status changes similar to those found in PRES [11].Teoretically, CSF analysis should assist in diferentiating these diagnoses.However, as in this case, confrmatory 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 [10,12].If PRES is confrmed, treatment includes 2 Case Reports in Pediatrics  Case Reports in Pediatrics antiepileptics and blood pressure control [3].Prognosis of PRES in pediatrics is generally favorable, although some small studies suggest that higher levels of infammatory markers may be associated with worse outcomes [13].
Te current case is unique in in multiple aspects.First, while MIS-C is now a well-documented albeit rare SARS-CoV-2 complication, SARS-CoV-2-related-HLH in children has only once been reported [14].Second, this case highlights the successful management of HLH with early initiation of anakinra, a relatively new treatment regimen [9].Finally, the diagnosis and management of PRES during the treatment of SARS-CoV-2-related-HLH is a novel issue that presents several diagnostic challenges.
We considered three diagnostic possibilities following our patient's development of hypertension and seizure: (1) direct CNS HLH, (2) HLH-triggered-PRES, and (3) treatment-triggered PRES.MRI showed bilateral posterior subcortical hyperintensities confrming PRES, and CSF cytology eventually ruled out CNS HLH involvement [10,11].COVID-triggered PRES is well-documented in adult literature [15] but thought to be an unlikely etiology given the remote onset of SARS-CoV-2 infection.Te mechanism of HLH-associated PRES in our patient is likely multifactorial, involving an HLH-induced proinfammatory state exacerbated by steroid-induced hypertension as previously described [3].
An algorithm to avoid this kind of steroid-induced neurotoxic hypertension is well outlined in the treatment of acute lymphoblastic leukemia [16], 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 hypertension-associated PRES during the treatment of hyperinfammatory syndromes.

Conclusion
Tis report documents a case of SARS-CoV-2-triggered-HLH in a previously healthy child.Subsequent development of PRES emphasizes the need for institutional guidelines regarding the monitoring and management of acute hypertension and encephalopathy in patients undergoing corticosteroid treatment for MIS-C or HLH.
Evidence of prior SARS-CoV-2 infection Cytopenia in >2 cell lines b (i) Hemoglobin <90 g/L (ii) Platelets <100 × Fasting triglycerides ≥3.0 mmol/L (ii) Fibrinogen ≤1.5 g/L Hemophagocytosis on bone marrow biopsy or lymph nodes and no malignancy bs Low or absent NK cell activity (according to local laboratory reference) b Serum ferritin >500 mg/L b Elevated sIL-2R (CD25) > 2.400 IU/L b OR (i) Evidence of mutation in a known causative gene Other criteria No alternative diagnosis n/a A comparison of the diagnostic criteria for multisystem infammatory syndrome in children [1] and hemophagocytic lymphohistiocytosis [2].MIS-C, multisystem infammatory 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; soluble interleukin-2 receptor.a Systems include cardiac, renal, respiratory, hematologic, gastrointestinal, dermatological, and neurological.b At least fve of the eight criteria marked with "b" are required for diagnosis of HLH [2].