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 99^th-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

1. Nakra NA, Blumberg DA, Herrera-Guerra A, et al. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children (Basel) , 2020 7.

2. Henter J-I, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer , 2007 48: 124–131.

3. Lee G, Lee SE, Ryu K-H, et al. Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors. Blood Res , 2013 48: 258–265.

4. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol , 2014 66: 2613–2620. 5. Jung J, Bohn G, Allroth A, et al. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood , 2006 108: 362–369.

6. Miao Y, Zhu H-Y, Qiao C, et al. Pathogenic gene mutations or variants identified by targeted gene sequencing in adults with hemophagocytic lymphohistiocytosis. Front Immunol , 2019 10: 395.

7. Rubin TS, Zhang K, Gifford C, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood , 2017 129: 2993–2999.

8. Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol , 2010 6: 137–154.

9. Haddad E, Sulis ML, Jabado N, et al. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood , 1997 89: 794–800.

10. Jovanovic A, Kuzmanovic M, Kravljanac R, et al. Central nervous system involvement in hemophagocytic lymphohistiocytosis: a single-center experience. Pediatr Neurol , 2014 50: 233–237.

11. Deiva K, Mahlaoui N, Beaudonnet F, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology , 2012 78: 1150–1156.

12. Murphy L, Maloney K, Gore L, et al. Hypertension in pediatric acute lymphoblastic leukemia patients: prevalence, impact, and management strategies. Integr Blood Press Control , 2022 15: 1–10.

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.