A Rare Case of Measles-Associated Hemophagocytic Lymphohistiocytosis in an Infant

Measles continues to be a threat in most European countries due to suboptimum vaccination coverage. Although measles leads to several complications, measles-related hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Herein, we present a case of a four-month-old male infant, the first child of unrelated, healthy parents, with no significant medical history or unexplained infant death in the family, otherwise healthy, who was diagnosed with measles-associated HLH and was successfully treated with IV dexamethasone and IV immunoglobulin (IVIG). Additionally, we review previously reported cases of HLH secondary to measles and highlight the diagnostic and therapeutic challenges associated with its early recognition and treatment. High suspicion, early recognition, and appropriate treatment are essential for a favorable outcome of measles-associated HLH.


Introduction
A large measles epidemic has affected European countries in the past three years [1]. During this period, Greece saw the second largest measles outbreak in Europe [1]. In 2017, based on the local surveillance data from the Hellenic Center for Disease Control & Prevention, 968 cases were recorded, after three years without local endemic measles transmission, starting from a cluster of three imported cases in Northern Greece, concerning unvaccinated Romanian Roma siblings [2]. The outbreak has spread all over Greece, reaching 3150 reported cases, primarily in the southwestern country. Most cases were of Roma origin, especially children <10-year-old, followed by Greek nationals, mostly young adults, not immune to measles and some nonvaccinated healthcare professionals (HCPs) [2]. Overall, four deaths have been reported. Broad vaccination campaigns that were implemented afterward in refugee/migrant hosting sites prevented the extensive spread of measles in such populations [2]. Currently, further efforts focus on raising awareness among HCPs and on organizing vaccination campaigns in hard-to-reach vulnerable populations such as the Roma population where vaccination rates remain low.
Although measles is associated with high morbidity and mortality rates due to several complications, measles-induced HLH has been rarely described. Herein, we describe a case of an infant with potentially life-threatening measles due to associated HLH. Additionally, we review reported cases of measles-associated HLH and highlight the diagnostic and therapeutic challenges associated with its early recognition and treatment.

Case Presentation
A four-month-old male infant, the first child of unrelated, healthy parents, with no significant medical history or unexplained infant death in the family, otherwise healthy, presented with severe respiratory distress due to measles-associated pneumonitis (nine days after the disease onset). His initial physical examination revealed a febrile in poor general condition, with a respiratory rate at 70/min, oxygen saturation at 93%-94%, and diffuse crackles and wheezing. He had a generalized erythematous maculopapular rash, while Koplik spots were not visible. There was no conjunctivitis, lymphadenopathy, or hepatosplenomegaly. Admission laboratorytests including full-blood-count, C-reactive protein (CRP), procalcitonin, kidney/liver function, and serum electrolytes were normal. Measles IgM antibodies were detected serologically. Initial and repeated blood-cultures did not yield any pathogen. Abdominal ultrasound in admission was normal, while chest X-ray presented only mild inflitrations and no signs of pneumonia ( Figure 1). He was met on nebulized racemic epinephrine and oxygen administration, and was started on IV cefotaxime due to a potential concomitant bacterial co-infection, suspecting sepsis due to affected clinical condition.

Chest X-ray in admission showing mild infiltration
Five days later, he was still in poor general condition with persistent respiratory distress and fever, while hepatosplenomegaly was revealed in the new ultrasound ( Figure 2).

Discussion
While fHLH is caused by mutations in genes involved in perforin-dependent lymphocyte cytotoxicity, sHLH is associated with infection, malignancy, or rheumatic conditions [3][4]. It is often difficult to distinguish the two HLH forms. sHLH is our most likely diagnosis due to the absence of a positive family history, parental consanguinity, and familiar history of unexplained pediatric death. Our patient rapidly responded to the initial treatment with a long remission state, further reducing the possibility of fHLH, that is often more severe, associated with frequent relapses and higher mortality rates. Fever, splenomegaly, hyperferritinemia, cytopenias associated with respiratory distress, and/or multiorgan failure should prompt a strong consideration of sHLH [5]. Remarkably, although blood cell-lines were within the normal range, it is the drop from previous levels that may herald HLH development [5]. fHLH cannot be excluded considering the early-life onset of HLH as well as previous reports showing that infectious agents may trigger fHLH. Therefore, molecular investigation of fHLH mutations and/or NK-function and soluble-CD25 assessment may be recommended, especially in the context of a possible future reactivation.
Measles-induced sHLH has been previously reported in five cases ( Table 2). All cases presented with pneumonitis [7][8][9][10][11], while only three had also cerebromeningeal symptoms [7,9]. Three cases occurred in immunocompetent children [8,[10][11]. Among the adults, there was an immunocompetent 18-year-old man with acute respiratory distress [10] and a 17-year-old boy with high risk acute lymphoblastic leukemia [11]. Death occurred in a previously healthy 25month-old boy with hemophagocytic syndrome, and acute disseminated demyelinating encephalitis and a 17-year-old boy with high-risk acute lymphoblastic leukemia [9,11]. To our knowledge, this is the first case of measles-associated sHLH in an infant.  The molecular mechanism involved in measles-induced HLH is not yet defined. CD150/signaling-lymphocytic-activation-molecule, a T/B/dendritic cell glycoprotein, is a costimulatory receptor involved in T-cell activation and a cellular receptor for measles virus [12][13]. Considering that CD150-induced signal transduction is controlled by SAP/SH2D1A gene that is aberrant in X-linked lymphoproliferative disease and fHLH, measles virus may affect CD150 function in a way similar to genetic disorder leading to transient excessive macrophages, NK cells and lymphocytes activation, leading in turn to excessive immunoactivation, characterizing sHLH. Therefore, in cases of measles-induced HLH, where a genetic disorder is suspected, SAP/SH2D1A mutation should be investigated; albeit, further research is required to verify this assumption.
Finally, another issue worth mentioning is that measles-induced sHLH management was quite challenging. Firstly, the use of steroids in viral-induced sHLH has been widely debatable. Although, most studies reported no impact on the course of disease progression, a single one described reversal of cytopenia and respiratory failure with pulsed steroids [10]. Therefore, we opted to initiate treatment with immunomodulatory agents (high-dose corticosteroids and IVIG) rather than the standard HLH-2004-protocol, to balance immunosuppression, ready to immediately switch to HLH-2004-protocol at the first sign of failure, something that was not required due to our patient's acute response. This is in accordance with the previous reports supporting the use of IVIG and/or corticosteroids for the first-line treatment of virus-induced sHLH [14][15]. Such an approach may avoid etoposide-induced toxicity. HLH-2004-protocol may be considered in cases with poor clinical response or if disease progression is suspected. Besides, the distinction between sepsis and HLH is often difficult, being two acute hyperinflammatory reactions, potentially fatal without early recognition and with completely different management that is critical for a favorable outcome. A high index of clinical suspicion of measles-associated sHLH is required for early diagnosis and prompt treatment. Sen et al. had suggested that a serum ferritin >10 000 µg/L is strongly supportive of HLH [16]. Similarly, Machowicz et al. suggested that in the presence of hyperferritinemia, splenomegaly, marked cytopenias, hypofibrinogenemia, low CRP, characteristic cytokine profile, hypertriglyceridemia, the other HLH criteria should be assessed [17].

Conclusions
Amidst a period of measles outbreaks across Europe due to suboptimum vaccination coverage, increased awareness of possible measles-induced sHLH, together with early recognition and initiation of appropriate treatment is crucial to prevent a cytokine storm progressing to multiorgan failure. More intensive efforts are essential to improve vaccination rates and control outbreaks leading to enhanced herd immunity. Such an approach is critical for the protection of unvaccinated young infants as well as immunocompromised patients who are at the highest risk of measles-related sHLH.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.