A case report of idiopathic Hemophagocytic lymphohistiocytosis in an immunocompetent adult

Abstract Hemophagocytic lymphohistiocytosis poses a diagnostic dilemma due to the absence of specific clinical and laboratory findings, especially in adults. Despite greater recognition of the disease, secondary idiopathic forms are still reported.


| INTRODUCTION
The authors report the clinical case of an idiopathic Hemophagocytic lymphohistiocytosis (HLH) in an adult patient, first appearing with nonspecific symptoms, followed by sepsis-like evolution requiring advanced life support. Despite exhaustive study, no etiology for HLH was identified, including infectious, malignancy, autoimmune, or genetic causes.
Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory syndrome of excessive immune activation, due to cytokine overproduction. [1][2][3] It is largely underdiagnosed in adults 4 and is a life-threatening disease, especially if diagnosed late. There are two forms of the disease: primary (that includes familiar forms) and secondary or acquired, usually due to infections, malignancy, and autoimmune/autoinflammatory diseases 1-3 ; both forms have similar clinical characteristics. 4 Despite the etiology, HLH is an important cause of fever of unknown origin and extreme elevation of ferritin, associated with multiple organ involvement. Initial signs and symptoms of HLH can mimic common diseases, like infections. 2 Previously established diagnostic criteria (HLH-2004) are controversial and do not reflect, especially in adults, all described clinical manifestations, due to extrapolation of pediatric recommendations and studies. [1][2][3][4] A new tool, HScore, was created to improve diagnosis, but clinical disease heterogeneity is not always represented by available scores. There is still a poor recognition of HLH but, nowadays, diagnosis of this clinical entity reemerged, motivated by COVID-19 pandemic-an HLH-like syndrome has been reported in association with SARS-CoV-2 5 (this case was not contemporary to this situation).

| CASE PRESENTATION
A 49-year-old woman presented with one-week history of anorexia, asthenia, pruritus, abdominal pain, nausea, and liquid stools. The patient had poor living conditions and suffered from mild cognitive impairment and blindness since childhood. On admission, she presented with fever (38.2ºC), pain on right superior abdominal quadrant, and scratchy skin lesions ( Figure 1); a short stature and a dysmorphic face were noted; no neurologic findings. Laboratory study carried out showed: anemia, leukocytosis, and thrombocytosis; high sedimentation velocity, d-dimers, fibrinogen, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), triglycerides, soluble IL-2 receptor, and interleukin-6 levels; hypergammaglobulinemia; mild cythocolestasis; hypoalbuminemia; and low high-density lipoprotein (HDL) values. Natural killer (NK) cell activity was normal (Table 1).
The study performed allowed the exclusion of liver and heart disease, malignancy, infectious, and autoimmune diseases, as well as genetic defects-HLH Panel by nextgeneration sequencing and karyotype ( Table 2).
The patient had a long hospital stay and recurrent deterioration episodes with hypotension, high fever, and other organic dysfunctions. She was admitted to intensive care unit. Although fulfilling only 4 criteria for diagnosis of HLH (HLH-2004), the patient presented a HScore of 185 points (indicating a 70%-80% probability of HLH), and treatment with dexamethasone and cyclosporine was initiated. Clinical stability was achieved, with gradual improvement of initial symptoms, specifically of anemia and hyperferritinemia.
After discharge, there was no adherence to therapeutic prescription with clinical relapse resulting in hospital readmission.
The patient remains under hematology follow-up, although she is not eligible for hematopoietic stem cell transplantation (HSCT) due to poor family support and no identified underlying genetic defect.

| DISCUSSION
Two diagnostic challenges are relevant in context of HLH. First, a high degree of suspicion is required because of variable clinical presentations, lack of specificity of clinical and laboratory findings, and diversity of causes; prompt recognition of HLH syndrome and diagnosis of underlying cause are critical to enable urgent and appropriate treatment. 6 Second, it is important to distinguish familial HLH (FHL) from secondary HLH, because HSCT is recommended in FHL. 3 Furthermore, in the case presented, despite exhaustive study, no etiology for HLH was identified, including infectious, malignancy, autoimmune, or genetic causes. Exclusion of FHL was also important due to limited number of reports of adult-onset of HLH primary form. Despite greater recognition of the disease, secondary idiopathic forms of HLH are still reported. 4,[6][7][8][9][10][11][12] The presence of dysmorphic face, short stature, mild cognitive impairment, and blindness could suggest Laurence-Moon-Bardet-Biedl syndrome, but genetic testing was not performed. No association between this hereditary disease and HLH was previously reported in literature.
Differential diagnostic workup should not delay initiation of HLH-specific treatment in those who are acutely ill. Indeed, adults with HLH have poor outcomes even with aggressive treatment. 3 In the case presented, once treatment was started, clinical stability was achieved, with clinical and analytical improvement-gradual improvement of initial symptoms and hemoglobin levels and decreased of ferritin, CRP, sedimentation velocity, and LDH levels.
Due to the absence of most characteristic and common features present in pediatric literature reports, HScore was used in this case to guide diagnosis, but above all, clinical judgment and a high index of suspicion were required. Features of HLH in adults are still in debate, and there are no established criteria for this population, so current diagnostic criteria should be used with caution. Frequently, diagnosis of HLH is made for patients who only partly meet the most stringent criteria, and this presumptive diagnosis depends on a careful consideration of the presence or absence of specific elements embedded in diagnostic criteria, results of additional laboratory tests, and a nuanced view of overall clinical status. This emphasizes that clinical judgment should be encouraged instead of relying solely on strict adherence to pre-established diagnostic criteria, especially in adults.
Mild elevation in leukocytes probably reflects balanced effects of cytokines (eg: IL-6 and IFN-γ), different release patterns, and concurrent effects on inflammatory markers of each.
We present a clinical case of a secondary idiopathic HLH in an adult patient, first appearing with unspecific complaints, followed by sepsis-like evolution and requiring advanced life support. Clinical judgment and a high index of suspicion are required. This report intends to contribute to the framing of clinical recommendations for this rare, heterogeneous, and complex clinical entity.