“A Dangerous Black Box:” Idiopathic Hemophagocytic Lymphohistiocytosis in Adult Patients—A Case Report and Review of the Literature

Agbariah, Nada; Sanz, Javier; Rovó, Alicia

doi:https://doi.org/10.1155/2022/5867129

Case Reports in Hematology

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Case Report | Open Access

Volume 2022 | Article ID 5867129 | https://doi.org/10.1155/2022/5867129

“A Dangerous Black Box:” Idiopathic Hemophagocytic Lymphohistiocytosis in Adult Patients—A Case Report and Review of the Literature

Nada Agbariah,¹Javier Sanz,²and Alicia Rovó¹

Academic Editor: Pier Paolo Piccaluga

Received12 Jul 2022

Revised20 Nov 2022

Accepted22 Nov 2022

Published03 Dec 2022

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially life-threatening condition characterized by aberrant inflammation that can be related to genetic or sporadic forms. In both forms, triggering factors may be involved. Early detection of the underlying cause is crucial for therapeutic decision, while early intervention might be associated with better outcomes. The largest descriptions in the literature on HLH refer to pediatric cases. Adolescents and adults may also be affected, but there is scarce evidence regarding their diagnosis and management. We describe here the case of a 68-year-old Swiss woman with HLH, in whom an extensive search for underlying causes was performed, but neither trigger nor pathogenic variant was found. An early intervention first with dexamethasone and later with cyclosporine was performed. The patient showed a favorable response and did not require further hospitalization; however, one year after diagnosis, it was not possible to suspend cyclosporine due to recurrence of laboratory inflammation signs by drug tapering. The occurrence of HLH idiopathic forms represents a challenge; failure to identify the underlying triggering cause generates uncertainty, endless diagnostic investigations, and consequently additional delays in the treatment. This manuscript addresses the difficulties on this issue.

1. Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening condition characterized by a cytokine storm that is provoked by aberrant activation of macrophages and T cytotoxic cells [1, 2]. Clinically, HLH patients present with fever, splenomegaly, and a sepsis-like syndrome. The laboratory findings are hyperferritinemia, bicytopenia or pancytopenia, activation of the coagulation cascade, hypertriglyceridemia, often hepatitis, and multiorgan dysfunction [3–5]. Pathophysiology is complex: key factors are the presence of predisposing immunodeficiency and significant immune activation [6]. Although sepsis can trigger HLH, it is important to identify underlying associated HLH as soon as possible, because immunosuppressive therapy is required to suppress the cytokine storm of HLH, a strategy that is not present systematically in sepsis guidelines [7, 8].

The mortality of HLH is highly dependent on provoking conditions and lies between 20% and 88% [9–11]. There are two forms of HLH: the primary/genetic one, more frequent in children, is caused by pathogenic variants in genes involved in lymphocytic cytotoxicity and immune regulation. The secondary form, more frequent in teenagers and adults, is associated with different medical conditions, such as infections with Epstein–Barr virus (EBV) or cytomegalovirus (CMV), malignancy, and rheumatologic diseases and more recent cases reported due to SARS-CoV-2 infection or vaccination or after chimeric antigen receptor T-cell (CART) therapy infusions among others [6, 12–17]. Furthermore, in a variable number of patients, despite extensive investigations, no trigger has been found to explain HLH and they will be considered as idiopathic forms. The latter represents a particular challenge since physicians often might insist on endless diagnosis searches that could lead to an unacceptable delay in the treatment.

HLH is a condition better known in children than in adults [1], although awareness regarding HLH in the adult population is increasing. The incidence of HLH in the pediatric population is 1 in 300.000 [12, 13, 18], whereas the real incidence of HLH in the adult population remains unknown; however, in the last 10 years, the number of cases reported in the literature in the adult population has significantly increased [4, 19, 20]. Diagnostic tools such as HLH-2004 [21] are based on pediatric populations, and despite being applied to adult patients, their interpretation must be performed with caution [22]. In contrast, the HLH-score (HScore), which was published in 2014, is based on an adult population [23] and relies on the summation of points assigned for 9 variables (immunosuppression, fever, organomegaly, triglyceride, ferritin, glutamic oxaloacetic transaminase, fibrinogen, cytopenia, and hemophagocytosis features in bone marrow aspirates), which correlate with the probability of having HLH. The Hscore ranges from 0 to 337, giving a probability of having HLH ranging from <1% to ≥99% [23].

There are recommendations for the treatment of HLH in pediatric patients, and for example, HLH-2004 [24], an established treatment protocol for adult HLH patients, is however missing. Thus, treatment of adult HLH patients follows existing recommendations for pediatric patients with a variety of nonstandard adaptations. It is common practice to start the treatment with glucocorticoids and another immunosuppressive drug, such as cyclosporine. The use of etoposide, as recommended by HLH-2004, despite being frequently used, is still discussed in adult patients. Allogenic stem cell transplantation has rarely been reported in adults with secondary HLH [25].

A literature search was performed in PubMed using MeSH terms (performed on January 23^rd, 2022; HLH adult). Among the 1,192 results, 28 cohorts including more than 10 adult patients published from 2010 were identified and evaluated (Table 1).

2. Case Presentation

We report the case of a 68-year-old Swiss woman who presented to a peripheral hospital in Switzerland after consulting her general doctor about loss of weight (8 kg) in the last month, a maculopapular rash, fatigue, loss of appetite, palpitations, headaches, and cough for 2 weeks. The general doctor assigned her to the peripheral hospital after measuring 39.5°C fever and noticing very high liver parameters in the blood test.

She had a history of pericarditis at the age of 65 years, and paroxysmal atrial fibrillation and depression were also noted.

The family history was negative for hematological diseases.

The laboratory workup at admission showed normocytic, normochromic nonregenerative moderate anemia, mild thrombocytopenia, high D-dimer, slightly lower fibrinogen, liver insufficiency, and high triglycerides. The ferritin level increased (7,069 μg/L, reference value: 10–120 μg/L). An ultrasound scan of the abdomen showed splenomegaly (12.5 cm). The SARS-CoV-2 polymerase chain reaction (PCR) test, chest X-ray, lumbar puncture, blood culture, serology for EBV, CMV, human immunodeficiency virus (HIV), hepatitis A, B, C, and E, Coxiella, parvovirus B19, and Bartonella, and search for Mycobacterium tuberculosis (QuantiFERON test) were negative. After one week of hospitalization, her clinical condition deteriorated, and she was transferred to our center with the suspicion of HLH. At admission, the patient presented with markedly reduced general conditions; she was febrile (38.6°C), hemodynamically compensated, her BMI was 18.5 kg/m², and the laboratory tests showed a progressive increase in CRP up to 190 mg/l, hypoosmolar hyponatremia, increased liver values, coagulopathy, and pancytopenia (Table 2). An HScore for reactive HLH was calculated, showing 209/337 points with an estimated probability for HLH of 93% (Table 3). Therefore, therapy with dexamethasone 15 mg/day was immediately started. Additional investigations were performed, including transthoracic echocardiography, computed tomography (CT) of the chest, abdomen, and pelvis, and a biopsy of the liver, skin, and bone marrow; however, none of these examinations contributed to the identification of an underlying trigger for HLH. The bone marrow showed a large number of macrophages but did not show any sign of hemophagocytosis. Furthermore, a rheumatologic disease could be excluded based on negative screening for autoantibodies (antinuclear antibodies, Hep-2, SsA, PR3 antineutrophil cytoplasmic antibodies, and myeloperoxidase antineutrophil cytoplasmic antibodies) and missing related symptoms. After 1 week of treatment, slight clinical and laboratory improvements allowed doctors to start tapering dexamethasone, and the patient was discharged home after 4 weeks of hospitalization.

Four days later, she presented to her scheduled control in the outpatient clinic of hematology with worsened fatigue. The laboratory workup showed an increase of ferritin to 49′036 mcg/L while still being under 5 mg dexamethasone/day. We therefore increased the dexamethasone dose to 16 mg/day and started with cyclosporine, with a trough level goal between 100 and 200 ng/ml. Because up to that point no cause of HLH could be identified, the investigation was completed with positron emission tomography-computed tomography (PEC-CT), which showed intensive metabolic activity behind the right patella and in the ascending and sigmoid colon. Gastroscopy and colonoscopy performed afterward excluded gastrointestinal neoplasia and local inflammatory diseases. Additionally, leg magnetic resonance imaging (MRI) was performed, which suggested pigmented villonodular synovitis (PVNS), a benign entity unlikely to cause HLH, and thus considered an incidental finding.

Only after 3 months from the manifestation of symptoms, the patient reported a significant improvement in her general condition, including regaining appetite and weight.

Furthermore, we performed a genetic analysis searching for variants in genes related to primary HLH (perforin 1 (PRF1), syntaxin 11 (STX11), syntaxin binding protein 2 (STXBP2), and UNC13D), revealing no pathogenic variants.

The diagnostic workup is summarized in Table 4.

Vitamins and substrates (folic acid, iron, zinc, and vitamin B12) were administrated to sustain hematopoiesis.

Six months after the diagnosis, the patient was completely back to her routine life with no symptoms and completely normalized laboratory findings (Table 2). Slow tapering to discontinue cyclosporine was performed, but immediately before planned drug withdrawal, laboratory signs of inflammation with increased liver values at a 9-monthfollow-up were observed, and a low dose of cyclosporine was reinstalled. Currently, one year after the diagnosis, the patient is doing well, and tapering of cyclosporine is still ongoing.

3. Discussion/Conclusion

Several causes have been described as possible triggers of HLH in adult patients (Table 4). Nevertheless, the case presented here did not show any underlying trigger despite an exhaustive search.

The most important contribution of bone marrow investigations in HLH is the diagnosis or exclusion of hematological diseases. In the bone marrow cytology and biopsy of the case reported here, there was no evidence of lymphoma or other hematological diseases, which may have triggered HLH, and there was also no evidence of hemophagocytosis. Indeed, hemophagocytosis in the bone marrow is reported in just 25% of HLH cases [26]. It is important to note that finding a hemophagocytosis phenomenon in the bone marrow is neither specific nor sensitive for HLH [27]. Furthermore, in our case, a skin biopsy was performed to rule out Sézary syndrome due to the presence of maculopapular exanthema erythematosus of unknown origin. Likewise, due to the persistence of liver test abnormalities, a liver biopsy was also performed. The results of both biopsies did not show lymphoma or other relevant findings, and in both samples, no hemophagocytosis phenomenon was observed.

Performing PET-CT on HLH patients contributes to the diagnosis of lymphoma and other malignant or inflammatory diseases [28–30].

After excluding a secondary cause of HLH in our patient and despite the low probability due to age, as well as the lack of positive family history, we considered the possibility of primary/genetic HLH. This form is better known in children and often associated with other abnormalities such as immunodeficiency or albinism, such as in Griscelli syndrome [31]. Panel sequencing of HLH-associated genes or exome sequencing have made a great deal of contribution to the diagnosis of congenital forms, particularly in children. In fact, with these investigations, molecular explanation could likely be found in 58% of the studied pediatric patients even in the absence of familial syndromes [32]. The most common pathogenic variants reported in 14% of the cases associated with HLH in adults were identified in PRF1, STXBP2, and UNC13D [33]. In our patient, the analysis of these genes was negative.

With the first suspicion of HLH, despite not knowing the triggering cause, an early intervention first with dexamethasone and later with cyclosporine was performed, as suggested by other authors [1, 5]. The patient initially responded well to glucocorticoid monotherapy, but while tapering at one month (Table 2), she had a relapse. A careful glucocorticoid tapering method combined with another immunosuppressive (cyclosporine) drug was afterward successful in this case.

In the literature review, we found 28 case series or studies published after 2010 based on the adult population [11, 26, 28, 30, 34–57]. Cohorts were collected from different countries and reported on a number of patients, from 12 [46] to 264 [38]. A meta-analysis [11] analyzing 2,197 patients was also included. We found that the most common trigger reported for secondary HLH in adults was malignancy, both solid cancer and hematological diseases, with a weighted average of 50% (from 0% to 72%). The second most common trigger was infection with 39% (from 0% to 76%) and autoimmune diseases with 10% (0% to 58.3%). Idiopathic HLH was reported in 24/28 studies, and the weighted average was 9.4% (0% to 50%). The different observed prevalence of triggers may be explained by the differences in the median age of the studied population. Furthermore, not all centers had the same possibility and easy access to diagnostic tools such as MRI or PET-CT and therefore were not included in publications. This diversification in patients and used diagnostic methods may partially contribute to the variability of the prevalence of idiopathic HLH.

Regarding the mortality, some studies reported just the 30-day mortality, others the mortality during the hospitalization or for the whole follow-up. For this analysis, we focused on the 30-day mortality, which was 38%, and on the overall mortality, which was 53%. In addition, mortality may be influenced by different factors, such as the prevalence of different underlying diseases, comorbidities, and age of the observed population, as well as the experience and resources of the center in diagnosing and treating HLH rapidly.

HLH is a life-threatening condition and requires rapid diagnosis and therapy. Unknown origin of HLH may be frustrating for both physicians and patients. According to our experience, it is very important to perform a complete diagnostic test, including tissue biopsy, different imaging studies, and genetic analysis whenever possible. All possible triggers should be searched because specific treatment of the underlying “trigger” disease may play a key role in management [5]. Every diagnostic and therapeutic step must be explained clearly to the patient to keep high compliance, which is essential in this process that may last several months in some cases. Our patient was very consistent with the prescribed medications and the appointments in our outpatient clinic, and she also had great support from her husband. They understood how dangerous her condition was; nowadays, they are happy with the outcome and the treatment received, and the patient is still under follow-up. A close follow-up is recommended after the first episode of idiopathic HLH to allow early diagnosis of an eventual relapse.

With currently available diagnostic methods, idiopathic forms of HLH still exist. Considering the high reported rate of mortality in many series, it is important to emphasize that in seriously affected patients, the lack of a trigger should not delay the initiation of immunosuppressive treatment, which should be started as soon as possible and should be complemented by the search for underlying causes.

We can conclude that despite the recent contributions of some publications, there is clearly a deficit in the understanding of HLH in adults. Due to the rarity of its presentation, only joint efforts of many centers investigating this disease in a prospective way will better identify its epidemiological, diagnostic, and therapeutic aspects, allowing for tailored management of HLH adults in the future.

Data Availability

Data analyzed in this study were reanalysis of the existing data, which are openly available at locations cited in the reference section.

Ethical Approval

Ethical approval is not required for this study.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Nada Agbariah and Alicia Rovó contributed to conception and design of the study. Nada Agbariah wrote the first draft of the manuscript. All the authors contributed to manuscript revision, and read and approved the submitted version.

References

P. La Rosée, A. C. Horne, M. Hines et al., “Recommendations for the management of hemophagocytic lymphohistiocytosis in adults,” Blood, vol. 133, no. 23, pp. 2465–2477, 2019.
View at: Publisher Site | Google Scholar
L. Zhang, J. Zhou, and L. Sokol, “Hereditary and acquired hemophagocytic lymphohistiocytosis,” Cancer Control, vol. 21, no. 4, pp. 301–312, 2014.
View at: Publisher Site | Google Scholar
Z. K. Otrock and C. S. Eby, “Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis,” American Journal of Hematology, vol. 90, no. 3, pp. 220–224, 2015.
View at: Publisher Site | Google Scholar
A. H. Filipovich and S. Chandrakasan, “Pathogenesis of hemophagocytic lymphohistiocytosis,” Hematology-Oncology Clinics of North America, vol. 29, no. 5, pp. 895–902, 2015.
View at: Publisher Site | Google Scholar
K. Bauchmuller, J. J. Manson, R. Tattersall et al., “Journal of the Intensive Care Society,” Haemophagocytic lymphohistiocytosis in adult critical care, vol. 21, no. 3, pp. 256–268, 2020.
View at: Publisher Site | Google Scholar
M. B. Jordan, C. E. Allen, S. Weitzman, A. H. Filipovich, and K. L. McClain, “How I treat hemophagocytic lymphohistiocytosis,” Blood, vol. 118, no. 15, pp. 4041–4052, 2011.
View at: Publisher Site | Google Scholar
R. Machowicz, G. Janka, and W. Wiktor-Jedrzejczak, “Similar but not the same: Differential diagnosis of HLH and sepsis,” Critical Reviews in Oncology, vol. 114, pp. 1–12, 2017.
View at: Publisher Site | Google Scholar
R. Machowicz, G. Janka, and W. Wiktor-Jedrzejczak, “Your critical care patient may have HLH (hemophagocytic lymphohistiocytosis),” Critical Care, vol. 20, no. 1, pp. 215–224, 2016.
View at: Publisher Site | Google Scholar
G. Griffin, S. Shenoi, and G. C. Hughes, “Hemophagocytic lymphohistiocytosis: an update on pathogenesis, diagnosis, and therapy,” Best Practice & Research Clinical Rheumatology, vol. 34, no. 4, p. 101515, 2020.
View at: Publisher Site | Google Scholar
M. Arca, L. Fardet, L. Galicier et al., “Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: Impact of triggering disease and early treatment with etoposide,” British Journal of Haematology, vol. 168, no. 1, pp. 63–68, 2015.
View at: Publisher Site | Google Scholar
M. Ramos-Casals, P. Brito-Zerón, A. López-Guillermo, M. A. Khamashta, and X. Bosch, “Adult haemophagocytic syndrome,” The Lancet, vol. 383, no. 9927, pp. 1503–1516, 2014.
View at: Publisher Site | Google Scholar
R. Q. Cron, S. Davi, F. Minoia, and A. Ravelli, “Clinical features and correct diagnosis of macrophage activation syndrome,” Expert Review of Clinical Immunology, vol. 11, no. 9, pp. 1043–1053, 2015.
View at: Publisher Site | Google Scholar
C. E. Allen, X. Yu, C. A. Kozinetz, and K. L. McClain, “Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis,” Pediatric Blood and Cancer, vol. 50, no. 6, pp. 1227–1235, 2008.
View at: Publisher Site | Google Scholar
M. R. Hines, C. Keenan, G. Maron Alfaro et al., “Hemophagocytic lymphohistiocytosis-like Toxicity (carHLH) after CD19-specific CAR T-cell therapy,” British Journal of Haematology, vol. 194, no. 4, pp. 701–707, 2021.
View at: Publisher Site | Google Scholar
R. D. Sandler, R. S. Tattersall, H. Schoemans et al., “Diagnosis and management of secondary HLH/MAS following HSCT and CAR-T cell therapy in adults; A review of the literature and a Survey of practice within EBMT Centres on Behalf of the autoimmune diseases working party (ADWP) and transplant complications working party (TCWP),” Frontiers in Immunology, vol. 11, p. 524, 2020.
View at: Publisher Site | Google Scholar
L. V. Tang and Y. Hu, “Hemophagocytic lymphohistiocytosis after COVID-19 vaccination,” Journal of Hematology & Oncology, vol. 14, no. 1, pp. 87–95, 2021.
View at: Publisher Site | Google Scholar
A. Prilutskiy, M. Kritselis, A. Shevtsov et al., “SARS-CoV-2 infection-associated hemophagocytic lymphohistiocytosis,” American Journal of Clinical Pathology, vol. 154, no. 4, pp. 466–474, 2020.
View at: Publisher Site | Google Scholar
A. M. Schram and N. Berliner, “How I treat hemophagocytic lymphohistiocytosis in the adult patient,” Blood, vol. 125, no. 19, pp. 2908–2914, 2015.
View at: Publisher Site | Google Scholar
Y. R. Kim and D. Y. Kim, “Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults,” Blood Res, vol. 56, no. S1, pp. 17–25, 2021;56 April.
View at: Publisher Site | Google Scholar
J. West, T. R. Card, M. J. Bishton et al., “Incidence and survival of haemophagocytic lymphohistiocytosis: a population‐based cohort study from England,” Journal of Internal Medicine, vol. 291, no. 4, pp. 493–504, 2021.
View at: Publisher Site | Google Scholar
J.-I. Henter, A. Horne, M. Arico´ et al., “HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis,” Pediatric Blood and Cancer, vol. 48, no. 2, pp. 124–131, 2007.
View at: Publisher Site | Google Scholar
L. Naymagon, “Can we truly diagnose adult secondary hemophagocytic lymphohistiocytosis (HLH)? A critical review of current paradigms,” Pathology, Research & Practice, vol. 218, no. 2020, Article ID 153321, 2021.
View at: Publisher Site | Google Scholar
L. Fardet, L. Galicier, O. Lambotte et al., “Development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome,” Arthritis & Rheumatology, vol. 66, no. 9, pp. 2613–2620, 2014.
View at: Publisher Site | Google Scholar
G. E. Janka and K. Lehmberg, “Hemophagocytic syndromes - an update,” Blood Reviews, vol. 28, no. 4, pp. 135–142, 2014.
View at: Publisher Site | Google Scholar
A. Hayden, S. Park, D. Giustini, A. Y. Y. Lee, and L. Y. C. Chen, “Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review,” Blood Reviews, vol. 30, no. 6, pp. 411–420, 2016.
View at: Publisher Site | Google Scholar
S. Rivière, L. Galicier, P. Coppo et al., “Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients,” The American Journal of Medicine, vol. 127, no. 11, pp. 1118–1125, 2014.
View at: Publisher Site | Google Scholar
E. Gars, N. Purington, G. Scott et al., “Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis,” Haematologica, vol. 103, no. 10, pp. 1635–1641, 2018.
View at: Publisher Site | Google Scholar
L. Yuan, Y. Kan, J. K. Meeks, D. Ma, and J. Yang, “18F-FDG PET/CT for identifying the potential causes and extent of secondary hemophagocytic lymphohistiocytosis,” Diagnostic and interventional radiology, vol. 22, no. 5, pp. 471–475, 2016.
View at: Publisher Site | Google Scholar
S. Jacob, B. L. Dunn, Z. P. Qureshi et al., “Ticlopidine-clopidogrel-and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the southern network on adverse reactions (SONAR),” Seminars in Thrombosis and Hemostasis, vol. 38, no. 08, pp. 845–853, 2012.
View at: Publisher Site | Google Scholar
J. Kim, S. W. Yoo, S. R. Kang, H. S. Bom, H. C. Song, and J. J. Min, “Clinical implication of F-18 FDG PET/CT in patients with secondary hemophagocytic lymphohistiocytosis,” Annals of Hematology, vol. 93, no. 4, pp. 661–667, 2014.
View at: Publisher Site | Google Scholar
G. Ménasché, E. Pastural, J. Feldmann et al., “Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome,” Nature Genetics, vol. 25, no. 2, pp. 173–176, 2000.
View at: Publisher Site | Google Scholar
I. K. Chinn, O. S. Eckstein, E. C. Peckham-Gregory et al., “Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis,” Blood, vol. 132, no. 1, pp. 89–100, 2018.
View at: Publisher Site | Google Scholar
K. Zhang, M. B. Jordan, R. A. Marsh et al., “Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH,” Blood, vol. 118, no. 22, pp. 5794–5798, 2011.
View at: Publisher Site | Google Scholar
F. Li, Y. Yang, F. Jin et al., “Clinical characteristics and prognostic factors of adult hemophagocytic syndrome patients: a retrospective study of increasing awareness of a disease from a single-center in China,” Orphanet Journal of Rare Diseases, vol. 10, no. 1, pp. 20–29, 2015.
View at: Publisher Site | Google Scholar
A. M. Schram, P. Comstock, M. Campo et al., “Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years,” British Journal of Haematology, vol. 172, no. 3, pp. 412–419, 2016.
View at: Publisher Site | Google Scholar
M. Oto, K. Yoshitsugu, S. Uneda, M. Nagamine, and M. Yoshida, “Prognostic factors and outcomes of adult-onset hemophagocytic lymphohistiocytosis: a retrospective analysis of 34 cases,” Hematology Reports, vol. 7, no. 2, pp. 5841–5851, 2015.
View at: Publisher Site | Google Scholar
J. Li, Q. Wang, W. Zheng et al., “Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients,” Medicine, vol. 93, no. 2, pp. 100–105, 2014.
View at: Publisher Site | Google Scholar
S. H. Lim, S. Park, J. H. Jang et al., “Clinical significance of bone marrow hemophagocytosis in adult patients with malignancy and non-malignancy-induced hemophagocytic lymphohistiocytosis,” Annals of Hematology, vol. 95, no. 2, pp. 325–335, 2016.
View at: Publisher Site | Google Scholar
Y. Zheng, G. Hu, Y. Liu et al., “The role of 18F-FDG PET/CT in the management of patients with secondary haemophagocytic lymphohistiocytosis,” Clinical Radiology, vol. 71, no. 12, pp. 1248–1254, 2016.
View at: Publisher Site | Google Scholar
F. Arslan, S. Alp, Y. Büyükasık, M. C. Ozkan, F. Şahin, S. Basaran et al., “Hemophagocytic lymphohistiocytosis in adults: low incidence of primary neoplasm as a trigger in a case series from Turkey,” Mediterr J Hematol Infect Dis, vol. 10, no. 1, pp. e2018047–7, 2018.
View at: Publisher Site | Google Scholar
P. Brito-Zerón, B. Kostov, P. Moral-Moral et al., “Prognostic factors of death in 151 adults with hemophagocytic syndrome: Etiopathogenically Driven analysis,” Mayo Clinic Proceedings: Innovations, Quality & Outcomes, vol. 2, no. 3, pp. 267–276, 2018.
View at: Publisher Site | Google Scholar
S. Kapoor, C. K. Morgan, M. A. Siddique, and K. K. Guntupalli, “Intensive care unit complications and outcomes of adult patients with hemophagocytic lymphohistiocytosis: a retrospective study of 16 cases,” World Journal of Critical Care Medicine, vol. 7, no. 6, pp. 73–83, 2018.
View at: Publisher Site | Google Scholar
Y. Miao, H. Y. Zhu, C. Qiao et al., “Pathogenic gene mutations or variants identified by targeted gene sequencing in adults with hemophagocytic lymphohistiocytosis,” Frontiers in Immunology, vol. 10, no. MAR, p. 395, 2019.
View at: Publisher Site | Google Scholar
Q. Zhang, L. Li, L. Zhu et al., “Adult onset haemophagocytic lymphohistiocytosis prognosis is affected by underlying disease: analysis of a single-institution series of 174 patients,” Swiss Medical Weekly, vol. 148, no. 37–38, p. w14641, 2018.
View at: Publisher Site | Google Scholar
M. Zhou, L. Li, Q. Zhang et al., “Clinical features and outcomes in secondary adult hemophagocytic lymphohistiocytosis,” QJM: International Journal of Medicine, vol. 111, no. 1, pp. 23–31, 2018.
View at: Publisher Site | Google Scholar
V. Kumar, B. Sharma, and A. S. Nigam, “Case series of hemophagocytic lymphohistiocytosis from a tertiary care centre: an underdiagnosed entity,” Turk Patoloji Derg, vol. 35, no. 3, pp. 207–212, 2019.
View at: Publisher Site | Google Scholar
S. Jumic and S. Nand, “Hemophagocytic lymphohistiocytosis in adults: associated Diagnoses and outcomes , a Ten-year experience at a single institution,” Journal of Hematology, vol. 8, no. 4, pp. 149–154, 2019.
View at: Publisher Site | Google Scholar
S. Birndt, T. Schenk, B. Heinevetter et al., “Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry,” Journal of Cancer Research and Clinical Oncology, vol. 146, no. 4, pp. 1065–1077, 2020.
View at: Publisher Site | Google Scholar
N. D. Diack, B. S. Kane, S. Fall et al., “Adult hemophagocytic lymphohistiocytosis in Sub-Saharan Area: a retrospective study of 26 cases,” Cureus, vol. 12, no. 3, p. e7258, 2020.
View at: Publisher Site | Google Scholar
Y. Pandey, D. Atwal, M. Konda et al., “Hemophagocytic lymphohistiocytosis in adults,” Baylor University Medical Center Proceedings, vol. 33, no. 3, pp. 326–330, 2020.
View at: Publisher Site | Google Scholar
A. Bichon, J. Bourenne, J. Allardet-servent, L. Papazian, D. Mokart, and M Gainnier, “High Mortality of HLH in ICU,” Regardless Etiology or Treatment, vol. 8, pp. 1–9, 2021.
View at: Google Scholar
J.-S. Ahn, S.-Y. Rew, M.-G. Shin et al., “Clinical significance of clonality and Epstein-Barr virus infection in adult patients with hemophagocytic lymphohistiocytosis,” American Journal of Hematology, vol. 85, no. 9, pp. 719–722, 2010.
View at: Publisher Site | Google Scholar
Y. T. Tseng, W. H. Sheng, B. H. Lin et al., “Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults,” Journal of Microbiology, Immunology, and Infection, vol. 44, no. 3, pp. 191–197, 2011.
View at: Publisher Site | Google Scholar
M. Shabbir, J. Lucas, J. SK. Lazarchick, and K. Shirai, “Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature,” Hematological Oncology, vol. 29, no. 2, pp. 100–106, 2011.
View at: Publisher Site | Google Scholar
H. Park, D. Kim, J. Lee, J. Lee, S. Kim, and Y. Park, “Clinical Features of Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis from Causes Other than Lymphoma,” An Analysis of Treatment Outcome and Prognostic Factors, pp. 897–904, 2012.
View at: Google Scholar
S. A. Parikh, P. Kapoor, L. Letendre, S. Kumar, and A. P. Wolanskyj, “Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis,” Mayo Clinic Proceedings, vol. 89, no. 4, pp. 484–492, 2014.
View at: Publisher Site | Google Scholar
T. Barba, D. Maucort-Boulch, J. Iwaz et al., “Hemophagocytic lymphohistiocytosis in intensive care Unit: a 71-caseStrobe-Compliant retrospective study,” Medicine, vol. 94, no. 51, pp. 23188–e2327, 2015.
View at: Publisher Site | Google Scholar

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Copyright © 2022 Nada Agbariah et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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