Etiological stratification and prognostic assessment of haemophagocytic lymphohistiocytosis by machine learning on onco-mNGS data and clinical data.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, complicated and life threatening hyperinflammatory syndrome that maybe triggered by various infectious agents, malignancies and rheumatologic disorders. Early diagnosis and identification of the cause is essential to initiate appropriate treatment and improve the quality of life and survival of patients. The recently developed Onco-mNGS technology can be successfully used for simultaneous detection of infections and tumors. Methods: In the present study, 92 patients with clinically confirmed HLH were etiologically subtyped for infection, tumor and autoimmunity based on CNV and microbial data generated by Onco-mNGS technology, and a predictive model was developed and validated for the differential diagnosis of the underlying disease leading to secondary HLH. Furthermore, the treatment outcomes of patients with HLH triggered by EBV infection and non-EBV infection were evaluated, respectively. Results: The current study demonstrated that the novel Onco-mNGS can identify the infection and malignancy- related triggers among patients with secondary HLH. A random forest classification model based on CNV profile, infectious pathogen spectrum and blood microbial community was developed to better identify the different HLH subtypes and determine the underlying triggers. The prognosis for treatment of HLH patients is not only associated with CNV, but also with the presence of pathogens and non- pathogens in peripheral blood. Higher CNV burden along with frequent deletions on chromosome 19, higher pathogen burden and lower non-pathogenic microbes were prognosis factors that significantly related with unfavorable treatment outcomes. Discussion: Our study provided comprehensive knowledge in the triggers and prognostic predictors of patients with secondary HLH, which may help early diagnosis and appropriate targeted therapy, thus improving the survival and prognosis of the patients.

Acute hepatitis A with haemophagocytic lymphohistiocytosis: G-6PD deficiency-induced haemolytic anaemia and bile cast nephropathy.

Hepatitis A virus (HAV) infection typically presents as a self-limiting illness but it can cause debilitating symptoms and rarely fulminant hepatitis (acute liver failure), which is often fatal. WHO estimates that in 2016, 7134 persons died from hepatitis A worldwide (accounting for 0.5% of the mortality due to viral hepatitis). Fulminant hepatic failure is observed in less than 1% of cases of acute viral hepatitis A. Haemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of excessive inflammation and tissue destruction owing to abnormal immune activation. Acquired HLH due to viral infections (also known as virus-associated haemophagocytic syndrome) is most commonly associated with Epstein-Barr virus and cytomegalovirus (CMV). HAV-associated HLH has been rarely reported. Haemolysis of mild to moderate degree is not unheard of in cases of hepatitis A, which is often immune-mediated. Here, we present the case of a man in his 30s, with G6PD deficiency unmasked by acute viral hepatitis A, which later on progressed to hyperacute liver failure, HLH and renal failure.

Haemophagocytic lymphohistiocytosis post-ChAdOx1 nCoV-19 vaccine: A rare case.

The severe acute respiratory syndrome coronavirus 2 pandemic started in December 2019, spread like wildfire and took an immense toll on human life. ChAdOx1 nCoV-19 vaccine was used worldwide for the prevention of Covid-19. Covid-19 has been implicated in the causation of severe haemophagocytic lymphohistiocytosis (HLH) syndrome. However, the same has not been reported with ChAdOx1 nCoV-19 vaccine in the literature. We report a young man who developed secondary HLH post-ChAdOx1 nCoV-19 vaccination.

Haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis in a patient with leprosy.

Multidrug therapy has significantly reduced the global burden of Hansen's disease; however, complications from long-term treatment persist. A male resident of southern Kentucky, in his 30s and of Micronesian descent, presented with worsening abdominal pain associated with anorexia, fatigue, functional decline and occasional haemoptysis. He was compliant with multidrug therapy for leprosy. Laboratory investigations revealed pancytopenia. He was initially treated under a sepsis protocol and later switched to high-dose steroids due to a suspected immune reaction from missed corticosteroid doses. Despite aggressive treatment for refractory pancytopenia, the patient's condition deteriorated, and he passed away from cardiac arrest. Posthumous bone marrow biopsy revealed haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis with bone marrow infiltration. This case highlights the importance of proactive fungal screening in immunocompromised leprosy patients, particularly in endemic regions, as early detection and timely intervention can prevent severe complications.

Autoimmune encephalitis followed by hemophagocytic lymph histiocytosis: a case report.

Objective: This study aims to report three cases of autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis. Methods: Data of relevant patients treated between 2019 and 2022 were retrospectively collected from the Department of Neurology at the Second Affiliated Hospital of Guangzhou Medical University. Results: The age at onset of the three patients was 37, 63, and 36 years, respectively. All three patients were female and presented with cognitive dysfunction and seizures. Behavioral and psychological symptoms were also observed in two cases. All patients were positive for autoantibodies in both the cerebrospinal fluid and serum, while two showed multiple abnormal brain signals on magnetic resonance imaging. All patients exhibited hypocytosis and elevated soluble CD25 and serum ferritin levels. The final diagnoses in two cases were lymphomas, while the remaining case without tumors suffered from a severe infection. All patients received immunotherapy, and the two with lymphoma received anti-tumor treatment. The patient with infection died, and two patients with tumors improved after chemotherapy. Conclusion: Autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis is a rare and severe condition. Prompt attention should be paid to the decline in blood cell counts, particularly in patients who show a slight improvement after immunotherapy or have a risk of lymphoma. Screening for potential tumors and infections and early treatment may help these patients.

[Hemophagocytic syndrome secondary to invasive NK cell leukemia and T-cell lymphoma treated with the modified MINE protocol: report of three cases and literature review].

Lymphoma-associated hemophagocytic syndrome is aggressive with rapid progression, particularly in NK/T cell lymphoma. The MINE regimen is a salvage treatment for aggressive non-Hodgkin lymphoma. In our center, the modified MINE regimen was applied to treat three patients with hemophagocytic syndrome secondary to aggressive NK cell leukemia and T-cell lymphoma. The modified MINE regimen showed good efficacy against NK/T cell lymphoma, control of the inflammatory state of secondary hemophagocytic syndrome, and good tolerability.

Hemophagocytic Lymphohistiocytosis in the Context of Hematological Malignancies and Solid Tumors.

Hemophagocytic lymphohistiocytosis (HLH) has been described for decades in association with malignancies (M-HLH). While its mechanism is unknown, M-HLH has a poor prognosis, ranging from 10% to 30% overall survival. Mature T-cell lymphomas, diffuse large B-cell lymphoma, and Hodgkin lymphoma, with or without viral co-triggers such as Epstein-Barr virus, are among the most frequent underlying entities. Most M-HLH cases occur at the presentation of malignancy, but they may also occur during therapy as a result of immune compromise from chemotherapy (HLH in the context of immune compromise, IC-HLH) and (typically) disordered response to infection or after immune-activating therapies (Rx-HLH, also known as cytokine release syndrome, CRS). IC-HLH typically occurs months after diagnosis in the context of fungal, bacterial, or viral infection, though it may occur without an apparent trigger. Rx-HLH can be associated with checkpoint blockade, chimeric antigen receptor T-cell therapy, or bispecific T-cell engaging therapy. Until recently, M-HLH diagnosis and treatment strategies were extrapolated from familial HLH (F-HLH), though optimized diagnostic and therapeutic treatment strategies are emerging.

Iatrogenic HLH.

Hemophagocytic lymphohistiocytosis (HLH) can be categorized as either primary (familial, generally occurring in infants) or secondary (sHLH, occurring at any age in association with a variety of conditions) and is mainly triggered by infections, autoimmune diseases, and malignant conditions. Our understanding of the pathophysiology of sHLH is still evolving, and among the causes and associations with the syndrome, those putatively associated with iatrogenic causes remain among the most poorly understood due to the rarity of these entities and the multiple confounders so often present in the patients in whom they are reported. Herein, we present a review of the literature to describe the diagnostic and therapeutic challenges of sHLH associated with iatrogenic causes and discuss some of the challenges and future directions in our efforts to better understand these complex conditions for the advancement of patient outcomes.

Cytokine Storm and Sepsis-Induced Multiple Organ Dysfunction Syndrome.

There is extensive overlap of clinical features among familial or primary HLH (pHLH), reactive or secondary hemophagocytic lymphohistiocytosis (sHLH) [including macrophage activation syndrome (MAS) related to rheumatic diseases], and hyperferritinemic sepsis-induced multiple organ dysfunction syndrome (MODS); however, the distinctive pathobiology that causes hyperinflammatory process in each condition requires careful considerations for therapeutic decision-making. pHLH is defined by five or more of eight HLH-2004 criteria [1], where genetic impairment of natural killer (NK) cells or CD8+ cytolytic T cells results in interferon gamma (IFN-γ)-induced hyperinflammation regardless of triggering factors. Cytolytic treatments (e.g., etoposide) or anti-IFN-γ monoclonal antibody (emapalumab) has been effectively used to bridge the affected patients to hematopoietic stem cell transplant. Secondary forms of HLH also have normal NK cell number with decreased cytolytic function of varying degrees depending on the underlying and triggering factors. Although etoposide was uniformly used in sHLH/MAS in the past, the treatment strategy in different types of sHLH/MAS is increasingly streamlined to reflect the triggering/predisposing conditions, severity/progression, and comorbidities. Accordingly, in hyperferritinemic sepsis, the combination of hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC) reflects reticuloendothelial system dysfunction and defines sepsis-associated MAS. It is demonstrated that as the innate immune response to infectious organism prolongs, it results in reduction in T cells and NK cells with subsequent lymphopenia even though normal cytolytic activity continues (Figs. 30.1, 30.2, 30.3, and 30.4). These changes allow free hemoglobin and pathogens to stimulate inflammasome activation in the absence of interferon-γ (IFN-γ) production that often responds to source control, intravenous immunoglobulin (IVIg), plasma exchange, and interleukin 1 receptor antagonist (IL-1Ra), similar to non-EBV, infection-induced HLH.

[Etiology, Clinical Characteristics and Prognosis of Secondary Hemophagocytic Syndrome].

OBJECTIVE: To understand the etiology, clinical characteristics and prognosis of secondary hemophagocytic syndrome (HLH), so as to improve the understanding of HLH and reduce the rates of misdiagnosis and missed diagnosis of HLH. METHODS: A retrospective study was conducted to analyze the cause, clinical characteristics, laboratory findings, therapy and outcomes of 75 adult patients with secondary HLH admitted to our hospital from January 2015 to December 2021. Follow-up continued until the last discharge time. RESULTS: Among 75 patients, infection-related HLH was the most common (45.33%), followed by lymphoma-related HLH (17.33%). Fever was the most common clinical manifestation (97.67%). Laboratory indicators such as NK cell activity (98.31% low or absent), sCD25 (93.22% increased), and serum ferritin (94.44% elevated) had higher sensitivity in diagnosis. By comparing the clinical manifestations and laboratory indicators of HLH patients with different causes, sex, lymph node enlargement and bone marrow morphology were more valuable for the diagnosis of primary disease (all P <0.05). By comparing the treatment and clinical outcomes of HLH patients with different causes, the highest clinical remission rate (83.3%) was achieved in patients with autoimmune disease-related HLH treated with hormone+cyclosporine (P <0.05). The overall 12-month survival rate of all patients was 26.7%, in which the infection-related HLH was the lowest (14.7%) while autoimmune disease-related HLH was the highest (63.6%). CONCLUSION: The causes and clinical characteristics of adult secondary HLH are varied, with poor prognosis and heterogeneity in disease severity. It is important to identify HLH cause early for diagnosis and needed to further understand HLH.

Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy.

The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors for these toxicities has led to targeted treatment approaches which can mitigate them successfully. The three toxicities of particular interest are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS). Each of these is characterized by cytokine storm and hyperinflammation; however, they differ mechanistically with regard to the cytokines and immune cells that drive the pathophysiology. We summarize the current state of the field of CAR-T-associated toxicities, focusing on underlying biology and how this informs toxicity management and prevention. We also highlight several emerging agents showing promise in preclinical models and the clinic. Many of these established and emerging agents do not appear to impact the anti-tumor function of CAR-T, opening the door to additional and wider CAR-T applications.

Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

Intravascular large B-cell lymphoma as a covert trigger for hemophagocytic lymphohistiocytosis complicated with capillary leak syndrome: a case report and literature review.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed.

Transient erythroblastopenia of childhood after COVID-19 infection: a case report.

BACKGROUND: Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2, was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic. CASE PRESENTATION: This manuscript reports a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and complete absence of erythroblasts at the bone marrow needle aspiration with signs of erythrophagocytosis, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection. CONCLUSION: This report highlights a newly described continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS-CoV-2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future.

Lymphoma-associated hemophagocytic syndrome: a retrospective, single-center study of 86 patients.

To explore the clinical features, treatment, and prognosis of patients with lymphoma-associated hemophagocytic syndrome (LAHS) in a real-world clinical setting. We retrospectively examined LAHS patients diagnosed at our center between January 2016 and August 2023, focusing primarily on their clinical features, therapeutic approaches, overall response rate (ORR), and overall survival (OS). A combination of univariate and multivariate analyses was conducted to identify potential prognostic factors. A total of 86 patients diagnosed with LAHS were included to evaluate clinical characteristics and prognostic factors. Patients with T/NK cell lymphoma had a higher probability of developing hemophagocytic syndrome (HPS) during the clinical process than those with B cell lymphoma. The median survival time was 55 days for all patients, and 47 and 81 days for the T/NK cell LAHS and B cell LAHS cohorts, respectively (P = 0.025). Among the patients evaluated, the ORR was 42.2%. Patients starting with anti-lymphoma treatment had a better, albeit not significant, ORR than those beginning with anti-HPS treatment. In the univariate analysis, T/NK cell LAHS (P = 0.027), HPS onset at relapse (P = 0.036), higher baseline plasma EBV-DNA levels (> 4,000 copies/mL, P = 0.034), and treatments including cytokine adsorption and ruxolitinib (P < 0.001 and P = 0.017, respectively) were potentially associated with worse OS, while corticosteroid therapy benefited OS. In the multivariate analysis, T/NK cell LAHS (adjusted hazard ratio (aHR) = 2.007), cytokine adsorption therapy (aHR = 4.547), and corticosteroid therapy (aHR = 0.118) were independently associated with mortality. T/NK cell lymphoma was the main cause of LAHS and carried a worse prognosis. Whether anti-lymphoma or anti-HPS treatment should start first still requires prospective studies with larger sample sizes. The key point in controlling HPS is to block the cytokine storm promptly. Corticosteroid therapy is both effective and accessible and should be used early and in sufficient quantities.

Hemophagocytic lymphohistiocytosis associated with acute otitis media: A case report.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH is characterized by uncontrolled immune activation leading to fever, cytopenias, hepatosplenomegaly, coagulation abnormalities, and elevated typical markers. This condition can be genetic or secondary, with the latter often triggered by infections. Here, we present a unique case of HLH secondary to acute otitis media (AOM), a common ear infection. PATIENT CONCERNS: We describe a 4-year-old boy who initially presented with a high fever and otalgia, later diagnosed with bilateral AOM. Despite antibiotic treatment, his condition deteriorated. DIAGNOSIS: The patient fulfilled diagnostic criteria for HLH. INTERVENTIONS: Aggressive treatment by using combination therapy with immunoglobulins, intravenous steroids (dexamethasone), cyclosporine, and etoposide was performed. OUTCOMES: After 1 month of treatment, improvement in the otologic symptoms was observed, and hematological findings gradually improved and normalized. LESSIONS: The link between AOM and HLH may be associated with inflammatory responses and immunological mechanisms, highlighting the importance of considering HLH in severe infection cases. This case emphasizes the need for prompt diagnosis and management, especially in secondary HLH scenarios, to improve patient outcomes. It is imperative to be aware of the potential correlation between these 2 conditions, and healthcare professionals should consider the likelihood of HLH.

Spontaneously Resolved Suspected Hemophagocytic Lymphohistiocytosis or Macrophage Activating Syndrome Associated with Neonatal Lupus Erythematosus: A Case Report.

OBJECTIVES: To present a rare case of neonatal lupus erythematosus (NLE) associated with suspected hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). CASE PRESENTATION: A female infant weighing 2,995 g was born to a mother without medical history of any disease. At birth, the patient had erythematous papules on her face and trunk. She was admitted at 1 day of age with elevated C-reactive protein levels. The patient was diagnosed with NLE based on the presence of anti-Ro/SSA and anti-La/SSB antibodies. Thereafter, it became clear that the antibody levels in her mother were also elevated. At 20 days of age, the infant showed elevated transaminases, ferritin, triglyceride, and soluble interleukin-2 receptor levels. Although HLH or MAS was suspected, she did not fulfill the diagnostic criteria. Thereafter, these abnormal values spontaneously improved, and the skin rash improved with the use of topical steroids. The patient was discharged at 39 days of age. At 1 year of age, the patient's growth and development were normal. CONCLUSION: NLE should be considered in infants with an unexplained skin rash at birth. When a diagnosis is made, close observation of the infant's clinical features is needed to determine whether they will develop HLH or MAS.

Allogeneic hematopoietic stem cell transplant for familial hemophagocytic lymphohistiocytosis: a case report and literature review.

Objectives: This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene. Methods: A 6-year-old female child presented with unexplained febricity, splenomegaly, pancytopenia, hemophagocytic lymphohistiocytosis in bone marrow, decreased NK cell activity, soluble CD25 levels > 44000ng/ml. Genetic sequencing revealed a mutation in the UNC13D gene. Additionally, the patient experienced intermittent fever with seizures characterized by involuntary twitching of the left upper limb. Head magnetic resonance imaging (MRI) showed white matter lesions. Results: According to the HLH-2004 diagnostic criteria revised by the International Society of Histiocytosis the patient was diagnosed with FHL. Despite receiving HLH-2004 treatment, the disease relapsed. However, after a salvage allogeneic Hematopoietic Stem Cell Transplant (HSCT), febricity, abnormal blood cells, and neurological symptoms significantly improved. Conclusions: Prompt performance of allogeneic HSCT is crucial upon diagnosis of FHL, especially when neurological involvement is present.

HLH and Recurrent EBV Lymphoma as the presenting manifestation of MAGT1 Deficiency: A Systematic Review of the Expanding Disease Spectrum.

Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient's underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review.