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| Hemophagocytic lymphohistiocytosis (HLH) 2004, Diagnostic criteria for familial haematophagocytosis (from ref. 1 )
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Recently, there have been increasingly frequent reports on the occurrence of macrophage activation syndrome (MAS) in patients with inflammatory bowel disease (IBD). Clinically, MAS is characterized mainly by fever, hepatosplenomegaly, cytopenia, and elevated circulating ferritin and CD25. Mortality, even if diagnosed rapidly, is high.
To identify a...
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... is based on the fulfillment of a series of cri- teria established in 2004 1 (Table 1) ...
Similar publications
Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition caused by the hyperactivation of macrophages and T-cells, triggered by infection, malignancy, or underlying rheumatological conditions. It rarely presents as a first manifestation of a rheumatological condition. Macrophage activation syndrome (MAS)...
Lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disease. Differences between B cell and T cell lymphoma-associated HLH remain unclear, specifically clinical characteristics and survival. We retrospectively analyzed 30 lymphoma-associated HLH patients from July 2004 to October 2012. Patients were divided into B cell...
A 51-year-old previously healthy woman presenting with two-weeks of fever, flu-like symptoms, jaundice, and abdominal pain was found to have pancytopenia, transaminitis, and significantly elevated ferritin in the setting of an Epstein-Barr Virus (EBV) infection. Bone marrow biopsy revealed phagocytic macrophages consistent with findings of hemophag...
We performed a single-center, prospective trial to investigate the efficacy of PEG- asparaginase combined with liposomal doxorubicin, etoposide, and methylprednisolone (L-DEP) as an initial therapy for Epstein–Barr virus driven hemophagocytic lymphohistiocytosis (EBV-HLH). None of the patients received any chemotherapy after the diagnosis of EBV-HL...
We describe a case of a previous healthy 20-year-old male athlete who presented with an atypical clinical profile with multiorgan involvement within five weeks after confirmed SARS-CoV-2 infection, suggestive for multisystem inflammatory syndrome (MIS); MIS is a rare, potentially life-threatening complication associated with SARS-CoV-2. MIS shares...
Citations
... To date, information on the frequency and characteristics of the association between HLH/MAS and IBD comes primarily from the systematic reviews of single cases or small case series. These reviews identify young age, male sex, a diagnosis of Crohn disease, and the use of thiopurines or biological drugs as the main risk factors for the development of HLH/MAS in patients with IBD [10][11][12]. This study is the first to evaluate the correlation between pediatric IBD and HLH/MAS starting from a national IBD cohort, thus limiting selection bias. ...
... No difference in sex was observed, in accordance with other analyses focused on children [10,15]; thus, both male and female pediatric patients with IBD should be considered at risk for HLH/MAS. ...
... Moreover, it has been demonstrated that patients developing infection-induced HLH/MAS may have a genetic predisposition to the lack of control of the inflammatory cascade. Many variants and mutations in genes codifying for perforins, the molecules involved in cellular apoptosis, or involved in the cytotoxic activity of Natural Killer cells or cytotoxic T lymphocytes have been described [10,16]. ...
Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0 years (IQR 11.9–16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%) discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%) patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7 years (IQR 0.8–4.4).
Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency.
What is known?
• Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) is a rare complication of inflammatory bowel disease (IBD).
• HLH/MAS has been described in adult patients with IBD while pediatric cases are only anecdotal.
What is new?
• HLH/MAS primarily develops during adolescence in children with early-onset IBD and its prognosis is usually favorable.
• HLH/MAS is generally triggered by an infection in children with IBD who are on immunosuppressant treatment.
... In accordance with the Food and Drug Administration (FDA), VDZ can be used during pregnancy, but studies on human fetotoxicity are few and no long-term data is available [6,7] . Immunosuppressive drugs increase the risk of infections especially when used as combination [8,9] , but some treatments may also expose the patients to the reactivation of latent infections such as tuberculosis (TBC), hepatitis B (HBV) and C (HCV), Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), and Epstein Barr Virus (EBV) [10][11][12] . ...
... 16 Furthermore, several studies have documented an association between CMV reactivation with thiopurine medications. 17,18 However, the data behind this remains to be fully determined with larger studies. Our patient with UC had presented to us with CDI and was found to have an active CMV infection as demonstrated by positive IgM antibodies. ...
Macrophage activation syndrome is a life-threatening syndrome of uncontrolled immune activation with variable clinical presentation making early diagnosis difficult. It is often manifested by the development of multi-organ failure due to systemic inflammatory response. Patients with ulcerative colitis (UC) on purine antimetabolites are at high risk for severe myelosuppression due to the mechanism of thiopurine toxicity which potentially contributes to the development of macrophage activation syndrome. We present a case of a 39-year-old woman with a 2-year history of UC previously treated with 6-mercaptopurine (6-MP) and recent COVID-19 infection, who was admitted to our emergency department for C. difficile infection and subsequently developed macrophage activation syndrome. This case report also raises the question of whether abrupt discontinuation of 6-MP may have contributed to the worsening of the patient's symptoms of underlying hemophagocytic lymphohistiocytosis (HLH) and her rapid deterioration. Both macrophage activation syndrome and COVID-19 infection can produce a large number of pro-inflammatory cytokines termed "cytokine storm," but a pro-inflammatory cytokine panel breakdown helps to differentiate between the two. Our case report emphasizes the importance of close monitoring of patients on purine antimetabolite therapy who present with signs and symptoms of systemic toxicity.
... It has been well-known that autoimmune diseases can lead to the development of hemophagocytic lymphohistiocytosis (HLH), also known as macrophage activation syndrome (MAS). However, most of these AI diseases have been thought to predispose to HLH due to infectious or other underlying etiology rather than the disease itself [22][23]. Several studies have been done in this field regarding the cause of HLH in autoimmune diseases. ...
Among the autoimmune (AI) diseases, systemic lupus erythematosus (SLE) is known to mimic various disease processes and this can lead to under-diagnosis of macrophage activation syndrome (a dire complication). We aimed at performing a systematic review to identify trigger factors that could lead to the development of macrophage activation syndrome (MAS) in patients with SLE as well as identify factors that can affect mortality. We searched the following databases to extract relevant articles: PubMed, ScienceDirect, Cochrane library, Pro-Quest, and Google Scholar. We used search terms including but not limited to hemophagocytic syndromes OR hemophagocytic lymphohistiocytosis OR macrophage activation syndrome OR HLH OR secondary hemophagocytic lymphohistiocytosis AND systemic lupus erythematosus OR SLE. We screened the articles first by titles and abstracts and later by full text. After the application of our eligibility criteria, we identified eight studies to include in our final synthesis. The studies showed that lupus flare itself, as well as, time to onset and high systemic lupus erythematosus disease activity index (SLEDAI) scores, were major risk factors that led to the development of MAS. In addition, infections followed by drugs, underlying malignancy, and pregnancy were other potential trigger factors identified. Studies also detected that MAS development led to high intensive care unit (ICU) admissions and in-hospital mortalities with C-reactive protein (CRP) levels, age, presence of infection, leukopenia, thrombocytopenia, MAS throughout the hospital stay, and high liver function tests (LFTs) as signs of poor prognosis. Additionally, ferritin levels, LFTs, and triglyceride levels formed an important part of diagnostic criteria. However, our review was limited due to the absence of prospective studies and heterogeneity in the studies seen. More studies need to be done to identify various factors leading to hemophagocytic lymphohistiocytosis (HLH) in autoimmune diseases with validated criteria for MAS secondary to autoimmune diseases.
... Although it could be a serious adverse event, the risk of death due to myelotoxicity is relatively low (1%) (18). Other uncommon life-threatening hematological conditions, such as hemophagocytic lymphohistiocytosis (HLH) and other lymphoproliferative disorders have also been associated with TP (19). Pancreatitis and hepatotoxicity are other limiting side effects related to TP (20,21). ...
Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.
... Although CPT plays an important role in alleviating UC in mice, its mechanism is still unclear [22]. Current studies have shown that UC can activate proinflammatory signaling pathways in the body, leading to the increased phosphorylation of MAPKs and NF-κB signaling pathway-related proteins [23,24]. And our research also confirmed this. ...
Camptothecin (CPT) is a cytotoxic quinoline alkaloid isolated from the bark and branches of the Chinese tree Camptotheca acuminata. CPT inhibits topoisomerase I. It possesses various antitumor activities and is mainly used in the treatment of colon, ovarian, liver, and bone cancers as well as leukemia. CPT inhibits the expressions of inflammatory genes and can prevent death from chronic inflammation. Therefore, we investigated the effect of CPT treatment in ulcerative colitis (UC) using DSS-induced UC mouse model; after that, we explored its potential mechanisms. Here, we found that CPT exerted protection on DSS-induced UC in rats. In addition, the administration prominently reduced the disease activity index as well as colon length of the model rats and remarkably reduced the inflammatory cytokines. Further, CPT significantly reduced several vital proinflammatory proteins in LPS-induced RAW264.7 cells. In summary, our findings demonstrate that CPT is hopefully to act as a therapeutic agent for UC.
... Furthermore, there is a paucity of literature on this topic. One systematic review on this topic was performed in 2013, however SONIC to support combination therapy was conducted only three years earlier in 2010 and UC-SUCCESS was published one year later in 2014 [12][13][14]. While identifying 50 case reports at that time, it is not clear whether cases review was verified by a second author or how duplicate cases were adjudicated. ...
Background
Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive syndrome of excessive cytokine requiring prompt recognition and aggressive therapy.AimsWe aimed to systematically characterize HLH in moderate-to-severe inflammatory bowel disease (IBD).Methods
We performed a systematic review of the literature (PubMED; EMBASE) and FDA Adverse Event Reporting System in accordance with the PRISMA statement. Use of biologics was used as a surrogate definition for disease severity (consistent with usual and contemporary clinical management), to enable identification of rare HLH cases with the highest fidelity.Results58 cases of HLH occurring in IBD patients are known (mean age: 26.0 years, 70% male, 83% with Crohn’s disease, mean disease duration 7.0 years). 34.5% of patients were undergoing induction therapy at HLH diagnosis. All cases occurred on patients exposed to anti-TNF agents, but cases with anti-integrin or anti-IL-12/23 exposure were reported. 2/3 of cases did not report prior AZA/6MP exposure. Underlying opportunistic infection or lymphoma was found in > 80% of cases. Survival was 70% if promptly recognized and treated. Five patients restarted biologics after HLH resolved, and one patient developed recurrent HLH.ConclusionsHLH is rare among IBD patients exposed to biologic therapy. Most cases had an identifiable infection or malignancy at the time of diagnosis as well as history of immunomodulator use. Risk factors may include younger age, male gender, presence of Crohn’s disease, and induction phase of treatment. Our study is not intended to assess risk of HLH with specific IBD therapies.
... According to the functional characteristics, macrophages are mainly divided into pro-inflammatory macrophages (M1 polarized phenotype) and anti-inflammatory macrophages (M2 polarized phenotype). Previous studies found that macrophages are closely related to the development of IBD (Rubio & Schmidt, 2018;Leonardi et al., 2018;Fries et al., 2013), and it was confirmed that IBD can be alleviated by inhibiting M1 macrophage polarization and promoting M2 macrophage polarization (Daskalaki et al., 2019). Therefore, investigating the molecules that can affect macrophage polarization may provide new targets for IBD therapy. ...
Herein, we unfolded miR-98-5p mechanism in inflammatory bowel disease (IBD). IBD mouse model was established. The severity of colitis was assessed daily using the disease activity index (DAI). Murine peritoneal macrophages were stimulated by lipopolysaccharide (LPS). MiR-98-5p, tribbles homolog 1 (Trib1), M1 and M2 macrophage marker genes mRNA expression was analyzed. The relationship between miR-98-5p and Trib1 was explored using a luciferase reporter assay. The strategy of loss-of-function was used to explore the mechanism of miR-98-5p in macrophage polarization, inflammation and IBD. The results revealed that IBD mice had higher DAI index and miR-98-5p expression when compared to the Sham group. MiR-98-5p and Trib1 displayed a targeted regulation relationship. Knockdown of miR-98-5p transformed LPS-induced M1 macrophage polarization into M2 macrophage polarization and inhibited inflammation via up-regulating Trib1. However, shTrib1 reversed the effects. In vivo experiment, silencing of miR-98-5p, diminished the DAI and promoted M2 macrophage polarization. In conclusion, knockdown of miR-98-5p changed macrophage polarization to the M2 phenotype by increasing Trib1 expression, thereby alleviating IBD symptoms.
... 4 Triggers of HLH are not only confined to EBV but also include other infections such as cytomegalovirus and actinobacter. 5 Should we test for those agents, before starting IM in patients with IBD knowing that the incidence of HLH in the IBD population remains low? In addition, the proportion of EBV-naïve children with IBD on IM who convert to seropositive status without developing HLH needs to be clarified before supporting routine testing of EBV status in children with IBD before starting IM and avoidance of IM in those who are EBV-naïve. ...
The value of testing for Epstein-Barr virus status before starting immunosuppression in children with inflammatory bowel disease remains unproven.
... In addition, severe and potentially fatal EBV primary infections and post infectious lymphoproliferative disorders have also been associated with thiopurine use (46)(47)(48). This has prompted some to advocate for pre-treatment EBV serology testing and avoidance of thiopurines, if possible, in EBV seronegative individuals (48). ...
Thiopurines are a cheap, effective treatment option in the management of inflammatory bowel disease (IBD). However, with the growing choice of targeted therapies available, as well as the well-documented toxicities of thiopurines, the role of thiopurines has been questioned. Nevertheless, given their inexpense in an era of spiraling healthcare costs, thiopurines remain an attractive option in the right patients. In the age of personalized medicine, being able to predict patients who will respond as well as those that will develop toxicity to a treatment is vital to tailoring therapy. This review will summarize the available literature with respect to predictors of response and toxicity to thiopurines in order to guide management in IBD. Specifically, toxicities addressed will include myelotoxicity, hepatotoxicity, pancreatitis, alopecia, gastrointestinal and flu-like symptoms, and complications associated with Epstein-Barr virus. While more work needs to be done to further our ability to predict both response to and side effects from therapies, pharmacogenomic research shows significant promise in its ability to personalize our use of thiopurines.
