Growth in Children at Risk for Celiac Disease & Emapalumab for Hemophagocytic Lymphohistiocytosis

Briefly noted:  R Auricchio et al. Archives of Disease in Childhood 2020; Growth rate of coeliac children is compromised before the onset of the disease Thanks to Mike Hart for the reference.

Methods:   We analysed the growth patterns of infants at genetic risk of CD, comparing those who developed CD by 6 years of age (CD ‘cases’, 113 infants) versus those who did not develop CD by 6 years (no CD ‘controls’, 831 infants).

Key finding: The growth of children at risk of CD rarely fell below ‘clinical standards’. However, growth rate was significantly lower in cases than in controls. Our data suggest that peculiar pathways of growth are present in children who develop CD, long before any clinical or serological signs of the disease appear.

F Locatell et al. NEJM 2020; 382: 1811-22. This open-label study (n=34) investigated emapalumab, a human anti-interferon-gamma antibody, for the treatment of primary hemophagocytic lymphohistiocytosis (HLH). Of the 26 patients who completed the study, approximately 65% had a response (based on clinical and lab features) and were able to proceed to transplantation.

Related blog posts:

The MH Score: Separating primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome

“Sincerity is the key to success. Once you can fake that, you’ve got it made.”

–Groucho Marx

The above quote is not particularly related to this blog post –but I like it.

A recent study (F Minoia et al. J Pediatr 2017; 189: 72-8) provides data supporting a scoring system which helps distinguish primary hemophagocytic lymphohistiocytosis (HLH) from macrophage activation syndrome (MAS).

Background: “By convention, secondary HLH seen in rheumatic disorders is termed macrophage activation syndrome…occurs most commonly in systemic juvenile idiopathic arthritis (sJIA).”  Both HLH and MAS are life-threatening, though HLH tends to be more severe.  The treatment for the two disorders is much different.

HLH typically develops in the first year of life, though some remain asymptomatic until later.  Identification of pathologic mutations (primary HLH is not a single disease) is considered the gold standard, but this “takes weeks to complete and is not available in many resource-limited areas.”

In this study, the authors reviewed clinical features from 362 patients with MAS and 258 patients with HLH to develop a scoring system that more readily distinguished these conditions.The data from 80% of the patients was used to construct the scoring system and then this was validated with the remaining 20%.  MH Score:

  • Age of onset, years:                              0 points if >1.6 yr, 37 points if ≤1.6 yr
  • Neutrophil count, x 10 to the 9th/L:      0 points if >1.4, 37 points if ≤1.4
  • Fibrinogen, mg/dL:                               0 points if >131, 15 points if ≤131
  • Splenomegaly:                                      0 points if no, 12 points if yes
  • Platelet count, x 10 to the 9th/L:           0 points if >78, 11 points if ≤78
  • Hemoglobin, g/dL:                                0 points if >8.3, 11 points if ≤8.3

The age of onset and severe neutropenia are weighted the most heavily as they most heavily influence the odds ratio of having HLH; with multivariate analysis (Table 3), age of onset ≤1.6 yrs had an OR of 40.3, and neutrophil count ≤1.4 had an OR of 39.3.  All of the other parameters had OR between 2.9 and 4.4.  Hepatomegaly favored HLH as well but was not independently associated with the diagnosis.

How to use this scoring system:

  • In this cohort, the MH score ranged from 0 to 123.  The median value was 97 for HLH and 12 for MAS.
  • A cutoff of ≥60 yielded a sensitivity of 91% and specificity of 93% for the diagnosis of HLH.  Higher values increased the probability of HLH further.

Most laboratory studies were more abnormal with HLH; however, both ferritin elevation and LDH elevation were more pronounced with MAS.  Median ferritin was 5353 with MAS and 2910 with HLH.  Median LDH was 1230 with MAS compared with 696 with HLH.

This study validated the MH score for distinguishing HLH from MAS associated with sJIA; this can allow early introduction of aggressive treatment and appropriate genetic/immunologic evaluation.  The applicability of the MH score for distinguishing HLH from other conditions is unclear.  Further prospective evaluation of the MH score is needed.

My take: This is a very helpful study and is likely to influence diagnostic workup and management of these sick patients. Due to the liver and spleen abnormalities, pediatric gastroenterologists need to be able to recognize both HLH and MAS.

Related blog post:

What’s with $1040 -is a fine of $40 more going to make a difference?

Good Safety Data on Infliximab vis a vis Malignancy and Hemophagocytic Lymphohistiocytosis

Using data from 5766 pediatric participants with inflammatory bowel disease in a prospective DEVELOP study (JS Hyams, MC Dubinsky et al. Gastroenterol 2017; 152: 1901-14) provide more reassurance regarding the safety of infliximab.  This study took place between 2007 to 2016 and accounted for 24,543 patient-years of followup.  While the study examined rates of malignancy, the SEER database does not include non-melanoma skin cancer; thus, the authors did not have a suitable comparator for this outcome; there were two cases of basal cell carcinoma in the study population.  This article’s abstract was published on this blog previously: Infliximab Not Associated with Malignancy

Key findings:

  • There was NO increased risk of malignancy or hemophagocytic lymphohistiocytosis (HLH) in patients exposed to infliximab as monotherapy.
  • Malignancy risk was 0.46 per 1000 patient-years in patients with infliximab exposure compared with 1.12/1000 patient-years in patients who had no exposure to biologics.
  • HLH risk was 0 in those with infliximab monotherapy compared with 0.56 per 1000 patient-years in those who had no exposure to biologics.
  • Patients exposed to thiopurines with or without biologics did have increased risks of malignancy compared with comparative populations. 13 of 15 patients who developed a malignancy and all 5 patients who developed HLH had thiopurine exposure.
  • Thiopurine exposed patients had 0.75 malignancy events per 1000 patient-years compared to 0.27 malignancy events per 1000 patient-years for patients who had no thiopurine exposure
  • Thiopurine exposed patients had 0.29 HLH events per 1000 patient-years compared to 0 HLH events per 1000 patient-years for patients who had no thiopurine exposure
  • In their discussion, the authors note that after discontinuation of thiopurine therapy for 1 or more years, the standardized incidence ratio (SIR) for malignancy approached the non-exposed group (1.48 compared to 1.30); whereas ongoing or recent thiopurine exposure had SIR of 4.45.

Limitations: Study duration (<10 years). Hard to detect changes in rare malignancies

My take: In this largest prospective pediatric cohort to date, there is NO increased risk of malignancy (excluding non-melanoma skin cancer) or HLH with infliximab therapy; however, there is a trend towards increased risk among those with thiopurine exposure. Nevertheless, as malignancy is a rare event, very low increased risk of malignancy with infliximab cannot be entirely excluded.

Related blog posts:

For HLH:


Acute Liver Failure –Is There a Role for Steroids?

The title is not a simple question.

Some who support the use of steroids (for acute liver failure) should remember Galen’s assertion about a different treatment, circa 100 AD:   “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.”

Two recent publications offer conflicting advice about steroids for acute liver failure (ALF):

  • Hepatology 2014; 59: 612-21.
  • J Pediatr 2014; 164: 407-409.

The first study involved a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF from patients (n=361) prospectively enrolled in the ALF Study Group between 1998-2007.

  • Autoimmune, n=66, mean age 46 years
  • Indeterminate, n=164, mean age 39 years
  • Drug-induced, n=131, mean age 44 years

Outcomes:  Steroid use was associated with increased spontaneous survival (35% vs 23%) but this benefit did not persist with multivariate analysis.  In addition, steroid use was associated with lower survival in patients with the highest MELD scores. Furthermore, the authors discount the possibility of selection bias, noting that INR was higher in the no-steroid group.

In contrast, the second article, a case presentation/pediatric grand rounds article, states that “in our experience over the past decade, more than one-half of the children (56%) presenting with indeterminate acute hepatitis or ALF (after being evaluated) comprehensively …had a markedly elevated sIL-2R level (>5000 U/mL) concerning for immune activation but never fulfilling diagnostic criteria for HLH [hemophagocytic lymphohistiocytosis] during their course.”

Notably, of the patients presenting with elevation of sIL-2R to >5000 U/mL, most who survived with their native liver had received treatment with steroids.” (JPGN 2013; 56: 311-5.) “We propose that children presenting with indeterminate, progressive hepatitis or indeterminate ALF are candidates for prompt initiation of anti-inflammatory therapy when there is concomitant evidence of immune activation.”

In patients with ALF, part of the evaluation needs to include sIL-2R. Other assessments for immune dysregulation would include serum triglycerides, ferritin, “CD107a expression, perforin/granzyme B protein expression, and assessment for macrophage activation (soluble CD163).”

Bottomline: If HLH criteria are not met, but patients have marked elevation of sIL-2R (>5000 U/mL), empiric corticosteroids need to be considered. Perhaps there is a window of opportunity (before a patient develops a high MELD score).  At the same time, we need to acknowledge that our knowledge base remains incomplete and it is unclear whether this will improve the outcome.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Hemophagocytic Lymphohistioctosis: Advances

A recent medical progress report provides a concise update on hemophagocytic lymphohistiocytosis (HLH) (J Pediatr 2013; 163: 1253-59).

  • Table 1 summarizes the subtypes of HLH.
  • Atypical presentations include colitis and hypogammaglobulinemia.
  • Table 2 provides the diagnostic criteria.
  • The treatment approach is outlined as well.  In the short-term, with primary HLH, the goal is controlling the hyperinflammatory state (often with dexamethasone and etoposide).  The long-term goal aims to definitively correct the underlying genetic defect by allogeneic hematopoietic stem cell transplantation (HCT)

Other points:

  • A genetic diagnosis of familial HLH can be made in 40-80% of HLH cases with the identification of PRF1, UNC13D, STX11, and STXBP2 genes.
  • UNC13D are the predominant defects identified in Caucasians in U.S.
  • PRF1 is most common in African-American patients.
  • Ferritin remains an excellent screening tool.  A level >500 mcg/L is suggestive (but not specific) for HLH; a level >10,000 has much greater specificity (96%) along with fairly high sensitivity (90%).
  • HLH is commonly referred to as macrophage activation syndrome (MAS) in the setting of a rheumatologic illness.
  • There is no broad consensus on management of secondary HLH.  In MAS, therapy often includes pulsed steroids and/or cyclosporine.

Related blog post:

Don’t forget HLH

A recent clinical challenge (Gastroenterol 2013; 145: 289, 489) regarding a a 78-year-old with a 12-year history of ulcerative colitis serves as a good reminder to remember hemophagocytic lymphohistiocytosis (HLH) in inflammatory bowel disease patients with high fever, even in the presence of recognized viral infections like cytomegalovirus and Epstein-Barr virus which can trigger HLH.  Patients receiving immunosuppressive medications are at risk.

Other clinical points:

  • Consider HLH when cytopenias are present in addition to fever
  • Ferritin values >10,000 mcg/L serves as a good screen

Take-home point: HLH has a significant mortality rate.  Quick recognition can improve outcome.

Related blog post:

Diagnosing hemophagocytic lymphohistiocytosis  – gutsandgrowth

Diagnosing hemophagocytic lymphohistiocytosis (HLH)

HLH is difficult to diagnose –patients without HLH can meet the established criteria (see links below); and, especially early in the disease, patients with HLH may not meet the established criteria.  A study which will help with this difficulty has been published (J Pediatr 2012; 160: 984-90 and summary pg A1).  For pediatric gastroenterologists, HLH is important because some of our IBD patients may develop HLH and because some patients presenting with liver disease have HLH.

This study examined 756 consecutive patients with fever in Hematology/Oncology unit of China’s Children’s Hospital of Zhejiang between 2005-2010.  Three control groups also were studied: hematology-oncology patients without fever (n=202), healthy children (n=100), and previously-healthy children with bacterial sepsis (n=85).

A highly discriminating cytokine pattern was identified in 71 episodes of HLH.

  • Highly elevated IFN-γ : 94% sensitivity, 97% specificity for HLH using a cutoff of 100 pg/mL
  • Highly elevated IL-10
  • Modestly elevated IL -6
  • Combined use of IFN-γ (>75 pg/mL) & IL-10 (>60 pg/mL) had sensitivity of 93% and specificity of 99% for HLH

Using these cytokines may help establish a more rapid diagnosis of HLH and allow institution of critical therapy while avoiding implementation of the wrong treatment in patients who have other conditions.  In other studies (see below), there are other useful markers that have been identified.

Additional references:

  • -J Pediatr 2011; 159: 808.  HLH increased with Crohn’s Rx.  If fever >5days, can screen for HLH with ferritin (>500mcg/L) & lymphopenia.  Need to discontinue immunosuppression.  100-fold increase risk of HLH.  Diagnostic criteria for HLH pg 809. Newer criteria: molecular, low/absent NK activity & soluble CD-25 (ie. soluble IL-2 receptor) >2400 U/mL.
  • Hemophagocytic Syndrome  Link with powerpoint case presentation including diagnostic criteria for primary and secondary HLH.
  • Hemophagocytic lymphohistiocytosis (HLH) and related disorders  Link with review article by leader in field (A Filipovich, 2009).
  • -J Peds 2006; 149: 134-7.  Aftrican-american infants c HLH often have a specific defect in perforin gene -50delT-PRF1
  • -NEJM 2004; 351: 1120. case of twins c FELS. Impaired NK cell activity is key with absence of NK intracytoplasmic perforin in 20-40%.
  • -JPGN 2002; 34: 3A (pg 433.)  Liver failure with HLH.  mortality 84%, n=25.