The underlying mechanisms of reactive macrophage activation syndromes (rMAS) are not understood in detail, and there is no specific treatment. This observational study was prompted by intravenous immunoglobulin (IVIG), dramatically halting two distinct rMAS episodes in the same patient. We evaluated the potential benefits of IVIG administration in treating fulminant rMAS and the usefulness of monitoring serum ferritin levels as an indication for emergency treatment with IVIG. Ten females and 10 males experiencing 22 episodes of rMAS were recruited on the basis of serum ferritin levels ≥10,000 µg/l and/or direct evidence of haemophagocytosis in 11 intensive care units in secondary and tertiary care hospitals in Switzerland between October 1993 and May 2000. In individual patients, serially measured ferritin was closely related to disease activity. Abrupt increases of up to >100,000 µg/l could be observed within hours. Rapid and profound beneficial effects of emergency IVIG treatment were seen in 12 episodes of rMAS accompanied by a prompt decrease of serum ferritin. IVIG produced partial or delayed improvements in 5 patients. No apparent effects were seen in 5 patients. IVIG was only successful if started early during the ferritin run-up to peak values. In conclusion, IVIG is effective in at least a subgroup of adult rMAS when started at the beginning of the macrophage activation process. The monitoring of serum ferritin levels might be helpful in detecting macrophage activation in order to commence IVIG treatment early enough. Am. J. Hematol. 68:4-10, 2001.
The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) is a challenge. Thymus-and activation-regulated chemokine (TARC) has recently been reported to play a role in ABPA. The aim of this study was to compare the diagnostic value of TARC with that of known serological markers for diagnosis of ABPA in CF patients.The present study longitudinally followed 48 CF patients, of whom 12 had a diagnosis of ABPA according to Nelson's criteria, for 1-8 yrs with repeated measurements of serum total immunoglobulin (Ig)E, specific Aspergillus fumigatus IgE and IgG, specific IgE against recombinant A. fumigatus allergens (rAsp f) 1, 3, 4 and 6, and TARC.Median (interquartile range) TARC levels were 589 (465-673) pg?mL -1 in ABPA patients and 232(189-289) pg?mL -1 in non-ABPA patients. Receiver operating characteristic curves revealed that TARC was superior to the other markers for diagnosis of ABPA. Diagnostic accuracy was greater for TARC (93%) than for total IgE (74%), or rAsp f 4 (75%) or f 6 (79%). The present study indicates that thymus-and activation-regulated chemokine may be useful in the diagnosis of allergic bronchopulmonary aspergillosis in cystic fibrosis patients. However, larger studies are needed before thymus-and activation-regulated chemokine can routinely be used in diagnostic algorithms.
Derailed T-cell activation can give rise to life-threatening macrophage activation, the final common pathway of the different forms of reactive macrophage activation syndromes (rMAS). Besides inappropriate activation of the immune system, impaired termination of immune responses might be another mechanism leading to rMAS. The Fas (CD95)/Fas ligand (CD95 ligand) system functions in turning off immune responses by executing activation-induced cell death (AICD). Soluble Fas (sFas) and Fas ligand (sFasL) can interfere with their corresponding membrane-bound counterparts, qualifying them as potential parameters of impaired immune termination. Hence, sFas and sFasL were analyzed in sera of rMAS patients. We show that soluble Fas/CD95 (sFas) is elevated >2 SD over the mean of controls in all 8 rMAS episodes studied (mean 12.08 ± 6.12 ng/mL, range 3.7-20.2; controls 2.46 ± 0.49, range 1.5-2.9). sFasL was detected during five rMAS episodes (0.70 ± 0.49 ng/mL, range 0.16-1.28; controls all below the limit of detection of 0.1). In addition, both parameters decrease during convalescence, reflecting clinical evolution. In conclusion, sFas seems to be consistently elevated during acute rMAS. sFasL is detected only in a subgroup of our adult rMAS patients extending the recent finding of sFasL elevation in a majority of children with macrophage activation syndromes (Hasegawa et al. Blood 1998;91(8):2793-2799). By interfering with AICD, sFas and sFasL might contribute to the pathogenesis of at least a subset of rMAS. Am.
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