Intravenous Immunoglobulin in the treatment of resistant in antibiotics fever Immunocompromised Multiple Sclerosis patient

980604/759439/C/205

SUMMARY
Septic and immunocompromised patients are usually appear with impaired phagocytic function of neutrophils and monocytes. Recent clinical studies suggest that Intravenous Immunoglobulin (IVIG) , among its immunomodulatory effects, exerts an antimicrobial activity, improving the outcome of severely septic patients. On the other hand, prophylactic administration of IVIG reduces the number of infectious episodes in patients submitted bone marrow transplantation . In addition , IVIG administration has shown antipyretic activity in an experimental model of fever in rabbits. This paper is referred in 12 immunocompromised Multiple Sclerosis (MS) patients (8 female and 4 male) who experienced a dramatic decline of fever and a clinical improvement, after IVIG administration. All these patients were been admitted to hospital because they presented a long history of fever refractory to antibiotics. The observations shows that the IVIG is a useful therapeutic tool for these specific occasions and should be administrated immediately.

INTRODUCTION
Multiple Sclerosis (MS) is one of the most common non-traumatic neurological diseases characterized by the occurrence of demyelinating lesion within the Central Nervous System (CNS). The precise etiology of the disease suggests an autoimmune cause possibly triggered by an inflammatory factor which sets on the process for the eventual destruction of the myelin in CNS. Inflammatory disease do not only play a role in the etiology of MS but can also brings on unpleasant consequences in the course of the disease (1,4). Infection and septic are particularly dangerous especially when it is (3,8). In these cases IVIG is administered a particularly effective treatment (4,5). Recent clinical studies suggest that IVIG among its immunomodulatory effects exerts an antimicrobial activity improving the outcome of severely septic patients (3,8). At the same time IVIG reduces the number of infectious episodes and has a potent antipyretic activity (3,6). In this study we have collected and analyzed the results of an IVIG-based treatment in immunocompromises MS patients who experienced during the treatment a dramatic decline in fever in spite of resistance to antibiotics.

METHODS AND MATERIAL
Twelve immunocompromised MS patients were examined (8 female and 4 males) with "clinical definitive "MS according to the criteria of poser et al,(7) aged 18-46 years old, with a duration of disease of 6,92 +- 3,08 years. All patients were at least for a year in immunosuppressive therapy. The patients had been suffering from high fever episodes (up to 40⁰ c) for at least a week prior to entering the treatment with IVIG (0,5 gr/kgr for 5 days with every 2- months booster doses), with pathological laboratory finding such as Leukocytocis neurophilia, increased ESR and elevated CRP. In all patients extended tests attempting to isolate possible pathogens or other causes of fever including blood cultrers cultures of bronchial lavage and other biological fluids (urine, sputum etc.) widal, wright, Asto, Anti-HIV, anti CMV, antinuclear and anti-DNA antibodies proved negative. All these patients were admitted to the hospital because they presented a long history of fever refractory to antibiotics (Cefoxitin, Netilmicin, Azerponam, Omikocin etc) The neurological symptoms of the patients were evaluated at the beginning and at the end of the treatment based on the Kurtzke disability Status Scale (DSS) ranging from zero (normal neurological examination ) to ten ( death due to MS) .

RESULTS AND CONCLUSION
All patients receiving the IVIG treatment with one exception, experienced a decline in fever within a few days. A statistically significant improvement was found in all patients based on the Kurtzke DSS, after the end of the IVIG treatment (p<0,05). The results were sustained in general even 12 months after the beginning of treatment (table 1). Episodes of antibiotic resistant fever have not recurred since. In four of the patients who received a lower dose of IVIG a tendency of subsiding was realized while in the remaining 8 patients the results of the IVIG treatment was a steady improvement. Previous studies have suggested that IVIG has been a particularly effective treatment in a number of autoimmune neurological disorders such as myasthenia Gravis multifocal neuropathy,Guillain-Barre dermatomyositis, amyotrophic lateral Sclerosis, Chronic inflammatory demyelinating polyneuropathy and MS. Regarding the latter we know that IVIG administration, acts on MS patients by improving or stabilizing them in clinical disability, promotes the remyelination, a beneficial effects in the treatment of lower urinary tract dysfunction (1,2,4,5). While it is known that MS plays an important role in the basic treatment of MS due to the autoimmune factor in the pathogenesis of this disease, it is not known how effectively it could be used in complications such as infections or septic, which may have severe consequences especially in immunocompromised MS-patients suffering from antibiotic resistant fever. We know from recent clinical studies that IVIG among its immunomodulatory effects exerts a highly antimicrobial activity, improving the outcome of severely septic patients, reduces the number of infectious episodes and it has shown antipyretic activity (3,6,8). The observation of the results of the IVIG use in our patients corroborated all the above mentioned beneficial effects of it. It is also noteworthy that the sooner and the longer IVIG is administered, the longer the MS patients remain exacerbation free while they have shown a clear stabilized effects in clinical symptoms. It is giving quite important to note the fact that the clinical symptoms improvement remained steady of a long time period after the discontinuations of the treatment. Reflecting on our observation in light of the relevant literature we are led to the conclusion that IVIG must enjoy a pre-emminet position among the basic MS- treatment, as well as in cases of infections or complication.



TABLE 1 Clinical parameters and results of MS patients at the start, end and after 2 years of the IVIG treatment.

REFERENCES
1.ACHIRON A,GILAD R,MARGALIT R,GABBAV V, SAPOVA-DINHAS, COHEN IR et al, intravenous gammaglobulin treatment in Multiple Sclerosis and experimental autoimmune encephalomyelitis: delineation of usage and mode of action, J.Neurosurg Psychiatry 57:57-61, 1994. 2.FAZEKAS F, DEISENHAMMER F, SRASSER-FUCHS S, NAHLER G,MAMOLIB, Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing remitting Multiple sclerosis, Lancet 349:589-93,1997.
3.IWATA M,SHIMOZOTO T, TOKIWA H, TSUBUTA E, Antipyretic activity of a human immunoglobulin preparation for intravenous use in an experimental model of fever in rabbits, Infect immune 55:547-552:1987 4.KOUNTOURIS D, Intravenous immunoglobulin in the treatment of multiple sclerosis, Archives of Hellenic Medicine, volume 12, No 4, 264,1994 5.KOUNTOURIS D, KOLLIAS G, Treatment of lower urinary tract dysfunction in patients with multiple sclerosis by the use of intravenous immunoglobulin, Archives of Hellenic Medicine, volume 13,. No 4,313, 1996. 6.KOUNTOURIS D, ZIRAS N. Intravenous immunoglobulin in the treatment of antibiotic-resistant-feber of cancer patients. In cancer detection and prevention 20:485,1996. 7.POSER CM, PATUCN, SCHEINBERG L, MC DONALD W, DAVIS FA, EBERS GC, JONSON KP, SIBLEN WA, SILBERBEG DH,TOURTELLOTE WW, new diagnostic criteria of multiple sclerosis guidelines for research protocols, Ann Neurol 13:227-231,1983. 8.SULLIVAN KM, KOPECK KS, JACOMS,FISHER L,BUCKNER CD et al, Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation, N. England, J Medicine 323 (11):705.712.1990.
Reprinted from: 9^th European Congress of Clinical Neuropfysiology, Ljubljana, Slovenia, June 4-7,1998. Editors Eric V. Stalberg, Al W.De Weerd, Janez Zidar.Monduzzi Editore, International proceedings Division.