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832 Gastroesophageal reflux and severe combined immunodeficiency
390
Abstracts
J ALLERGY CLIN IMMUNOL JANUARY 1996
829
Elevated TNF-a A s s o c i a t e d w i t h N e u t r o p e n i a in C o m b i n e d I m m u n o d e f i c i e n c y (CID). 0 Hare' e MD/Ph S Winter MD. GA Hanissian MD. JE Gem MD. RE Ware MD/PhD, Durham, NC and Madison, WI Soon after birth, patient PA was noted to have erythroclermatitis and alopeeia. By age 2 months, lymphadenopathy, heptosplenomegaly, persistent neutropenia (0-100 cells/M), and lymphopenia were present. Multiple hospitalizations due to infections ensued. Treatment with GCSF gave no definitive improvement in PMN counts (0-200 ceils/M). A diagnosis of CID was made because of poor lymphocyte (lym) enumeration and proliferation studies, and absence of Ig production. Malignancy could not be detected and 4 separate chromosomal analyses were normal (nl). Bone marrow (BM) exhibited an apparent myeloid arrest. It was hypothesized that a serum inhibitory factor was suppressing PMN, and possibly lyre, development. Serum from PA enhanced patient and control lyre proliferation above that of ul serum. PA's serum inhibited both patient and control BM cell growth in soft agar prognnitc¢ assays, whereas patient colony formation was nearnormal in the presence of nl serum. Serum TNF-ot was 59 pg/nd (nl < 20 pg/ml) by ELISA assay. RT-PCR of RNA from BM mononuclear cells disclosed an elevated level of TNF-oc mRNA. Normalizing TNF-oc with concurrently amplified [3-actin by calculating ratios of densitometric readings gave 0.45i'0.07 and 0.13:t'0.03 (p < 0.01) for PA and control samples, respectively. Comparisons with 20 other cytokines and growth factors revealed no differences between PA and controls. Previous studies have implicated that TNF-(x is a potent inhibitor of myeloid development. We believe that this is the first report demonstrating that elevated TNF-ce in the bone marrow is associated with severe neutropenia in a patient. The process leading to dysregulation of TNFqx production could be responsible for both CID and nentropenia in PA, and perhaps plays a role in other conditions where neutropenia is a prominem feature.
831
O r a l R i b a v i r i n f o r G a s t r o i n t e s t i n a l A d e n o v i r u s in S e v e r e C o m b i n e d I m m u n o d e f i c i e n c y . SE Miller Phl) ML Tang MD/PhD, A M Garcia-Turner BS, JL Girth BS, TO Harville MD/PhD, Durham, NC JH presented at 5 months of age with respiratory distress, due to parainfluenza virus type RI (PFIII), as well as FTT. Clinical and laboratory evaluations led to a diagnosis of SCID. Many symptoms improved with lung-term nebulized Rihavirin and supportive care, but GI tract adenovirus (AV) created persistent management problems. For definitive therapy, JH received a maternal, T-ceil-depleted bone marrow stem cell transplant. T lymphocyte function reconstituted over the subsequent 3-4 months, resulting in elimination of the PFIII. GVHD affecting the bone marrow developed, resulting in life-threatening pancytopenia. Worsening GI symptoms with increase in stool AV were noted with the anti-GVHD therapy. We hypothesized that exacerbation of the AV infection was in part due to the immunosupressive treatment and, additionally, that the immune response generated against AV was resulting in simultaneous activation of maternal T lymphocytes capable of causing GVHD. Systemic AV infections can be devastating in immunocompromised patients, and the possibility of systemic spread in JH prompted us to treat with oral Ribavirin. To reduce risks of side effects, 20 mg/kg/day was initiated, with equivocal results. One week later, dosing of 200 mg/kg/day resulted in immediate clinical improvement (reduction in vomiting, loose stools, and abdominal cramping, and improved feeding). Stool AV was quantified by enumerating viral particles via electron microscopy. Post-treatment viral load was decreased to 20% of that of immediate pre-treatment levels. To our knowledge, this is the first report of oral Ribavirin therapy for GI tract AV infection. While long-term effects of R/bavirin remain unknown, it was demonstrated that such therapy can be life-saving in patients with immunodeficiencies and should be considered as a therapeutic option.
830
A 3-year-old Boy with ZAP-70
Deficiency, Thrombocytopenia and Ulcerative Colitis.
832
Gastroesophageal Reflux and Severe Combined I m m u n o d e f i c i e n c y A Boeck MD, RI Schiff MD/Phl). R H Buckler MD. Durham, NC Gastrointestinal symptoms are frequent in patients with severe primary immunodeficiencies, mainly from infections leading to intractable diarrhea, malabsorptiun, and failure to thrive. We also have noted frequent vomiting not associated with infections or medications. In a retrospective study, we reviewed the case histories of 71 patients who had been treated for severe combined immunodeficiency (SCID) between 1982 and 1995. We found clinically significant gastroesophageal reflux (GER) in 12 of the 71 patients (16.9°/o), much higher than has been reported in the normal population (0.3 to 0.1%). In many cases vomiting was not a significant problem and GER was not suspected until complications such as failure to thrive or aspiration pncumunia, developed. Diagnosis was made clinically and confirmed by barium swallow, pH probe study, and in some patients, endoscopy. The true incidence may be higher. Of patients treated between 1990 and the present, 9 of 36 (25%) had significantly increased GER compared with 3 of 37 patients (8.1%) in the previous years. Thus, with greater recognition and improved methodology for diagnosis, the observed incidence of GER has increased greatly. Seven of the twelve patients with GER (58 %) failed medical management with antacids, H2-blockers, and prokinctic agents, and undenvent surgical treatment (Nissen fundoplication). Indications for surgery included persistent esophagitis, pneumonia and growth failure. The reason for the high incidence of GER in patients with severe T cell disorders remains unclear. Early recognition and management is important in order to enable adequate nutrition and prevent damage to lungs and esophagus.
DE Parry MD. J Blumenthal MD. RH Tomar MD. SD Horowitz MD. ME Elder MD Phi:). JE Gem MD. Madison, WI and San Francisco, CA. Defective or absent ZAP-70, a T cell receptor associated protein tyrosine kinase, has recently been described as one of a number of genetic causes of severe combined immunodeficiency (SCID). In this report, we describe a male patient with ZAP-70 deficiency with unique clinical features. Our patient was well until 6 months of age when, based on a history of bloody dian-hea and weight loss, and colonic biopsy results, a presumptive diagnosis of ulcerative colitis (UC) was made. Following treatment with sulfasalazine and prednisone, the bowel disease went into remission. He subsequently developed oral candidiasis, chronic eczematous dermatitis, and persistent otitis media and sinusitis with intermittent fevers. At age 16 months, thrombocytopenia (<7000/ul) was noted which resolved with IVIG treatment. Immunological studies demonstrated: IgG 9.25 (pre-IVIG), IgA 3.78, IgM 3.64(g/1); poor antibody responses to tetanus, diphtheria and E. eoli; total lymphocytes 3700/ul, CD4 1400hJl, and CD8 37/ul. Lymphocyte proliferation studies showed PHA stimulation < 5% of control, absent antigen and mitogen responses, but normal proliferation with either calcium ionophore + PMA, or mixed lymphocyte culture (MLC). ZAP-70 protein was undetectable in PBMCs by Western blot. While this patient has several features in common with other reported ZAP-70 deficient patients (normal CD4 numbers, virtually absent peripheral CD8, recurrent infections, chronic dermatitis, diarrhea), this case represents the first association of ZAP-70 deficiency with two potentially autoimmune diseases 0AC and thrombocytopenia). In addition, the repeatedly normal values for MLC suggest that allogeneic T cell activation is mediated by intrscellular mechanisms that are independent of ZAP-70.
Abstracts
J ALLERGY CLIN IMMUNOL JANUARY 1996
829
Elevated TNF-a A s s o c i a t e d w i t h N e u t r o p e n i a in C o m b i n e d I m m u n o d e f i c i e n c y (CID). 0 Hare' e MD/Ph S Winter MD. GA Hanissian MD. JE Gem MD. RE Ware MD/PhD, Durham, NC and Madison, WI Soon after birth, patient PA was noted to have erythroclermatitis and alopeeia. By age 2 months, lymphadenopathy, heptosplenomegaly, persistent neutropenia (0-100 cells/M), and lymphopenia were present. Multiple hospitalizations due to infections ensued. Treatment with GCSF gave no definitive improvement in PMN counts (0-200 ceils/M). A diagnosis of CID was made because of poor lymphocyte (lym) enumeration and proliferation studies, and absence of Ig production. Malignancy could not be detected and 4 separate chromosomal analyses were normal (nl). Bone marrow (BM) exhibited an apparent myeloid arrest. It was hypothesized that a serum inhibitory factor was suppressing PMN, and possibly lyre, development. Serum from PA enhanced patient and control lyre proliferation above that of ul serum. PA's serum inhibited both patient and control BM cell growth in soft agar prognnitc¢ assays, whereas patient colony formation was nearnormal in the presence of nl serum. Serum TNF-ot was 59 pg/nd (nl < 20 pg/ml) by ELISA assay. RT-PCR of RNA from BM mononuclear cells disclosed an elevated level of TNF-oc mRNA. Normalizing TNF-oc with concurrently amplified [3-actin by calculating ratios of densitometric readings gave 0.45i'0.07 and 0.13:t'0.03 (p < 0.01) for PA and control samples, respectively. Comparisons with 20 other cytokines and growth factors revealed no differences between PA and controls. Previous studies have implicated that TNF-(x is a potent inhibitor of myeloid development. We believe that this is the first report demonstrating that elevated TNF-ce in the bone marrow is associated with severe neutropenia in a patient. The process leading to dysregulation of TNFqx production could be responsible for both CID and nentropenia in PA, and perhaps plays a role in other conditions where neutropenia is a prominem feature.
831
O r a l R i b a v i r i n f o r G a s t r o i n t e s t i n a l A d e n o v i r u s in S e v e r e C o m b i n e d I m m u n o d e f i c i e n c y . SE Miller Phl) ML Tang MD/PhD, A M Garcia-Turner BS, JL Girth BS, TO Harville MD/PhD, Durham, NC JH presented at 5 months of age with respiratory distress, due to parainfluenza virus type RI (PFIII), as well as FTT. Clinical and laboratory evaluations led to a diagnosis of SCID. Many symptoms improved with lung-term nebulized Rihavirin and supportive care, but GI tract adenovirus (AV) created persistent management problems. For definitive therapy, JH received a maternal, T-ceil-depleted bone marrow stem cell transplant. T lymphocyte function reconstituted over the subsequent 3-4 months, resulting in elimination of the PFIII. GVHD affecting the bone marrow developed, resulting in life-threatening pancytopenia. Worsening GI symptoms with increase in stool AV were noted with the anti-GVHD therapy. We hypothesized that exacerbation of the AV infection was in part due to the immunosupressive treatment and, additionally, that the immune response generated against AV was resulting in simultaneous activation of maternal T lymphocytes capable of causing GVHD. Systemic AV infections can be devastating in immunocompromised patients, and the possibility of systemic spread in JH prompted us to treat with oral Ribavirin. To reduce risks of side effects, 20 mg/kg/day was initiated, with equivocal results. One week later, dosing of 200 mg/kg/day resulted in immediate clinical improvement (reduction in vomiting, loose stools, and abdominal cramping, and improved feeding). Stool AV was quantified by enumerating viral particles via electron microscopy. Post-treatment viral load was decreased to 20% of that of immediate pre-treatment levels. To our knowledge, this is the first report of oral Ribavirin therapy for GI tract AV infection. While long-term effects of R/bavirin remain unknown, it was demonstrated that such therapy can be life-saving in patients with immunodeficiencies and should be considered as a therapeutic option.
830
A 3-year-old Boy with ZAP-70
Deficiency, Thrombocytopenia and Ulcerative Colitis.
832
Gastroesophageal Reflux and Severe Combined I m m u n o d e f i c i e n c y A Boeck MD, RI Schiff MD/Phl). R H Buckler MD. Durham, NC Gastrointestinal symptoms are frequent in patients with severe primary immunodeficiencies, mainly from infections leading to intractable diarrhea, malabsorptiun, and failure to thrive. We also have noted frequent vomiting not associated with infections or medications. In a retrospective study, we reviewed the case histories of 71 patients who had been treated for severe combined immunodeficiency (SCID) between 1982 and 1995. We found clinically significant gastroesophageal reflux (GER) in 12 of the 71 patients (16.9°/o), much higher than has been reported in the normal population (0.3 to 0.1%). In many cases vomiting was not a significant problem and GER was not suspected until complications such as failure to thrive or aspiration pncumunia, developed. Diagnosis was made clinically and confirmed by barium swallow, pH probe study, and in some patients, endoscopy. The true incidence may be higher. Of patients treated between 1990 and the present, 9 of 36 (25%) had significantly increased GER compared with 3 of 37 patients (8.1%) in the previous years. Thus, with greater recognition and improved methodology for diagnosis, the observed incidence of GER has increased greatly. Seven of the twelve patients with GER (58 %) failed medical management with antacids, H2-blockers, and prokinctic agents, and undenvent surgical treatment (Nissen fundoplication). Indications for surgery included persistent esophagitis, pneumonia and growth failure. The reason for the high incidence of GER in patients with severe T cell disorders remains unclear. Early recognition and management is important in order to enable adequate nutrition and prevent damage to lungs and esophagus.
DE Parry MD. J Blumenthal MD. RH Tomar MD. SD Horowitz MD. ME Elder MD Phi:). JE Gem MD. Madison, WI and San Francisco, CA. Defective or absent ZAP-70, a T cell receptor associated protein tyrosine kinase, has recently been described as one of a number of genetic causes of severe combined immunodeficiency (SCID). In this report, we describe a male patient with ZAP-70 deficiency with unique clinical features. Our patient was well until 6 months of age when, based on a history of bloody dian-hea and weight loss, and colonic biopsy results, a presumptive diagnosis of ulcerative colitis (UC) was made. Following treatment with sulfasalazine and prednisone, the bowel disease went into remission. He subsequently developed oral candidiasis, chronic eczematous dermatitis, and persistent otitis media and sinusitis with intermittent fevers. At age 16 months, thrombocytopenia (<7000/ul) was noted which resolved with IVIG treatment. Immunological studies demonstrated: IgG 9.25 (pre-IVIG), IgA 3.78, IgM 3.64(g/1); poor antibody responses to tetanus, diphtheria and E. eoli; total lymphocytes 3700/ul, CD4 1400hJl, and CD8 37/ul. Lymphocyte proliferation studies showed PHA stimulation < 5% of control, absent antigen and mitogen responses, but normal proliferation with either calcium ionophore + PMA, or mixed lymphocyte culture (MLC). ZAP-70 protein was undetectable in PBMCs by Western blot. While this patient has several features in common with other reported ZAP-70 deficient patients (normal CD4 numbers, virtually absent peripheral CD8, recurrent infections, chronic dermatitis, diarrhea), this case represents the first association of ZAP-70 deficiency with two potentially autoimmune diseases 0AC and thrombocytopenia). In addition, the repeatedly normal values for MLC suggest that allogeneic T cell activation is mediated by intrscellular mechanisms that are independent of ZAP-70.