Short- and long-term follow-up after fecal microbiota transplantation as treatment for recurrent Clostridioides difficile infection in patients with inflammatory bowel disease.

Background: Patients with inflammatory bowel disease (IBD) are at an increased risk of developing Clostridioides difficile infection (CDI). Treatment of CDI in patients with IBD is challenging due to higher failure rates and concomitant IBD activity. Objectives: We performed a multicentre cohort study in patients with IBD who received fecal microbiota transplantation (FMT) for recurrent CDI (rCDI), to further investigate factors that influence the clinical outcome and course of both rCDI and IBD. Design: This is a multicentre cohort study conducted in five European FMT centres. Methods: Adult IBD patients treated with FMT for rCDI were studied. Cure was defined as clinical resolution of diarrhoea or diarrhoea with a negative C. difficile test. The definition of an IBD flare was record based. Long-term follow-up data were collected including new episodes of CDI, IBD flares, infections, hospital admissions, and death. Results: In total, 113 IBD patients underwent FMT because of rCDI. Mean age of the patients was 48 years; 64% had ulcerative colitis. Concomitant rCDI was associated with an IBD flare in 54%, of whom 63% had received IBD remission-induction therapy prior to FMT. All FMT procedures were preceded by vancomycin treatment, 40% of patients received FMT via colonoscopy. CDI cure rate was 71%. Long-term follow-up data were available in 90 patients with a median follow-up of 784 days (402-1251). IBD activity decreased in 39% of patients who had active IBD at baseline, whereas an IBD flare occurred in only 5%. During follow-up of up to 2 years, 27% of the patients had infections, 39% were hospitalized, 5% underwent colectomy, and 10% died (median age of these latter patients: 72 years). Conclusion: FMT for rCDI in IBD patients is safe and effective, and IBD exacerbation after FMT is infrequent. Further studies should investigate the effects on IBD course following FMT.

Experimental chronic glomerulitis.

Three of 16 rabbits injected (intravenously) daily with crystalline bovine serum albumin (BSA) for periods in excess of 10 wk developed chronic glomerulonephritis. In vivo, animals with chronic proteinuria formed variable quantities of soluble complex after injection of antigen while animals without proteinuria exhibited rapid removal of the injected BSA. In vitro studies demonstrated that a major part of the antibodies produced by rabbits with chronic nephritis lacked precipitating properties. Interpretations of these observations were presented in the discussion. It is suggested that, in addition to quantity, quality of antibody plays an important role in the development of chronic serum sickness. Complexes formed with nonprecipitating antibody, which are less rapidly removed from circulation, would have a greater opportunity to deposit in glomeruli and induce inflammation.

Vasculitis in association with australia antigen.

Six patients with biopsy-proven polyarteritis nodosa and chronic Australia antigenemia are described. Evidence was found in these patients for the presence of circulating immune complexes composed of Australia antigen and immunoglobulin. In addition, in two patients immunofluorescent studies localized Australia antigen, IgM, and complement in the blood vessel walls.

Immunologic studies of autoimmune disease in NZB-NZW F1 mice. I. Binding of fluorescein-labeled antinucleoside antibodies in lesions of lupus-like nephritis.

For the past 3 years NZB and NZW mice have been maintained by sister-brother matings from English breeder stock. NZB/NZW F(1) hybrids developed lupus-like nephritis during the 6th to 7th month and few survived beyond the 8th month. Renal tissues of these animals were examined with fluorescein-labeled antinucleoside sera, specific for thymine and cytosine, for the presence of denatured DNA in GCW, and with labeled antibody to mouse IgG for the presence of excess host globulin in the same areas. The following results have been obtained: (a) All 51 hybrids, over 5 months of age, had an excess of mouse globulin in GCW. 40 animals between the ages of 5 and 12 months showed, in the same areas, antigens which bound one or both of the antinucleoside antibodies. (b) Renal tissues of 19 NZB mice, 5-19 months old, and 27 NZW mice, 2-18 months old, were examined. Excess host globulin was seen in GCW of 13 NZB and 20 NZW animals. The tissues of only two old NZB mice, 14 months of age, bound antinucleoside antibody but none of the other animals did. The association of rapidly fatal lupus-like nephritis in NZB/NZW F(1) mice with denatured DNA and mouse globulin in GCW supports the hypothesis involving this antigen-antibody complex in the pathogenesis of the disease.

Myxovirus antibody increases in human connective tissue disease.

Antibodies to measles and parainfluenza type 1 viruses were significantly increased in systemic lupus erythematosus and Reiter's syndrome. Of the individuals with highest titers of measles antibody, 75 percent had neurologic illness. Persistent virus infection may be a factor in the pathogenesis of these diseases.

Studies of cryoproteins in systemic lupus erythematosus.

Cryoproteins observed in patients with systemic lupus erythematosus were shown to be of "mixed type," consisting largely of IgG and IgM. The IgM moiety possessed anti-IgG globulin reactivity and precipitated in the cold after mixing with a source of IgG. The IgM fraction of one cryoprotein precipitated only with the same patient's IgG. Antisera prepared against purified cryoproteins regularly recognized IgM, IgG, the 11 S component of C', and alpha(2)-macroglobulin. C'4 (beta(1E)) and C'3 (beta(1C)) were recognized by four and two antisera, respectively. Antisera prepared against two cryoproteins reacted (after absorption) only with the sera of origin. These "unique" antigens were associated with IgM, were destroyed by mercaptoethanol treatment, and, in one patient, were shown to disappear subsequent to clinical improvement.

Binding of immunoglobulin G aggregates and immune complexes in human sera to Staphylococci containing protein A.

Using the Cowan I strain of Staphylococcus aureus, we compared the binding properties of human monomeric immunoglobulin (Ig)G and oligomeric or complexed IgG. Heat-aggregated IgG served as a model for complexed IgG and heat-killed, formalin-fixed S. aureus (StaphA) as a cellular receptor for IgG, in determining the parameters for oligomeric and monomeric binding. Because of its capacity for multipoint attachment, complexed IgG binding was favored over monomeric IgG binding, and this preferential binding was demonstrated kinetically in equivalent forward rates of binding but in a much slower rate of release from StaphA receptors. From binding studies, we determined which conditions maximize complexes IgG binding and minimized monomeric IgG binding and applied them to the development of an assay for aggregated IgG and immune complexes in human sera. The StaphA binding assay that was devised is quantitative, sensitive, and not complement dependent. It is relatively unaffected by factors such as heparin, complement fixation, native antibodies, and immunoglobulin concentrations, but is affected by the presence of rheumatoid factors. It compares favorably with two other complement-dependent assays of immune complexes, the 125I-Clq binding assay and the Raji cell assay, in terms of sensitivity and the size of immune complexes detected. Studies on the potential of the assay for detecting, isolating, and characterizing immune complexes in biological fluids are presented.

Identification of bacterial antigens in circulating immune complexes of infective endocarditis.

The presence of circulating immune complexes (IC) in patients with infective endocarditis has been well documented but the contributions of host and bacterial components to these IC have not been defined. To study this question, IC were isolated from serum of a patient with Streptococcus faecalis endocarditis by differential polyethylene glycol precipitation and competitive binding to staphylococcal protein A. A rabbit antiserum raised against the purified IC had reactivity by crossed immunoelectrophoresis primarily with an antigen derived from the cytoplasm of the infective organism. The antigen was a protein with a 12,000-dalton molecular mass. In situ radiolabeling of the IC bound to the protein A demonstrated a component of the same molecular mass as the bacterial antigen recognized by the antiserum. The patient serum had multiple antibody specificities reactive with bacterial antigens, including the antigen recognized by the rabbit anti-IC antiserum. These techniques for isolation and characterization of circulating IC may have value in the study of IC diseases in which the inciting antigens are not known.

Localization of fluorescein-labeled antinucleoside antibodies in glomeruli of patients with active systemic lupus erythematosus nephritis.

Renal tissues from two groups of patients were studied with fluorescein-labeled (Fl-) antibodies (Abs) to immunoglobulins, complement, and antibodies prepared in rabbits against BSA conjugate of 5-methyluridine (T) and cytidine (C), the latter two of which react specifically with denatured DNA. The first group consisted of 13 SLE patients, and the second consisted of 53 patients with non-SLE nephropathies. The data obtained from the two groups of patients were used for comparison, and they showed the following:(a) Fl-Abs to immunoglobulins and complement were bound in the glomeruli of tissues from all patients with active SLE glomerulonephritis characterized by deposits of foreign material in glomerular capillary walls (GCW). The fluorescent pattern was granular, corresponding to the distribution of the glomerular deposits, as seen by electron microscopy. Fl-Abs reactive with thymine and cytosine were bound in the GCW of eight of the nine patients with active SLE glomerulonephritis and showed the same granular distribution. The capacity of these latter Fl-Abs to stain the GCW was removed by absorption with the homologous antigen or denatured DNA.(b) Fl-Abs to immunoglobulins, complement, and pyrimidine bases of DNA did not react with the GCW of two SLE patients without clinical and histologic evidence of glomerulonephritis or with the sclerotic glomeruli of two uremic patients with chronic "burned out" lupus nephritis.(c) The glomeruli of 47 of the 53 patients with other nephropathies bound Fl-Abs to immunoglobulins and complement to some extent, and in 26, the localization appeared as marked as in the patients with active SLE glomerulonephritis. Fl-Abs reactive with thymine and cytosine were bound in the GCW of only one of the renal tissues from the 53 non-SLE patients. In the remaining 52, no binding was seen.(d) The findings are consistent with the hypothesis that antigen-antibody complexes, formed by denatured DNA, specific antibody, and complement, are present in the deposits of foreign material accumulated in the GCW of patients with active SLE glomerulonephritis, and that they may contribute to the pathogenesis of this renal disease.

Epidemiology of childhood IDDM in U.S. Virgin Islands from 1979 to 1988. Evidence of an epidemic in early 1980s and variation by degree of racial admixture.

OBJECTIVE: The epidemiology of insulin-dependent diabetes mellitus (IDDM) was evaluated in a predominantly black population in the U.S. Virgin Islands. RESEARCH DESIGN AND METHODS: Primary ascertainment of diabetic subjects was by retrospective review of hospital and clinic records, and IDDM was defined by Diabetes Epidemiology Research International Group criteria. RESULTS: For the period 1979-1988, 28 children less than 15 yr of age were diagnosed with IDDM resulting in an average annual IDDM incidence rate (IR) of 7.5/100,000 (95% confidence interval 4.7-10.3). A significant increase in IDDM incidence (P less than 0.01) was observed when the IR rose to 28.4/100,000 in 1984. White children had the highest IR (28.9/100,000). The IR for Hispanics (7.2/100,000) was slightly higher than that for blacks (5.9/100,000). Among black children, a slight but nonsignificant male excess in incidence was observed (male-female ratio 1.5). When black or Hispanic patients were compared with age-matched control subjects with respect to grandparental race, the diabetic subjects had a greater percentage of white ancestry (P less than 0.02 and P less than 0.05, respectively). The incidence of IDDM in Caribbean blacks (West Indians) in the U.S. Virgin Islands was similar to blacks in the U.S. CONCLUSIONS: The epidemic of IDDM in 1984 provides support for a possible pandemic in the early 1980s.

Vasculitis with hepatitis B antigenemia: long-term observation in nine patients.

The development of generalized necrotizing vasculitis in association with hepatitis B antigenemia is the first example in man of a chronic rheumatic disease presumably caused by a viral infection. This report reviews the experience in nine biopsy-proven cases of hepatitis B-associated necrotizing vasculitis followed for up to six years. The natural history of the disease is emphasized and the manifestations of patients with vasculitis who carry hepatitis B antigen are compared with those of vasculitis patients who are antigen negative.

Arthralgia associated with acute urinary retention. A syndrome of probable viral etiology.

Four patients are described in whom paresthesia and arthralgia developed in association with acute urinary retention. Neurologic and musculoskeletal complaints persisted for varying periods, up to five year, after cessation of urinary symptoms. Significantly elevated titers to Herpes simplex and Herpes zoster viruses were observed in three and four subjects, respectively, although none exhibited cutaneous lesions of herpetic infection. The symptom complex, presumably the result of viral radiculitis, may present in varying patterns that can be confused with lumbar disc protrusion, obstructive uropathy or primary rheumatic disorder. Diagnostic studies requisite for documentation of a viral etiology of the syndrome are discussed.

Induction of polymeric IgA rheumatoid factors in infective endocarditis.

IgA and IgM rheumatoid factor activity, circulating immune complex levels, and antinuclear antibodies were measured in 17 patients with subacute or chronic infective endocarditis. Approximately three fourths of these patients had both IgA and IgM rheumatoid factors detectable by radioimmunoassay, and IgA and IgM rheumatoid factor activity was strongly correlated (p less than 0.01). In three patients studied, IgA rheumatoid factor activity was predominantly polymeric as assessed by sucrose density ultracentrifugation (55 to 92 percent of total rheumatoid factor activity) and could bind radiolabeled secretory component. No correlations between rheumatoid factor activity and circulating immune complex levels or antibodies to nuclear antigens were observed. These observations indicate that circulating polymeric IgA antibodies do not necessarily signify a mucosal stimulus for IgA production and also demonstrate differences in the intensity and spectrum of autoantibody production when compared with autoimmune diseases.

Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets.

To assess the role of genetic factors in systemic lupus erythematosus (SLE), 12 twon pairs (seven definitely monozygotic, three definitely dizygotic) of which one or both twins had SLE, were studied and compared to 17 twin pairs (12 definitely monozygotic) previously described. In the present series, four of seven (57 per cent) definitely monozygotic pairs were clinically concordant for SLE, satisfying the preliminary criteria of the American Rheumatism Association (ARA). Concordance for the presence of antinuclear factor (ANF) and hypergammaglobulinemia was 71 and tinuclear factor (ANF) and hypergammaglobulinemia was 71 and 87 per cent, respiectively. These data closely agree with those on the 12 definitely monozygotic sets previously described. All three of the dizygotic sets in the present series were discordant for clinical SLE, although one clinically well twin had marked serologic abnormalities. Comparison of these data with thos from other first degree relatives of out twins clearly suggests a strong genetic component in the pathogenesis of SLE. The relative contribution of nongenetic and environmental factors to the expression of the disease is discussed.

Clinical and microbial features of prosthetic joint infection.

A one-year experience with prosthetic joint infection, in which 63 cases were identified, is reviewed. Thirty cases (48 percent) were early infections, in the first postoperative year, and 33 cases (52 percent) were late, occurring more than one year after implantation. Pain was the predominant symptom, but clinical clues suggesting infection were frequently absent, with fever in 43 percent and leukocytosis in only 10 percent. The radiographic appearance was more frequently abnormal in late infections (67 versus 37 percent, p less than 0.02). Staphylococci were predominant organisms, constituting 59 percent of prosthetic joint infections, and S. epidermidis was the predominant species in both early and later infections. Of the hematogenous infections, 11 of 13 occurred in the group with late infections; these were mostly nonstaphylococcal . Antigenic proteins of S. epidermidis were characterized by gel electrophoresis, but no infection-specific antigens could be identified when patient serum was compared with normal samples. Precipitating antibodies to the extracellular proteins of S. epidermidis were present in 50 percent of patients with S. epidermidis prosthetic joint infections, 27 percent of patients with nonstaphylococcal infections, 20 percent of patients with S. aureus infections, and 11 percent of normal subjects. In view of the increasing importance of prosthetic joint infection, further study of the pathogenesis of the infection and the host immune response is warranted.

High-dose intravenous methylprednisolone pulse therapy in systemic lupus erythematosus.

To determine guidelines for treatment with high-dose intravenous methylprednisolone in lupus nephritis, we prospectively assessed the response to pulse therapy in 34 patients. In 12 of them, serum creatinine decreased by at least 20 percent within two months of treatment whereas in the remaining 22 there was no such response. Patients who responded were characterized by recent deterioration in function whereas nonresponders had had a more stable antecedent course (p = 0.003). Responders also had more diffuse lesions on renal biopsy (p = 0.028), had higher levels of anti-DNA antibodies (p less than 0.05), and tended to have higher titers of immune complexes and lower total hemolytic complement. High-dose intravenous methylprednisolone therapy may lead to striking improvement in renal function in lupus nephritis, especially in the subset of patients with recent antecedent functional deterioration. This improvement was maintained in 60 percent of the patients who responded for at least six months.

Technetium-99m dimercaptosuccinic acid scintigraphy studies of renal cortical scarring and renal length.

UNLABELLED: The aims of this study were to validate 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy appearances with histopathological features of scarring; to evaluate the sensitivity and specificity of 99mTc-DMSA and ultrasound for the detection of renal scarring; to compare planar, pinhole and SPECT techniques when using 99mTc-DMSA; and to compare 99mTc-DMSA and ultrasound renal length measurement. METHODS: Reflux nephropathy was induced in large white pigs using established methods. To ensure that the abnormalities detected were scars and not inflammatory changes, the pigs were not studied until 3 mo after the treated episode of acute pyelonephritis confirmed by 99mTc-DMSA. RESULTS: Twenty pigs were enrolled in the study. Eleven reached the end point, but only nine pigs (18 kidneys) were available for analysis. Thirty-four scars were identified pathologically; 24 were present macroscopically and a further 10 were seen only on microscopy. Technetium-99m-DMSA abnormalities correlated with scars histopathologically with an accuracy of 92% versus that of ultrasound, 75% (p < 0.001). Technetium-99m-DMSA more accurately identified scarring with a higher sensitivity (76% versus 29%) and specificity (98% versus 92%) than ultrasound. On the 99mTc-DMSA study, pinhole imaging had the highest accuracy (92%) when compared with planar (90%) and SPECT (87%) data. These differences were not statistically significant. Renal lengths as measured on 99mTc-DMSA more closely correlated with length measurement at pathological examination than ultrasound. Technetium-99m-DMSA measurement was, on average, 6% higher than pathology, and ultrasound was, on average, 22% lower. CONCLUSION: Technetium-99m-DMSA appears to be the preferred method for the detection of renal cortical scarring and accurate renal length measurement when compared with ultrasound examination.

Radiological findings in Hallermann-Streiff syndrome: report of five cases and a review of the literature.

Hallermann-Streiff syndrome (HSS) is a rare disorder with an associated constellation of radiological findings that may aid in the diagnosis of affected individuals. We reviewed the skeletal surveys of 5 affected individuals and noted some characteristic and constant findings. Radiological findings can include a large, poorly ossified skull with decreased ossification in the sutural areas. There was an increase in the number of Wormian bones. Severe mid-facial hypoplasia was present along with a prominent nasal bone. The skull films also showed an abnormally obtuse or nearly straight gonial angle. The teeth appeared small. The long bones were thin and gracile in appearance and often showed poor demarcation of the cortex from the medullary portion. Abnormal bowing of the radius and ulna was seen neonatally in 2 cases. There was widening at the metaphyseal ends of the long bones. The ribs were thin, but normal in length. The vertebral bodies were noted to be small and 3 cases had platyspondyly. There was a decreased number of sternal ossification enters. The metacarpals were also thin and gracile in appearance with metaphyseal widening. We conclude that these characteristic radiological findings in the newborn with HSS can aid in the diagnosis, and a skeletal survey in suspected individuals may be valuable in confirming the diagnosis.

Prognostic and therapeutic implications of immunologic test results in rheumatic disease.

In systemic lupus erythematosus, some immunologic tests quantify disease activity, enable prediction of higher risk patterns of disease, and serve as therapeutic guides. In rheumatoid arthritis, serologic phenomena are significantly associated with more severe and sustained joint disease and with visceral manifestations (vasculitides and granulomas), but they have not been useful in monitoring the course of disease or response to therapy. In other rheumatic syndromes, a variety of antinuclear specificities show promise as marker antibodies, but their prognostic and therapeutic implications remain largely unexplored.