Necrotizing fasciitis of abdominal wall in AIDS.

Necrotizing fasciitis (NF) is an uncommon but potentially lethal soft-tissue infection. Mortality rate is high and has not changed since it was first described by Meleny. Although immunodeficiency is a risk factor for NF, there is only one reported case of NF in AIDS involving the cervical region. We report the first case of necrotizing fasciitis of the abdominal wall in an AIDS patient.

Analysis of the Kveim-Siltzbach test reagent for bacterial DNA.

The sarcoid spleen-derived reagent for the Kveim-Siltzbach test (KST) elicits a sarcoid-specific, granulomatous, cutaneous response used to establish the diagnosis of sarcoidosis. In the context of the ongoing discussion of a bacterial cause of sarcoidosis we asked the question whether bacterial DNA could be found in the KST reagent. For this purpose two different KST reagents, an identical preparation from a normal spleen, and a native sarcoid spleen were analyzed by polymerase chain reaction (PCR) employing universal primers detecting conserved DNA sequences coding for bacterial ribosomal 16S RNA. Neither KST reagents, the control preparation, nor the spleen yielded a positive signal, indicating that the preparations are free of bacterial contamination. Because the KST reagent elicits granuloma, these results do not support the hypothesis of a bacterial cause of sarcoid granuloma.

Immunology of sarcoidosis.

Because of its association with cutaneous anergy, sarcoidosis was originally viewed as a defect of cellular immunity. Supporting that misperception were early studies of peripheral blood lymphocytes that found lymphopenia and impaired lymphocyte responses to mitogens and recall antigens. The clue to a vast underlying network of complex hyperactive cellular immune functions was discovered in the paradoxical finding of in vitro spontaneous lymphoblastic transformation and lymphokine production. Subsequently, investigative focus shifted to the activated, proliferating T-helper lymphocytes, the lymphokines of which were found to function in the recruitment and retention of monocytes for granuloma development. T-helper lymphocytes also contributed to the mechanism of hypergammaglobulinemia through their influence on B cells. The most intriguing question about sarcoid immunology is the initiating factor that triggers the T-lymphocyte activation and proliferation in the first place. There is much to suggest that antigen processing and presentation launches the process. Because lymphocyte activation and proliferation antedate granuloma formation at K-S skin test sites and in the lung, we combined the harvesting technique of BAL with the K-S bioassay to show that granulomagenic antigen is being processed by monocyte-macrophages. The finding of autologous monocyte-macrophage granulomagenicity raises the distinct possibility that sarcoidosis is a unique cell-mediated type of autoimmune process. The isolation and identification of the granulomagenic factor is the exciting research frontier ahead.

Nonviable autologous bronchoalveolar lavage cell preparations induce intradermal epithelioid cell granulomas in sarcoidosis patients.

Intracutaneous injection of sarcoidosis patients with Kveim-Siltzbach antigen (KSAg), a particulate suspension of granulomatous sarcoidal spleen, induces an influx of T-helper lymphocytes and monocyte-macrophages followed by epithelioid cell granuloma formation. In the lung, similar granulomas form from an alveolitis of similar mononuclear cells, which may harbor a Kveim-like granulomagenic factor. To assess this possibility, preparations of nonviable autologous bronchoalveolar lavage cells (NABC) and KSAg were injected intracutaneously at different sites and biopsied at 4 to 5 wk. Of 22 sarcoidosis patients, nine (41%) developed typical granulomas at the NABC site, while all developed granulomas at the KSAg site. Responders to NABC had more recent onset of symptoms than nonresponders (3.2 versus 23.7 months, p less than 0.01), but did not have significantly higher percentages of lavage lymphocytes or more rosetting of lymphocytes about alveolar macrophages. None of 11 normal volunteers developed granulomas in response to NABC. Epithelioid cell granulomas at NABC and KSAg sites were similar by hematoxylin-eosin staining and by biotin-avidin-peroxidase immunohistochemical staining with monoclonal antibodies Leu-1, Leu-14, Leu-2a, Leu-3a, anti-interleukin-2 receptor, and polyclonal antibodies against lysozyme and alpha 1-anti-chymotrypsin. Symptomatic onset of sarcoidosis is associated with an autologous lavage cell factor that induces intradermal epithelioid cell granulomas that are immunophenotypically similar to Kveim-induced granulomas.

Hemoptysis in sarcoidosis.

The medical records of 433 patients with sarcoidosis were reviewed to determine the prevalence and significance of hemoptysis in this disease. Twenty-five patients (6%) were found to have hemoptysis. Nineteen of the 25 patients had mild hemoptysis, four had moderate, and two had massive hemoptysis. The clinical, roentgenographic, and laboratory features in patients with hemoptysis were compared with those from an age, race, and sex matched control group of sarcoidosis patients without hemoptysis. With the exception of eye involvement which occurred with greater frequency in control patients, no significant differences were found between the two groups. While bronchoscopy may be useful in establishing a diagnosis of endobronchial sarcoidosis, identification of a specific bleeding site is not likely in the absence of massive hemoptysis or localized radiographic abnormalities. Corticosteroid therapy may be useful to control hemoptysis in some patients.

Spontaneous production of interleukin-2 in the supernatants of cultured cutaneous sarcoidal granulomas.

Biopsies of cutaneous sarcoidal lesions were cultured for 24 hr in vitro, and the cell-free supernatants were examined for the presence of T cell growth factor (IL-2). Low levels of IL-2 were detected in these supernatants based on their ability to support the growth of cultured T cells. The apparent molecular mass of the active component in these supernatants, as assessed by exclusion chromatography, was 14,900 daltons. These findings suggest that IL-2 production within these sarcoidal lesions may be partly responsible for their evolution and maintenance.

Enhanced inflammatory response with histiocytes and epithelioid cells in rabbits to the intradermal injection of supernatants of cultured cutaneous sarcoidal granulomas.

This study was designed to examine the inflammatory response in rabbits to intradermal injections of lymphokine-containing supernatants from cultured cutaneous sarcoidal granulomas (sarcoidal supernatant). Cell-free sarcoidal supernatants and concurrently incubated culture medium controls, alone or mixed with heat-inactivated K-S antigen or BLB, were injected intradermally into rabbits. These were, compared to control results, increased inflammatory reactions with histiocytes and epithelioid cells at the injection sites in 9 out of 11 experiments using sarcoidal supernatants mixed with K-S antigen and in 8 out of 10 experiments with these supernatants mixed with BLB. Sarcoidal supernatant alone, control medium, or normal saline solution produced no inflammatory response. Supernatants from cultured normal skin tissues obtained from sarcoid patients and those obtained from surgical patients free of sarcoidosis, when mixed with K-S antigen or BLB, showed variable inflammatory responses similar to the response seen with sarcoidal supernatants, but these were not significantly different from those of their own controls. It was concluded that lymphokines released locally may initiate and maintain the formation of sarcoidal granulomata.

Dynamics and mechanism of the sarcoidal granuloma. Detecting T cell subsets, non-T cells, and immunoglobulins in biopsies at varying intervals of Kveim-Siltzbach test sites.

Punch biopsies of K-S test sites were studied by the use of monoclonal antibodies for the presence of T cells, T cell subsets, B cells, IgG, IgM, IgA, and kappa and lambda chains by an indirect and direct immunoperoxidase technique. A total of 10 biopsies were performed at intervals ranging from 6 hr to 34 days. Results revealed that at 6 hr there was an influx of T cells, predominantly helper cells, at the injection site, followed by an infiltration of monocytes, an infiltration that was maximal at 48 hr. By day 7 there was a marked increase in the number of T lymphocytes, predominantly helper cells, and a few persistent monocytes were seen. By day 12 there was evidence of granuloma formation with the appearance of some epithelioid cells and a few giant cells. These cells, along with helper T cells, were seen to have progressively increased in number when the confluent granulomas on the day 34 biopsies were studied. Epithelioid cells, however, did not show any reactivity with Leu-M3 monoclonal antibody, which stained the majority of peripheral blood monocytes. B cells were rarely present; immunoglobulins were absent in all biopsies. It was concluded that the evolution of the sarcoidal granuloma in response to K-S antigen is a purely cell-mediated phenomenon. Helper-inducer T cells appear to play a dominant role in its evolution and maintenance. Lack of reactivity of epithelioid and giant cells with Leu-M3 monoclonal antibody indicates either a different lineage from monocytes or a change in their phenotype.

Cutaneous manifestations of sarcoidosis. Relationships to other organ system involvement, abnormal laboratory measurements, and disease course.

The charts of 329 patients with sarcoidosis were reviewed to determine if there were significant associations between the presence of sarcoidosis skin lesions and other abnormalities. Sixty-four patients had either biopsy specimen-documented cutaneous granulomata or erythema nodosum (EN). Respiratory symptoms occurred in 41% of patients with skin lesions compared with 63% of patients with sarcoidosis without skin lesions. Among patients with skin lesions other than EN, splenomegaly occurred in 38%, hepatomegaly in 32%, and lymphadenopathy in 31% compared with 10%, 11%, and 56%, respectively, for patients with sarcoidosis without skin lesions. Thirty-two percent of patients with EN had progressive disease compared with 72% of patients with skin lesions other than EN; however, improved prognosis with EN was limited to white patients.

In vitro production of inhibitors of monocyte locomotion by the granuloma of sarcoidosis.

To assess the ability of the sarcoidal granuloma to modify peripheral mononuclear cell function, we assayed the culture supernatants of cutaneous granulomata for modulators of monocyte locomotion. The supernatants of granulomata from each of 11 patients contained a cell-directed inhibitor of monocyte leukotaxis. No inhibitory activity was detected in the supernatants of histologically normal skin biopsies. The inhibitor acted only on monocytes, possessed a molecular weight of 230,000 daltons, and was clearly distinct from migration inhibition factor (MIF), leukotactic lymphokines, and immunoglobulins. A physicochemically and functionally indistinguishable inhibitor was present in patient plasma. Production of the inhibitor by the granuloma required active protein synthesis. Culture supernatants also contained MIF and a leukotaxin inactivator. These observations indicate the potential of the sarcoidal granuloma to exert local and, perhaps, systemic regulation of inflammatory processes.

Ocular presentation of sarcoidosis in children.

Ocular manifestations of sarcoidosis in children are the second most common occurrence after hilar adenopathy and pulmonary abnormalities. We present the case history of a 14-year-old black boy who presented with redness of the left eye, blurred vision, and decreased visual acuity. He was subsequently diagnosed as having sarcoidosis. All patients with uveitis or ocular findings suggestive of sarcoidosis should have a through medical examination and a chest x-ray. Those suspected of or proven to have sarcoidosis should have a complete ophthalmological examination. Sarcoidosis in children appears to be more frequent than previously estimated.

The tuberculin specificity in humans of Mycobacterium tuberculosis antigen 5.

Mycobacterium tuberculosis antigen 5 is a protein antigen limited in distribution to M. tuberculosis and M. bovis and capable of eliciting typical delayed tuberculin skin test reactions in humans. A single large batch of this antigen was purified by immunoabsorbent affinity chromatography and used to skin test patients with tuberculosis and other mycobacterial infections and healthy persons in general populations in geographic areas where nonspecific tuberculin reactivity is frequently encountered. Antigen 5 was found to be no more specific as a tuberculin antigen than PPD. If the available data are accepted, then either a disparity in antigen recognition by antibody and T lymphocytes may exist or the widely accepted hypothesis attributing nonspecific tuberculin reactivity to antigenic cross reactivity with other mycobacteria may be incorrect.

Acute pulmonary histoplasmosis presenting as adult respiratory distress syndrome: effect of therapy on clinical and laboratory features.

Three patients with acute pulmonary histoplasmosis presented with extensive, diffuse bilateral infiltrates on chest roentgenograms. Fungal elements were seen in the bronchial secretions of two patients; Histoplasma capsulatum was grown from the third patient and from soil from the patients' workplace. Two patients were severely hypoxemic and required short courses of amphotericin B therapy; in one of these two, progressive deterioration dictated corticosteroid therapy as well, with a dramatic clinical response. Radiologic resolution of disease occurred more quickly in the treated patients. Initial pulmonary function tests suggested mild restriction in each, with normal test results by the fourth month of follow-up. Our experience suggests that amphotericin B may shorten the course of acute histoplasmosis and that corticosteroid therapy may be efficacious in controlling the symptoms related to hyperresponsiveness in fulminant primary disease.

Chlorambucil in sarcoidosis.

Ten patients with biopsy-proven sarcoidosis with progressive disease were treated with chlorambucil alone or in combination with corticosteroids. Eight of these ten patients showed some degree of improvement which may be attributable to chlorambucil. The responsive patients showed beneficial effects within three months of starting chlorambucil therapy. It is concluded that chlorambucil may be worth a trial in patients with progressive disease unresponsive to corticosteroids or where corticosteroids are contraindicated.

Kveim induced lymphocyte reactivity in patients and household contacts of patients with Crohn's disease.

In vitro lymphocyte thymidine uptake in response to validated Kveim antigen CR-1 was studied in 18 patients with Crohn's disease and in 30 of their household contacts. Two of the patients and 3 of the contacts demonstrated a stimulation index of 2 or greater. None of 15 control subjects demonstrated such reactivity. Lymphocytes from patient and household contact groups exhibited a greater mean increment in cpm than those from the control group (110, 130 and 33 cpm, respectively) (p < 0.05 and p < 0.005, respectively). This finding indicates a low level of lymphocyte reactivity to Kveim antigen in patients and in contacts, suggesting sensitization to Kveim antigen or to a cross-reacting antigen.

Nasal sarcoidosis with septal perforation.

A patient with systemic sarcoidosis in whom nasal symptoms were the presenting features is discussed. These symptoms remained unchanged following septal reconstruction and were refractory to treatment with systemic corticosteroids. She developed an anterior septal perforation while receiving methylprednisolone. Beclomethasone dipropionate inhaler was highly effective in relieving her nasal symptoms.