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Post-transplantation histoplasmosis may be acquired via inhalation, may result from endogenous reactivation, or may be derived from the allograft. The Histoplasma and Aspergillus enzyme-linked immunoassays are increasingly being relied upon for rapid diagnosis of fungal infections, especially in immunocompromised patients. We describe 4 cases of solid organ transplant recipients who had histoplasmosis and a falsely positive Aspergillus galactomannan (GM) obtained from the serum or bronchoalveolar lavage (BAL) fluid. We also report our experience, testing for Histoplasma antigen (Ag) in specimens positive for Aspergillus GM. From January 2007 through December 2010, of 2432 unique patients who had positive Aspergillus GM tests, 514 (21%) were tested for Histoplasma Ag, and 27 were found to be positive. Most specimens that tested positive for both Aspergillus and Histoplasma were obtained by BAL. False-positive tests for Aspergillus GM can occur in immunosuppressed patients who have histoplasmosis, and may obscure the correct diagnosis.

During a randomized double-blind placebo-controlled study testing the efficacy of itraconazole for prophylaxis of systemic and mucosal fungal infections in patients with acquired immune deficiency syndrome, 298 patients were enrolled with 295 evaluable. Of those, 46 patients were considered prophylaxis failures because of recurrent oral or esophageal candidiasis. Oropharyngeal fungal cultures were taken at the time of suspected thrush or Candida esophagitis, but not at baseline. All of the Candida spp. isolates were cultured on CHROMagar Candida medium then identified using API 20 AUX strips. Antifungal susceptibility testing was performed following the National Committee for Clinical Laboratory Standards M-27A guidelines. Sequential isolates were genotyped using randomly amplified polymorphic DNA. Polymerase chain reaction fingerprints were generated using two repetitive sequence primers, (GGA)7 and (GACA)4. The study group consisted of 23 patients, nine from the itraconazole arm and 14 from the placebo arm, who were prophylaxis failures and had more than two C. albicans isolates. Five of 23 had isolates showing a > or =4-fold reduction in susceptibility; four of these patients were in the itraconazole prophylaxis arm and one was in the placebo arm. Three of the five had yeast isolations showing changes in banding patterns over time. Such changes may indicate genetic changes in the same strain that could be linked to acquired resistance to itraconazole, or acquisition of a new strain, or emergence of a previously minor component of the original population.

Summary We report a case of relapse of coccidioidomycosis in an HIV-infected person who discontinued maintenance azole therapy following a response to antiretroviral therapy. This experience raises concern about the safety of withholding secondary prophylaxis for coccidioidomycosis in persons with HIV infection who have achieved immunological responses to antiretroviral therapy. Zusammenfassung Wir berichten uber einen Coccidioidomykose-Ruckfall bei einem HIV-infizierten Patienten, der die Azol-Erhaltungstherapie nach erfolgreicher antiretroviraler Therapie abgesetzt hatte. Dieses Geschehen beruhrt die Frage der Sicherheit der Sekundarprophylaxe der Coccidioidomykose bei HIV-Infizierten, deren Immunstatus sich nach antiretroviraler Therapie gebessert hat.

Donor-derived fungal infections can be associated with serious complications in transplant recipients. Most cases of donor-derived candidiasis have occurred in kidney transplant recipients in whom contaminated preservation fluid is a commonly proposed source. Donors with cryptococcal disease, including those with unrecognized cryptococcal meningoencephalitis may transmit the infection with the allograft. Active histoplasmosis or undiagnosed and presumably asymptomatic infection in the donor that had not resolved by the time of death can result in donor-derived histoplasmosis in the recipient. Potential donors from an endemic area with either active or occult infection can also transmit coccidioidomycosis. Rare instances of aspergillosis and other mycoses, including agents of mucormycosis may also be transmitted from infected donors. Appropriate diagnostic evaluation and prompt initiation of appropriate antifungal therapy are warranted if donor-derived fungal infections are a consideration. This document discusses the characteristics, evaluation and approach to the management of donor-derived fungal infections in organ transplant recipients.

Local immunity against acute pulmonary histoplasmosis was studied in the lung-associated lymph nodes of normal nonimmune mice infected intratracheally with live Histoplasma capsulatum yeasts. The phenotypes and distribution of cells in lung-associated lymph nodes and spleens were determined by flow cytometry. In addition, the immune responsiveness of these cells was evaluated by in vitro blastogenesis. Anti-H. capsulatum antibodies in serum and H. capsulatum antigen in tissue were measured by immunoassays. Cellular immune responses were greater in the lymph nodes than in the spleens. In lymph nodes 7 days after infection, a marked increase in the number of B lymphocytes caused the percentage to rise to 43%, compared with 26% in controls, and it remained elevated throughout the course of infection. A CD3+ cell that did not express CD4 or CD8 increased in number until it constituted 21% of lymph node cells, compared with 5% in controls, by day 14. The numbers of CD4+ and CD8+ T lymphocytes were modestly increased from days 7 to 35, but their percentages dropped because of the greater numbers of B lymphocytes and CD3+4-8- cells. Macrophages consistently constituted 2 to 3% of lymph node cells during the study. In spleens 7 days after infection, the percentage of macrophages in infected mice rose to 21%, compared with 9% in controls, but the total spleen cell number did not increase until day 14, when all cell subsets were nearly double in number. The in vitro blastogenic response of lymph node cells to H. capsulatum peaked at day 7, but spleen cell response was minimal during the course of infection. Histoplasma-specific serum immunoglobulin G antibodies reached peak levels by day 21 and remained high to the end of the study. In contrast, levels of antigen-specific immunoglobulin M antibodies were very low. These data suggest that antigen-specific immune responses occur in lung-associated lymph nodes and that this draining lymph node response may be an important component in host defense against Histoplasma lung infection.

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis ( P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC 50 ) for last-episode isolates from the itraconazole group was 0.125 μg/ml compared to 0.015 μg/ml for the placebo group subjects, P = 0.0001. The MIC 50 of fluconazole for the last isolates from the itraconazole group was 1.5 μg/ml compared to 0.5 μg/ml for the placebo subjects ( P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) ( P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) ( P = 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively ( P = 0.001); fluconazole susceptibility, 23 and 4%, respectively ( P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole.

Invasive aspergillosis is a serious and often fatal infection in patients who are neutropenic or have undergone solid organ or stem cell transplantation. Delayed diagnosis and therapy may lead to poor outcomes. Diagnosis may be facilitated by a test for galactomannan antigen detection using an enzyme immunoassay. Other rapid methods for diagnosis include (1--3)-beta-D: -glucan determination and polymerase chain reaction. The sensitivity and specificity of galactomannan antigenemia testing in serum and bronchoalveolar lavage specimens are high in patients with hematological malignancy, neutropenia, and receipt of stem-cell transplants. False positivity can be seen with concomitant administration of some antibiotics and infection by fungi other than Aspergillus.

Two cases of Histoplasma meningitis are presented, illustrating the difficulty in diagnosis and treatment. The first case occurred in a patient with acquired immunodeficiency syndrome as a relapse of disseminated histoplasmosis and resolved after prolonged treatment and ongoing antiretroviral therapy. The second case occurred in a cardiac allograft recipient as meningitis and focal brain lesions that responded to liposomal amphotericin B, but the patient died shortly after therapy was completed. Unfortunately, there are no prospective studies addressing the diagnosis and management of patients with histoplasmosis of the central nervous system from which to provide evidence-based guidelines for care. In the absence of such data, an approach will be presented on the basis of our experience and opinions.

We report a case of relapse of coccidioidomycosis in an HIV-infected person who discontinued maintenance azole therapy following a response to antiretroviral therapy. This experience raises concern about the safety of withholding secondary prophylaxis for coccidioidomycosis in persons with HIV infection who have achieved immunological responses to antiretroviral therapy.

Questions have arisen regarding the risk of developing symptomatic Histoplasma capsulatum infection among patients who undergo transplant-related immunosuppression in areas endemic for histoplasmosis. Our medical center is located in a hyperendemic area for histoplasmosis, where three large outbreaks occurred since 1978. We undertook a retrospective chart review of 137 patients who received allogeneic bone marrow transplant and of 449 patients who received solid organ transplant from January 1994 to December 1996 in order to assess the incidence of active histoplasmosis. Charts were reviewed before and after transplantation for clinical outcomes, H. capsulatum serologies and antigen results, and microbiological and radiological results. After a mean follow-up duration exceeding 16 months, no patient was diagnosed with histoplasmosis. In the absence of an outbreak, histoplasmosis is a rare infection following the immunosuppression of allogeneic bone marrow or solid organ transplantation even in a hyperendemic area. Pre-transplant serologies or chest radiographs consistent with prior infection were not associated with post-transplant histoplasmosis.

Advances in the management of fungal infections in AIDS justify this review. First, their incidence has fallen with the introduction of potent antiretroviral therapy. Now, most cases occur in patients with advanced HIV disease who have failed multiple antiretroviral regimens, are nonadherent to therapy, or treatment na ve. Immune reconstitution has reduced the incidence of these infections and permitted discontinuation of maintenance therapy. However, the immune response to antiretroviral therapy has resulted in paradoxical worsening in some cases, "so-called immune reconstitution inflammatory syndromes". Finally, new antifungal agents expand our treatment choices. This review updates management of fungal infections in AIDS.

Histoplasmosis is an important cause of morbidity and death in HIV-infected patients. Significant developments concerning the diagnosis, treatment, follow-up, and prophylaxis of histoplasmosis are discussed. Itraconazole is highly effective at both inducing and maintaining remission in mild to moderate cases of disseminated histoplasmosis. In cases of moderate to severe disease, amphotericin B remains the therapy of choice. A table presents comparative results of treating mild to moderate disseminated histoplasmosis with the drugs itraconazole versus fluconazole. Currently, no resistance of Histoplasmosis capsulatum to itraconazole has emerged from prolonged therapy. Maintenance therapy for life is recommended for patients with CD4 counts less than 100; however, feasibility studies are evaluating the possibility of its discontinuance. While no prophylaxis recommendations currently exist, patients with CD4 counts less than 100 who are exposed to histoplasmosis are recommended to begin oral itraconazole (200 mg daily).

Clinical aspects of treatment of invasive aspergillosis, infections caused by dematiaceous fungi, and mycoses caused by endemic, dimorphic fungi, are described in this review.

Reactivation may be a mechanism for the development of histoplasmosis in AIDS. In this study, histoplasmosis was reactivated by the depletion of CD4 and CD8 lymphocytes in mice. CD4 and/or CD8 depletion beginning 1 month after intratracheal infection and continuing for 2 months caused reactivation with a 2.1 log/g increase in the lungs and a 1.5 log increase in the spleen of B6C3F1 mice. Because control animals showed persistent infection, a subsequent experiment sought to determine the long-term outcome in competent mice. Twelve of 32 immunocompetent mice died at weeks 26-52 of infection, and 4 survivors appeared to be clinically ill; all ill mice had high fungus burdens, whereas cultures were sterile in the healthy mice. Eight of the surviving healthy-appearing mice underwent autopsy 2 years after infection, and cultures were sterile. Thus, 16 of 32 immunocompetent mice exhibited progressive infection. CD4 and/or CD8 depletion exacerbated infection, but a chronic progressive and ultimately fatal infection occurred in half the immunocompetent mice.

To determine the efficacy and safety of amphotericin B oral suspension (ABOS) for the treatment of fluconazole refractory oral candidiasis in persons with HIV infection.A prospective, multicenter, open label trial at 25 study centers within the AIDS Clinical Trials Group.Individuals with diffuse oral candidiasis after 14 days of treatment with 200 mg of fluconazole daily (more than five plaques or a single plaque3 cm largest length) were treated with ABOS, 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days. Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months. Relapses during maintenance ABOS were treated by increasing the dose to four times daily.To demonstrate an ABOS clinical response rate33% and a treatment-limiting toxicity rate50%. Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques, the largest being3 cm largest dimension.Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 x 10(6) cells/l were enrolled. Four subjects were excluded from the analysis because of inadequate follow-up after randomization (n = 3) or the presence of active esophageal disease (n = 1). Of the remaining 54 subjects, 23 (42.6%; 95% lower confidence interval, 31.1%) were classified as responders after 28 days. Five subjects (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%).Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral candidiasis.

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC(50)) for last-episode isolates from the itraconazole group was 0.125 microg/ml compared to 0.015 microg/ml for the placebo group subjects, P = 0.0001. The MIC(50) of fluconazole for the last isolates from the itraconazole group was 1.5 microg/ml compared to 0.5 microg/ml for the placebo subjects (P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P = 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole.

In a prospective, randomized, double-blind trial, 149 patients with advanced human immunodeficiency virus (HIV) infection were randomized to receive itraconazole capsules (200 mg daily) and 146 to receive a matched placebo. Both groups were monitored for evidence of fungal infections. Baseline characteristics of the two groups were similar. Failure of prophylaxis occurred in 29 (19%) of the itraconazole recipients and 42 (29%) of the placebo recipients (P = .004; log-rank test). There were 6 invasive fungal infections in the itraconazole group (4, histoplasmosis; 1, cryptococcosis; 1, aspergillosis) and 19 in the placebo group (10, histoplasmosis; 8, cryptococcosis; 1, aspergillosis) (P = .0007; log-rank test). Itraconazole significantly delayed time to onset of histoplasmosis (P = .03; log-rank test) and cryptococcosis (P = .0005; log-rank test). Prophylaxis failure due to recurrent or refractory mucosal candidiasis occurred with similar frequency in the two groups (itraconazole, 15%; placebo, 16%). A survival benefit was not demonstrated. Itraconazole generally was well tolerated. Primary prophylaxis with itraconazole capsules prevents histoplasmosis and cryptococcosis in patients with HIV infection.

Low-dose methotrexate sodium therapy used for nonmalignant disease has been associated with a variety of opportunistic infections with pathogens occurring in patients with defective cellular immunity. This article describes the unusual development of disseminated histoplasmosis as a probable complication of immunosuppression resulting from use of methotrexate.We report the cases of three patients in whom disseminated histoplasmosis developed while receiving low-dose methotrexate therapy for psoriasis. Disease manifestations were unusually severe in two of the three patients. All three cases were disseminated, and two cases resulted in illnesses requiring intensive medical treatment. Each patient responded appropriately to antifungal treatment, although one patient has required long-term suppressive treatment because of persistent Histoplasma antigenuria. These cases illustrate the risk for opportunistic fungal infections in patients receiving low-dose methotrexate therapy for nonmalignant diseases.Histoplasma should be added to the list of pathogens to be suspected in patients receiving such therapy.

Diabetic patients, as a consequence of various neurologic, vascular, and metabolic perturbations, are at high risk for developing infections of the soft tissue and bones of the feet. The microbial etiology of soft tissue in infections is best determined by cultures of a tissue curetting or aspiration, rather than a swab. Aerobic gram-positive cocci are the major pathogens in diabetic foot infections; these may be the sole isolate(s) in acute uncomplicated infections, but they are usually accompanied by aerobic gram-negative bacilli or anaerobes in chronic or previously treated infections. Carefully selected patients with mild infections can be treated as outpatients with oral antibiotics, but others require hospitalization and broad-spectrum parenteral antibiotics. Bone infections are frequently diagnosed on the basis of roentgenographs and nuclear medicine scans, but these methods are often inaccurate, and bone cultures should be obtained whenever possible.

There are many imaging procedures for diagnosing osteomyelitis, each with unique strengths and weaknesses. Plain radiographs are inexpensive and can be very accurate but may provide a delayed diagnosis. Computed tomography and magnetic resonance imaging are both excellent at differentiating soft tissue infection from osteomyelitis. Computed tomography, magnetic resonance imaging, and bone scans are accurate diagnostic tools for use when the bone has not be violated by surgery, trauma, or other structural alterations. When such changes are present, an Indium-111 leukocyte or Indium-111 polyclonal antibody study may be necessary for accurate diagnosis.

We have evaluated serological tests for the diagnosis of Staphylococcus aureus osteomyelitis. Antiteichoic acid antibodies were elevated in 17 of 23 patients with acute and 16 of 46 with chronic S. aureus osteomyelitis but in none of 33 patients infected with other gram-positive or gram-negative bacteria. Immunoglobulin G antibodies to S. aureus were elevated in 12 of 23 patients with acute and 22 of 47 with chronic S. aureus osteomyelitis, in 2 of 12 infected with other gram-positive bacteria, and in 4 of 21 with other gram-negative bacteria. Assays for S. aureus antibodies may be useful for identifying patients with S. aureus bacteremia complicated by metastatic sites of infection in bone and for identifying the etiological agents in patients with negative or mixed cultures or from whom cultures are not readily available. Prospective studies are needed to test these hypotheses.

Rheumatologic manifestations were noted in 24 (6.3%) of 381 patients with symptomatic histoplasmosis who were seen during a recent epidemic in Indianapolis. Typically, these patients had rapidly additive, rather than migratory, arthritis or arthralgia, which was symmetric in 50%. Ten patients had oligo- or monarticular disease. Knees, ankles, wrists, and small joints of the hand were the most common sites affected. Eleven patients had erythema nodosum. The rheumatologic manifestations were usually mild and, in all but 2 patients, resolved without treatment or with a brief course of nonsteroidal antiinflammatory drugs. The joint disease in patients with erythema nodosum was essentially the same as that seen in patients who did not develop skin lesions. However, those without erythema nodosum more frequently exhibited systemic features, e.g., chills, fever, anemia, and elevated erythrocyte sedimentation rates. Rheumatologic complaints led 16 of the patients in this series (67%) to seek medical attention, and in 3 patients they constituted the sole presenting complaint.

Four monoclonal antibodies (MAbs) were produced by immunizing mice with a disrupted yeast cell homogenate of Histoplasma capsulatum. MAbs 1 and 2 reacted only with the yeast cell antigens of H. capsulatum and Blastomyces dermatitidis, whereas MAbs 3 and 4 showed broader cross-reactivity. MAb 3 cross-reacted with B. dermatitidis, Paracoccidioides brasiliensis, Sporothrix schenckii, and Candida albicans, and MAb 4 cross-reacted with B. dermatitidis, C. albicans, Coccidioides immitis, Aspergillus fumigatus, and Mycobacterium tuberculosis. All four MAbs exhibited unique specificity when reacted with three different strains of H. capsulatum (G217B, A811, and P-IN). MAb 1 belonged to the IgG2b subclass, MAb 3 belonged to the IgG1 subclass, and MAbs 2 and 4 belonged to the IgG3 subclass. MAbs 1, 2, and 3 formed bands in the Western immunoblot assay; the two dominant distinct bands had apparent molecular masses of 72 and 62 kilodaltons.

Specific antibodies have previously been found to impair detection of staphylococcal antigen by solid-phase radioimmunoassay. The inhibitory effect of heat-labile serum factors on the detection of antigen is now described. Heating of serum at 56 C for 30 min prior to addition of antigens of Pseudomonas aeruginosa or Staphylococcus aureus improved sensitivity by eight- to 32-fold. Heating was less effective when performed after addition of antigen. Treatment with zymosan reduced the inhibitory effect of serum, although less effectively than did preheating. Antigen in buffer was detected with 16 times less sensitivity in antibody-coated tubes exposed to fresh serum than in tubes exposed to heated serum. These findings suggest that complement factors can interact with antibody in coated tubes and at least some antigens and thereby inhibit detection of antigen. The finding that heat treatment improved the sensitivity of Ausria II -125 (Abbott Laboratories, North Chicago, Illinois) for hepatitis B surface antigen is of potential immediate clinical applicability.

We have reviewed the three-phase bone scans, radiographs, and histologic findings of 39 diabetic patients with serious foot problems. The sensitivity and specificity of bone scans were 83% and 75%, respectively, for osteomyelitis of the small bones of the foot. The positive and negative predictive values were 87% and 69%, respectively. The radiographs were less sensitive (62%) and less specific (69%), with predictive values of 80% (positive) and 47% (negative).

Alpha- or beta-acetylglucosamine are major antigen determinants of ribitol teichoic acids of the cell walls of coagulase-positive staphylococci. Teichoic acid antibodies have been detected by quantitative immunoprecipitation methods, agar-gel diffusion, counterimmunoelectrophoresis, crossed immunoelectrophoresis, radioimmunoassay and enzyme-linked immunosorbent assay. Almost all adults have detectable antibodies if a sufficiently sensitive method is used. Elevated concentrations of teichoic acid antibodies result from a recent staphylococcal disease such as endocarditis, bacteremia with metastatic foci of abscesses in which drainage and/or antibiotic therapy is delayed, but increases in teichoic acid antibodies are infrequent in transient staphylococcal bacteremia such as from infected intravascular cannulae or abscesses in patients who are treated early. Detection of high concentrations of teichoic acid antibodies may allow a specific bacteriological diagnosis earlier than cultures, when cultures are negative as in partially treated endocarditis, and when cultures are difficult to obtain or evaluate such as deep seated abscesses, drainage from osteomyelitis or pneumonias. In addition, elevated concentrations of teichoic acid antibodies in patients with staphylococcal bacteremia are strong presumptive evidence for endocarditis, metastatic foci, or abscesses.

The purposes of this study were to determine whether antigen is excreted by patients with Legionnaires disease early enough after the onset of symptoms to be useful for making therapeutic decisions and whether antigen excretion ends when successful treatment is concluded. Specific antigen was detected in the urine of 14 (88%) of 16 patients with Legionnaires disease during days 1 to 3 of symptoms, 33 (80%) of 41 patients during days 4 to 7, 25 (89%) of 28 patients during days 8 to 14, and 11 of 11 patients after day 14, by solid-phase immunoassays for serogroup 1 Legionella pneumophila antigen. Antigen excretion persisted for 42 days or longer after the onset of treatment in at least 15 patients. The longest documented duration of excretion was 326 days. We conclude that antigen can be detected approximately as often early after symptoms begin as later, allowing meaningful therapeutic decisions to be made, but that prolonged antigen excretion may negate the diagnostic value of urinary antigen detection for relapsing or recurrent L. pneumophila pneumonia.

An enzyme-linked immunosorbent assay was developed to detect urinary antigen excreted by patients with Legionnaires' disease. Of 47 patients tested, antigen was detected in 39. Of these 39 specimens, 35 gave clearly positive results by visual analysis; four others required spectrophotometric verification of positive results. Antigen was not detected in any of 178 urine specimens from patients with other pulmonary, bacteremic or urinary tract infections after a quick and simple confirmatory test. The assay required more time to perform than a previously described radioimmunoassay but was of equivalent sensitivity and specificity and did not require expensive equipment or contract with radioactive reagents. We conclude that enzyme-linked immunosorbent assay is a rapid, sensitive and specific means for rapidly diagnosing legionnaires' disease that can be performed in clinical laboratories unwilling or unable to use radioisotopes.

A 41-year-old man was admitted for evaluation of hemoptysis, dysphagia, and pleuritic chest pain associated with a mediastinal mass. Esophagography demonstrated a fistula between the mass and the esophagus. Results of histoplasmosis complement fixation serologic testing suggested an active infection. A methenamine silver stain of a lymph node obtained at mediastinoscopy revealed Histoplasmosis capsulatum. The patient was successfully treated with amphotericin B. This is believed to be the first reported case of an esophageal fistula as a complication of mediastinal histoplasmosis successfully treated with amphotericin B.

Three cases of acute histoplasmosis demonstrated, in addition to the usual serologic findings, strongly positive precipitins against farmer's lung antigens. Twelve additional serums from patients with acute histoplasmosis were subsequently studied. Forty percent of these patients demonstrated positive precipitins against organic dust antigens.

The mating type distribution among the 28 Histoplasma capsulatum isolates obtained from the histoplasmosis outbreaks which occurred in Indianapolis in 1978-1979 and 1980-1981 was studied. The overall ratio of + and - types was 1:2.5. The isolates from disseminated patients showed a 1(+):1(-) ratio while the isolates from non-disseminated pulmonary cases showed a 1(+):4(-) ratio. The frequency of the + type in these outbreaks was three times higher than that of the previous study. This was due to an unusually high prevalence of the + type among the patients with disseminated histoplasmosis.

Radioimmunoassays for IgM and IgG histoplasmal antibodies were developed and proved to be specific for their respective immunoglobulin classes, sensitive, and reproducible. Elevated IgM antibodies were detected in 59.8% of patients with histoplasmosis and 7.9% of control subjects. Elevated IgG antibodies occurred in 80.4% of patients with histoplasmosis but in only 12.9% of control subjects. Radioimmunoassay was nearly twice as sensitive as complement fixation for identifying patients with mild, presumably asymptomatic, infection. Of 13 patients with serologic follow-up at least 1 yr later, elevated IgM antibodies cleared, whereas IgG antibodies persisted in 7. In an epidemiologic investigation of a recurrent histoplasmosis outbreak, only the radioimmunoassay was able to prove the hypothesis that construction for a swimming complex was the source of exposure. These assays promise to be useful for clinical and epidemiologic investigations.

Piperacillin sodium, a new penicillin with remarkable in vitro activity against Pseudomonas aeruginosa and other Gram-negative bacilli, and gentamicin sulfate were compared with carbenicillin disodium and gentamicin in a prospective, randomized, double-blind comparison for treating serious Gram-negative infections. Of the 32 patients whose courses were "evaluable" for efficacy, 12 of 14 who received piperacillin and gentamicin and 13 of 18 who received carbenicillin and gentamicin had favorable outcomes. Of the 99 patients whose courses were evaluable for toxicity, nine of 51 recipients of piperacillin and gentamicin and 15 of 48 recipients of carbenicillin and gentamicin suffered clinical reactions possibly, probably, or definitely related to the penicillin. No statistically significant differences were found in the two groups in the frequencies of biochemical abnormalities, including hypokalemia, that occurred in 19 or 44 recipients of piperacillin and gentamicin and 16 of 45 recipients of carbenicillin and gentamicin. Thus, this study did not prove differences in efficacy of toxicity for piperacillin and gentamicin plus carbenicillin and gentamicin for serious Gram-negative infections.

Nine previously healthy children were seen with unique, and in several instances, unreported manifestations of acute histoplasmosis. Presenting manifestations included: obstructive airway disease; subacute parotitis; unilateral cervical lymphadenopathy; anterior mediastinal mass-simulating neoplasm; immune hemolytic anemia; a cutaneous lesion with regional lymphadenopathy; mediastinal mass and pericardial effusion; pulmonary infarction; and a symptom complex of cervical lymphadenopathy, CSF pleocytosis, arthritis, and interstitial nephritis. In eight children histoplasmosis was not initially considered, and the correct diagnosis was made only after complex, and sometimes invasive, diagnostic evaluation and considerable delay. All patients recovered fully without antifungal therapy. Reports of uncontrolled trials of new antifungal agents for treatment of histoplasmosis in immunocompetent hosts should be cautiously evaluated.

A radioimmunoassay (RIA) for human IgG antibodies to Staphylococcus epidermidis was compared with an agar-gel-diffusion assay in patients with a variety of infections. The RIA was sensitive and reproducible and discriminated between endocarditis and uncomplicated bacteremias due to coagulase-negative staphylococci. Anti-S epidermidis antibodies by RIA were elevated in 16 (89%) of 18 patients with coagulase-negative staphylococcal endocarditis but in none of 28 patients with uncomplicated bacteremia (n = 18) or with blood culture contaminated with these organisms (n = 10). Cross-reacting IgG antibodies to S epidermidis antigens were also detected by RIA in 13 (76%) of 17 patients with Staphylococcus aureus endocarditis but in none of 17 patients with nonvalvular S aureus bacteremias and in none of 25 patients with endocarditis or bacteremia caused by other pathogens. Agar-gel-diffusion assay was less sensitive than RIA for detecting coagulase-negative staphylococcal endocarditis, being positive in nine (50%) of 18 such patients. This RIA may be useful in distinguishing patients with endocarditis from those with nonvalvular staphylococcemias or blood culture contamination.

Histoplasmosis is a respiratory fungal infection with significant morbidity and mortality, and also has been recently recognized, with increasing frequency, in patients with acquired immunodeficiency syndrome (AIDS). It is caused by Histoplasma capsulatum - a dimorphic fungus which exists in the mycelial form in nature and in the yeast form in susceptible hosts. At least, 40 million human infections with Histoplasma have been recognized in the USA and this number is increasing annually by approximately 500,000 new cases (1, 4). Histoplasmosis has been reported from at least 60 countries and appears to have a circumglobal distribution (7).

During 2 recent epidemics of histoplasmosis in Indianapolis, 7 patients with hilar adenopathy and joint complaints were identified who were initially considered to have sarcoidosis, but in whom histoplasmosis was ultimately diagnosed on the basis of a positive culture for Histoplasma capsulatum or serologic studies. Articular features were the sole presenting complaints in 3 of these patients. All had arthralgias, which were generalized or confined to the lower extremities and were additive rather than migratory. Only 1 patient had joint swelling. Two had erythema nodosum. In all but 1 patient, the articular symptoms resolved rapidly and completely with minimal therapy. The data emphasize that sarcoidosis is a diagnosis of exclusion and that granulomatous infectious diseases must be excluded in patients with hilar adenopathy and joint disease.

Histoplasmosis is a fungus disease of nearly worldwide distribution. Because of its wide distribution and tendency to be endemic near large cities, it is the most common systemic mycosis in the United States, with an estimated 500,000 new infections per year. Although millions of persons in the United States have been infected with this fungus, few show signs of disease. Histoplasmosis has emerged as an important opportunistic infection in immunocompromised patients, including those with AIDS. This review of histoplasmosis builds upon basic descriptions found in standard texts, incorporating important recent observations.

We developed a latex agglutination test to detect antigen(s) of serogroup 1 Legionella pneumophila in urine and evaluated its ability to diagnose legionnaires' disease. Antigen was detected in 46, or 70%, of 66 patients with serogroup 1 legionnaires' disease but in none of 51 patients with various bacteremic infections nor 60 with urinary tract infections. One of 50 patients with other pulmonary infections was antigen-positive, an immunosuppressed patient with Pneumocystis carinii infection. Seven other patients infected with P. carinii were negative. When compared with radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) using serial dilutions of a single antigen-containing urine, latex agglutination was 16-fold less sensitive. However, 82% of RIA- or ELISA-positive specimens were positive by latex agglutination. Latex agglutination is simpler and more rapid than ELISA or RIA, and it should prove valuable in situations where ELISA or RIA are unavailable or unaffordable.