Suppressor thymus-derived lymphocytes in fungal infection.

Thymus-derived lymphocyte (T-cell) function, as determined in vivo by cutaneous reactivity to several antigens and in vitro by responsiveness to mitogens and antigens, was assessed in 14 patients infected with a variety of fungal organisms. While all patients manifested a normal frequency of peripheral blood T cells, only seven patients reacted to at least one of the antigens used for cutaneous testing and demonstrated normal in vitro T proliferative responses. Three patients exhibited cutaneous anergy but normal in vitro T-cell reactivity while four patients demonstrated persistent anergy and marked in vitro T-cell hyporeactivity which was independent of activity of infection, concurrent medication, or any associated disorders. The marked diminution of in vitro T-cell reactivity noted for these later four patients was not due to a deletion of antigen- or mitogen-reactive cells. Thus, patients' cells which had been initially cultured for 7 days without any mitogenic or antigenic stimulus and which were subsequently washed and recultured with phytohemagglutinin, concanavalin A, or histoplasmin demonstrated a marked increase in their responsiveness. Moreover, this reactivity noted for recultured cells could be suppressed by a nonphagocytic, nonadherent, nonimmunoglobulin-bearing, sheep red blood cell rosette-forming population of cells isolated from the fresh peripheral blood mononuclear cells of the same patient. While these "regulator" T cells were capable of suppressing T-proliferative responses to antigens and mitogens, they did not diminish pokeweed mitogen-induced immunoglobulin synthesis by normal bone marrow-derived lymphocytes. Patients in whom suppressor "T" cells were found were at risk for relapsing, disseminated fungal infection.

Treatment of fungal infections with flucytosine.

Treatment with flucytosine of 20 patients with fungal infections gave favorable results in four patients with crytococcal infections, two of four patients with disseminated candidiasis, eight of ten patients with urinary tract infections due to Candida albicans and Torulopsis glabrata, and tow of three patients with miscellaneous infections due to Calbicans. Two patients with crytococcal meningitis and altered host resistance and one patient with an aorto femoral graft infection due to C albicans were treated with flucytosine and smphotericin B. The infection was eradicated in one of the patients with meningitis, and cultures from an infected arterial graft became negative. Adverse side effects of flucytosine included mild leukopenia and thrombocytopenia, a transient increase in alkaline phosphatase and glutamic oxaloacetic transaminase, and nausea and diarrhea.

Idiopathic late-onset immunoglobulin deficiency with functional T-cell deficiency.

The common features in our two patients were late onset of infections that are known to complicate both T-cell and B-cell deficiencies, decreased numbers of circulating B-cells with low serum immunoglobulin levels, and normal numbers of circulating T-cells, which were, however, defective in the response to delayed hypersensitivity skin test antigens and to mitogens in vitro. The composite of clinical and immunologic aberrations is consistent with the presence of an immune deficiency involving the B-cell system quantitatively and the T-cell system qualitatively.

Idiopathic late-onset immunoglobulin deficiency. Clinical observations in 50 patients.

Fifty patients with late-onset idiopathic immunoglobulin deficiency were studied and the frequency of various clinical associations and complications was observed. Men and women were equally affected, although the age at onset in men peaked in the third decade whereas it was more uniformly distributed in women. Sinobronchopulmonary infections were common and were caused by Haemophilus influenzae. Diplococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus: bronchiectasis occurred in 28 per cent. Thirty patients (60 per cent) had diarrhea, which was often associated with steatorrhea, giardiasis, achlorhydria, abnormal Schilling tests and morphologic abnormalities on small bowel biopsy specimens, including nodular lymphoid hyperplasia; three patients had pernicious anemia. In the 20 patients without diarrhea these abnormalities were not observed except for giardiasis in one patient and achlorhydria in two patients. Cholelithiasis occurred in both groups in about a third of the patients tested. A high degree of susceptibility to neoplasia was noted. Thyroid abnormalities, including primary hypothyroidism and Graves' disease, were observed in six patients. Additional occasional findings were vitiligo, keratoconjunctivitis sicca and arthritis. Splenomegaly occurred in 14 (28 per cent) patients. The percentage of B lymphocytes in the blood was determined in 10 patients; it was normal or slightly decreased in eight patients and low in two patients.

Infections due to group C streptococci in man.

Although a common cause of infection in animals, group C streptococci are rarely noted to be pathogenic in man. A total of 150,000 blood cultures obtained at the Mayo Clinic from 1968 to 1977 revealed group C streptococci in only eight patients. Acute bacterial endocarditis, meningitis, pheumonia, cellulitis and bacteremia due to group C streptococci are described in a host who had undergone immunosuppression (immunosuppressed host), and the relatively few cases previously reported are reviewed. Although severe, these infections may respond favorably to penicillin therapy. Endocarditis caused by group D streptococci is acute and destructive, and associated with early cardiac decompensation. The manifestations of cellulitis and pneumonia are similar to those when group A streptococci are causative organisms. Meningitis due to group C streptococci is acute and severe, and responds slowly to antimicrobial therapy. Colonization also occurs.

Selective bowel decontamination to decrease gram-negative aerobic bacterial and Candida colonization and prevent infection after orthotopic liver transplantation.

Gram-negative bacterial and fungal infections are a major cause of morbidity and mortality following liver transplantation. We therefore used selective bowel decontamination (SBD) to eliminate the endogenous source of gram-negative aerobic bacteria and Candida pathogens in an attempt to reduce the high incidence of infection related to these organisms. Thirty consecutive patients undergoing liver transplantation were treated with SBD starting 3 days prior to donor search and continuing for 21 days postliver transplantation. Selective bowel decontamination consisted of administering nonabsorbable antibiotics (Polymixin E, gentamicin, Nystatin) and a low bacterial diet. Surveillance cultures of the throat and rectum were obtained to monitor efficacy of selective bowel decontamination. In addition, in the posttransplant period, tracheal, wound, blood, and bile cultures were obtained to screen for gram-negative bacterial and Candida colonization and infection. Our baseline surveillance culture revealed that 29/30 (97%) of recipients were colonized with gram-negative aerobic bacteria and 16/30 (53%) with Candida. Three days after selective bowel decontamination was started, 26/30 (87%) were free of gram-negative bacteria, and 100% were free of Candida colonization of the gastrointestinal tract. There was a similar reduction in the oropharyngeal gram-negative aerobic bacteria and Candida colonization. In the first 30 days following liver transplantation, gram-negative infections were not diagnosed in any of our patients. Following discontinuation of SBD, recolonization of the gastrointestinal tract with gram-negative aerobic bacteria and Candida occurred within 5 days in 26/28 (90%) and 11/28 (35%), respectively. Our study suggests that prophylactive administration of nonabsorbable antibiotics will markedly reduce gram-negative aerobic bacterial and Candida colonization and appears to reduce the high incidence of infection related to these organisms in the early posttransplant period.

Efficacy of ganciclovir in liver and kidney transplant recipients with severe cytomegalovirus infection.

Twelve liver and 5 kidney transplant recipients with severe cytomegalovirus infection were treated with Ganciclovir (7.5 mg/kg/day, intravenously). Ten were evaluable (compatible clinical picture, organ involvement shown histopathologically or by culture, viremia, and absence of concomitant infection). All 17 patients were studied for adverse drug side effects. A total of 9 evaluable patients survived the infection; 1 died during treatment due to infection or drug toxicity. A death 19 days after completion of treatment was due to unrelated causes. Patients became afebrile after 2-9 days (mean, 5.3 days) of treatment. Liver function improved, pulmonary infiltrates cleared, and hypoxemia reversed during therapy. Viremia ceased during therapy in 9 patients; asymptomatic viruria persisted or recurred in 6 of 7 patients studied. No relapses occurred during follow-up (7-17 months; mean, 13 months). Transient neutropenia and thrombocytopenia occurred in 3 and 1 patients, respectively. Ganciclovir appears promising for treatment of severe CMV infection in patients with kidney or liver transplants.

The clinical manifestations of infective endocarditis.

Frequently, the presence of endocarditis is disguised. The emphasis of this description of the clinical manifestations of endocarditis is on the various modes of presentation, rather than on individual symptoms and signs. Endocarditis can manifest with cardiac, pulmonary, ophthalmic, central nervous system, renal, orthopedic, phthisic, and peripheral vascular disorders. The following clinical data are most useful in helping to establish a diagnosis of endocarditis: a history of fever, anorexia, weight loss, and back pain; a search for petechiae; splenomegaly; and daily examination, especially cardiac auscultation and funduscopic examination, of those patients in whom incomplete evidence exists at admission. The most helpful laboratory tests include those revealing anemia, increased erythrocyte sedimentation rate, abnormalities in the urine compatible with nephritis, or embolization. In patients who have not received antimicrobial therapy just before the diagnostic workup, one set of three blood cultures is sufficient to isolate the offending microorganism in about 95% of cases.

Antifungal agents used for deep-seated mycotic infections.

The main emphasis in this paper is on the broad-spectrum antifungal agent amphotericin B and the narrow-spectrum agent flucytosine. Amphotericin B remains the cornerstone of antifungal therapy. For the treatment of cryptococcal meningitis, the current recommendation is for the combined use of amphotericin B and flucytosine. 2-Hydrostilbamidine is used only in indolent cases of blastomycosis; this condition is usually treated with amphotericin B. A number of newer agents and combinations of drugs also warrant mention, but clinical experience is limited and these agents or combinations have not been approved for clinical use. Not all patients from whom fungal agents are isolated require treatment and the extent of the fungal infection should be determined when possible for evaluation of the need for treatment.

General principles of antimicrobial therapy.

In the initial therapy of life-threatening infections in which a bacterial cause is suspected, the emphasis should be on broad antibiotic coverage in contrast to definitive therapy, which is dependent on microbial isolation and, when indicated, in vitro susceptibility tests. In severe infections, antimicrobial agents should be given parenterally, at least initially. The need for optimal dosage is emphasized. This is particularly important when aminoglycosides are administered, for there is a tendency to use inadequate dosage because of concern for potential side effects with these agents. The problems leading to recurrence and persistence of fever during antimicrobial therapy include failure to diagnose and drain abscesses, superinfection, drug fever, and clinical or microbiologic errors. Combinations of antibiotics are indicated in severe infections in severe infections due to Pseudomonas aeruginosa, enterococcal group D streptococci, Klebsiella pneumoniae, and Cryptococcus neoformans. Laboratory aid for the selection of antimicrobial therapy can be of great value but need not always be done, because certain microorganisms have stable, predictable susceptibilities, for example, Streptococcus pneumoniae and Streptococcus pyogenes. Cautious conservatism is advocated with regard to the use of new antimicrobial agents.

Antiviral agents.

Only a few agents with antiviral activity are available for regular clinical use. Amantadine hydrochloride is effective in the prophylaxis of influenza A2. Idoxuridine and adenine arabinoside have found application as topical agents in the treatment of herpes simplex keratitis. Adenine arabinoside is also under investigation in the treatment of disseminated infections due to herpes zoster and herpes simplex. Ribavirin, an agent with a wide spectrum of activity in vitro, has not fulfilled expectations in clinical trials. Because of the near eradication of smallpox, methisazone has become less important as a prophylactic agent in smallpox.

Vancomycin.

Vancomycin is a narrow-spectrum bactericidal antibiotic used primarily for treatment of serious staphylococcal infections. It is the alternative therapy of choice when the penicillins and cephalosporins cannot be used. Vancomycin is also used in (1) methicillin-resistant Staphylococcus aureus infections; (2) streptococcal endocarditis in conjunction with an aminoglycoside in patients intolerant of penicillin or ampicillin; (3) infections, including those involving prosthetic devices, caused by gram-positive organisms with multiple antibiotic resistance; (4) antibiotic-induced enterocolitis caused by Clostridium difficile; and (5) prophylaxis for endocarditis in patients who are at risk and cannot tolerate a penicillin, cephalosporin, or erythromycin. The major toxic effect associated with the use of vancomycin is ototoxicity, which may develop when serum levels exceed 30 micrograms/ml.

General principles of antimicrobial therapy.

Use of antimicrobial agents must be tailored to the individual patient, site of infection, and etiologic organism. The choice of drug should be based on efficacy, safety, low toxicity, and acceptable cost. Empiric therapy should be broad enough to cover the pathogens that are suspected of causing the infection, based on the site of infection and the type of host. Definitive therapy may differ from initial therapy and should be started as soon as specific laboratory and clinical data are available. Cautious conservatism is advocated with regard to the use of new antimicrobial agents. The effects of the agents on the microbial ecology and hospital environment should be considered. Judicious use is necessary to prevent antimicrobial pollution.

Antifungal agents used for deep-seated mycotic infections.

The main antifungal agents used for deep-seated mycotic infections are the broad-spectrum antifungal drug amphotericin B, the narrow-spectrum agent flucytosine, and the newer broad-spectrum agents ketoconazole, miconazole, and itraconazole. Amphotericin B remains the cornerstone of antifungal therapy. For the treatment of cryptococcal meningitis, the current recommendation is for the combined use of amphotericin B and flucytosine. Published clinical experience with the newer agents is limited. Not all patients from whom fungal agents have been isolated require treatment; the extent of the fungal infection should be determined, when possible, for evaluation of the need for treatment.

Antiviral agents.

Amantadine is well established as the preferred antiviral agent for the prophylaxis of influenza A and may also be beneficial therapeutically when used early in the course of the disease. Idoxuridine is applicable only in the treatment of herpetic keratitis. Currently, acyclovir is the most effective agent for the treatment of herpes simplex and varicella-zoster virus infections. Ribavirin has recently been released for use in aerosol form for severe respiratory syncytial virus infections that occur in infants and young children. Vidarabine, which previously was the drug of choice in the treatment of severe herpetic infections, has now been replaced by the more effective acyclovir. Ganciclovir, an experimental agent, has shown promise against cytomegalovirus infections in patients who have undergone kidney or liver transplantation, but its effects are only temporary in patients who have undergone bone marrow transplantation and patients with acquired immunodeficiency syndrome (AIDS) who have cytomegalovirus infections.

Antiviral agents.

Only a few agents with antiviral activity are available for routine clinical use. Amantadine hydrochloride is effective in the prophylaxis of influenza A. In addition, accumulated evidence shows that amantadine has some therapeutic effect when used early in the course of an influenza A infection. Idoxuridine and adenine arabinoside have found application as topical agents in the treatment of herpes simplex keratitis. Adenine arabinoside has also been approved for the treatment of disseminated infections due to herpes zoster and herpes simplex. Acyclovir sodium has been approved as a topical agent in the treatment of limited mucocutaneous herpes simplex viral infections in immunosuppressed patients and of initial episodes of genital herpes simplex infections in patients with normal immunity. Ribavirin, an experimental agent with a wide spectrum of activity in vitro, has not fulfilled expectations in clinical trials. Because of the eradication of smallpox, methisazone has become obsolete as a prophylactic agent in smallpox.

Antifungal agents used for deep-seated mycotic infections.

The main antifungal agents used for deep-seated mycotic infections are the broad-spectrum antifungal drug amphotericin B, the narrow-spectrum agent flucytosine, and the newer broad-spectrum agents miconazole and ketoconazole. Amphotericin B remains the cornerstone of antifungal therapy. For the treatment of cryptococcal meningitis, the current recommendation is for the combined use of amphotericin B and flucytosine. 2-Hydroxystilbamidine is used only in indolent cases of blastomycosis; however, this condition is usually treated with amphotericin B. Clinical experience with the newer agents is limited. Not all patients from whom fungal agents have been isolated require treatment; the extent of the fungal infection should be determined, when possible, for evaluation of the need for treatment.

General principles of antimicrobial therapy.

The initial treatment of suspected life-threatening bacterial infection should be sufficiently broad to cover the likely causative agents. Definitive therapy depends on microbial isolation, identification, and, when indicated, in vitro susceptibility tests. Parenteral therapy should be used, at least initially, and optimal doses are necessary. The dose is particularly important when aminoglycosides are administered; a concern for potential side effects with use of these agents had engendered a tendency to administer inadequate doses. The problems leading to recurrence or persistence of fever during antimicrobial therapy include failure to diagnose and drain abscesses, superinfection, drug fever, and clinical or microbiologic errors. Combinations of antibiotics are indicated in severe infections due to Pseudomonas aeruginosa, enterococcal group D streptococci, and Cryptococcus neoformans. Laboratory assistance for the selection of antimicrobial therapy can be valuable but is not always necessary because certain microorganisms--for example, Streptococcus pneumoniae and S. pyogenes--have stable, predictable susceptibilities. Cautious conservatism is advocated with regard to the use of new antimicrobial agents.

Vancomycin.

Vancomycin is a narrow-spectrum bactericidal antistaphylococcal antibiotic that was introduced in 1956 because of its efficacy against resistant penicillinase-producing staphylococci. It was effective for serious staphylococcal infections for which no satisfactory alternative to penicillin G was available at the time. When methicillin and the other semisynthetic penicillins and the cephalosporins were introduced, the role of vancomycin was relegated to the alternative therapy of choice when the penicillins and the cephalosporins could not be used. In the future, vancomycin may be used more frequently in (1) methicillin-resistant Staphylococcus aureus infections, (2) streptococcal endocarditis in conjunction with an aminoglycoside in patients intolerant to penicillin or ampicillin, (3) infections associated with prosthetic devices caused by organisms with multiple antibiotic resistance, and (4) antibiotic-induced enterocolitis associated with Clostridium difficile.

Idiopathic granulomatosis manifesting as fever of unknown origin.

Twenty patients with fever of unknown origin were found to have idiopathic granulomatosis of the liver, lymph nodes, spleen, or bone marrow. At the time of initial examination, these patients had persistent or recurrent fever and pronounced constitutional symptoms but few physical findings. The most common laboratory abnormalities were increased erythrocyte sedimentation rate in 18, abnormal results of liver function tests in 12, anemia in 11, and hypergammaglobulinemia in 10. Of the 20 patients, 14 required corticosteroids at the beginning of the illness for control of symptoms, especially fever. After 5 to 10 years of follow-up, an alternative diagnosis had been established in 5 of the 20 patients. Of the remaining 15 patients with fever and idiopathic granulomatosis, 6 are still receiving corticosteroids. Corticosteroid treatment did not result in progression or dissemination of an unrecognized infection. No clinical or laboratory abnormality helped to predict the need for long-term corticosteroid treatment.