Serial study of C-reactive protein during fungal esophagitis and enterocolitis.

C-reactive protein (CRP) responses were followed in weekly serum samples in the course of eight episodes of esophagitis (37 sera) and ten episodes of enterocolitis (45 sera) caused by Candida albicans in an equal number of patients with hematologic malignancies under antibacterial medication. During fungal esophagitis CRP was elevated, with peak values ranging from 73 to 380 mg/l (mean +/- SD: 170 +/- 104 mg/l). The same was true for fungal enterocolitis, with the peak values ranging from 54 to 225 mg/l (mean +/- SD: 146 +/- 56 mg/l). In both these conditions, antimycotic treatment was followed by clinical improvement, reduced or eliminated fungal growth and falling levels of CRP, occasionally down to the normal value (less than 6 mg/l). Thus, follow-up of CRP level is useful as an aid in the diagnosis of gastrointestinal candidosis and in evaluating its treatment.

Prospective study on humoral immune response induced by fungal infection in patients with hematologic malignancies.

To evaluate the immune response in an immunosuppressed population, antibodies against commercially available Candida albicans antigens were prospectively studied during 37 episodes of acute stomatitis caused by C. albicans and 36 episodes complicated by deep-seated mycoses in 62 adult patients with hematologic malignancies. During uncomplicated stomatitis in patients with acute leukemia, the mean peak IgM, IgG and IgA class enzyme-linked immunosorbent assay (ELISA) units differed significantly from the basic level preceding fungal infection. Mean time until peak values was 2.7-3.8 weeks after diagnosis of stomatitis. During systemic mycoses the antibody response was similar. Among patients with other hematologic malignancies, predominantly lymphomas, several were terminally ill and responded infrequently by antibody production. Similar results were given by Ouchterlony immunodiffusion and counterimmunoelectrophoresis. Thus, patients with acute leukemia showed an antibody response to fungal infection; the peak values, however, were somewhat delayed.

Follow-up of antibodies against single-stranded DNA in patients with haematological malignancies.

Antibodies against single-stranded DNA (ssDNA) were followed by enzyme-linked immunosorbent assay in weekly serum samples of 39 patients with acute myeloid leukaemia (AML), 11 with acute lymphatic leukaemia (ALL) and 26 with other haematological malignancies. Their frequency and mean level during the entire follow-up were higher than in sera of healthy blood donors. Patients with AML had the highest levels and prevalence of anti-ssDNA antibodies, i.e. overall frequencies of IgG class antibodies in patients with AML, ALL and other haematological malignancies were 97%, 82% and 58%, respectively. Antibodies of IgM class were less frequently found. Prevalence and levels of anti-ssDNA antibodies were already at least as high in newly diagnosed malignancies as later during the course of the disease. Following bacterial septicaemias, these antibodies were significantly low. No consistent correlations between levels of anti-Candida antibodies formed in response to fungal infections or concentrations of serum immunoglobulins and anti-ssDNA antibodies were found.

Levels of C-reactive protein in patients with hematologic malignancies.

The levels of C-reactive protein (CRP) were assayed in 282 serial sera of 70 patients with hematologic malignancies who were under antineoplastic medication, and surveyed with frequent blood cultures. The mean peak value of CRP in febrile patients with bacteriologically verified sepsis was 162 mg/l and differed significantly (p less than 0.001) from that (23 mg/l) of afebrile patients with negative blood cultures, but not from that (115 mg/l) of febrile patients without confirmed bacteremia. All the values in afebrile patients with negative blood cultures were less than 100 mg/l; 71% of their peak values were less than 40 mg/l. Thus the malignancy itself or its treatment did not considerably mount CRP response.

Susceptibility of fungi in mouthrinse specimens from patients with haematological malignancies.

Fungi isolated from mouthrinse specimens during episodes of acute pseudomembranous fungal stomatitis and deep-seated mycoses in patients with haematological malignancies were tested for susceptibility to seven antifungal agents. Topical treatment of stomatitis with clotrimazole or chlorhexidine did not induce any change in the susceptibility of oral Candida albicans. Treatment of deeper mycoses with 5-fluorocytosine, however, resulted in a significant increase in oral strains resistant to this agent. Of C. albicans strains isolated, 7% were resistant to 5-fluorocytosine greater than 32 micrograms/ml. One patient died of disseminated mycosis during treatment with this drug; the resistant C. albicans was isolated from the mouth, liver, spleen and kidneys. Strains of Torulopsis glabrata and C. krusei resistant to 5-fluorocytosine were also found in some patients. Organisms resistant to 5-fluorocytosine were generally sensitive to polyenes and imidazoles.

Broth dilution and disc diffusion methods in the susceptibility testing of pathogenic Candida albicans against four antimycotics.

Susceptibility of Candida albicans isolated from mouthrinse specimens during episodes of acute pseudomembranous candidiasis in patients with haematological malignancies was tested by the broth dilution and disc diffusion methods using 24 and 48 h of incubation. The time factor did not significantly affect the results with 5-fluorocytosine. With amphotericin B, prolonged incubation doubled the geometric mean MIC of C. albicans as well as the number of isolates with intermediate sensitivity. With the shorter incubation in the disc diffusion assay, few isolates showed lowered sensitivity to clotrimazole; at 48 h, however, this figure was as high as 54%. The yeasts were highly sensitive to ketoconazole at 24 h, whereas at 48 h the results were bizarre. At 24 h, correlations between disc diffusion and broth dilution methods were satisfactory, with clotrimazole and ketoconazole accounting for most of the discordancies. Accordingly, the disc diffusion results should be recorded at 24 h.

C-reactive protein response induced by fungal infections.

Serial determinations of C-reactive protein (CRP) were performed by single radial immunodiffusion in four groups of patients with fungal disease in order to determine its use as an aid to diagnosis. Elevated values (17-284 mg/l) of CRP were seen in 13 patients with fungal septicaemia before and/or within a few days after the first positive blood culture. C-reactive protein was not elevated in two patients with transient fungaemia. In 76 per cent (25/33) of deep-seated fungal infections in patients with malignant disorders of the blood CRP increased to 104-380 mg/l. In the remainder values of 36-92 mg/l were seen. In 37 per cent (19/51) of episodes of acute uncomplicated fungal stomatitis in patients with malignant disorders of the blood CRP rose to 110-320 mg/l. C-reactive protein was not found to be raised from the normal value (less than or equal to 6 mg/l) in 6 per cent of the episodes; in the rest, values below 100 mg/l were seen. CRP in 23 patients with acute fungal stomatitis but who were not immunocompromised remained normal. Thus, with regard to its ability to induce high (greater than 100 mg/l) CRP values, deep-seated fungal disease would seem to resemble bacterial rather than viral infection.

Antibodies against antigens of Candida albicans in patients with fungaemia and bacteraemia, studied by ELISA, precipitation, passive haemagglutination and immunofluorescence techniques.

Antibodies against commercially available antigens of Candida albicans were assayed in 54 sera from 24 patients with fungaemia and in 66 sera from 33 patients with bacteraemia. In patients with persistent fungaemia, antibody was found during the week after the fungus was first cultured from the blood, but peak titres did not usually occur until the end of the second week. A significant rise in titre in C. albicans infection was observed in 50% of paired sera tested by passive haemagglutination (PHA), indirect immunofluorescence (IF) and Ouchterlony immunodiffusion (ID). The same percentage was obtained by counterimmunoelectrophoresis (CIE) against candida metabolic antigens, whereas it was increased to 88% when somatic antigens were used. Enzyme-linked immunosorbent assay (ELISA) demonstrated a rise of titre in 25, 75 and 50% of sera in IgM, IgG and IgA assays, respectively. Sera from patients with transient fungaemia demonstrated persistent antibody titres. In paired sera from patients with bacteraemia, ID and CIE titres were low (greater than or equal to 4). There was an increase of candida antibodies in 0-9% of patients by ELISA, ID or CIE and in 18-21% by PHA or IF. Clinically significant fungaemia was most reliably differentiated serologically from bacteraemia by CIE S-antigen and ELISA IgG assays.

Enzyme-linked immunosorbent assay (ELISA) for IgM, IgG and IgA class antibodies against Candida albicans antigens: development and comparison with other methods.

An extract of Candida albicans was used as an antigen on microtitre plates in the enzyme-linked immunosorbent assay (ELISA) to measure IgM, IgG and IgA class antibodies in the sera of hospitalized patients. It was found that of these patient sera that reacted positively in Ouchterlony immunodiffusion (ID) when undiluted, 58% were also positive in the ELISA against the same antigen preparation. However, all the sera with an ID titre of 1:2 or higher were ELISA-positive, demonstrating especially IgG and IgA. Of the sera positive by counterimmunoelectrophoresis against somatic and metabolic antigens of C. albicans, 86% were positive by ELISA. Reactions in precipitin-negative sera, if they occurred, usually demonstrated IgM or IgA. The sera with high passive haemagglutination or indirect immunofluorescence titres against surface antigens of C. albicans were positive in the IgG and IgA assays, while approximately one third were positive in the IgM assay.

Oral mycoses and their treatment.

Mycoses of the mouth and nearby areas can be caused by both yeasts and filamentous fungi. They may appear either independently or as part of a systemic infection. It is typical of many mycoses that they occur as a consequence of local factors operating in the mouth, or in patients debilitated by severe diseases. Yeasts that are part of the normal microbial flora of man, among them especially Candida species, are the most frequent causative agents. Some tropical or semitropical infections may occur in Scandinavia and Finland, but they are rare. Local therapy with antimycotics is often effective in acute infections, whereas some chronic ones may make systemic administration necessary. Some of these infections are treated surgically.