Vee J. Gill

Cryptococcosis in the Acquired Immunodeficiency Syndrome

The clinical course and response to therapy of 27 patients with cryptococcosis and the acquired immunodeficiency syndrome were reviewed. Cryptococcosis was the initial manifestation of the syndrome in 7 patients, and the initial opportunistic infection in an additional 7. Meningitis was the commonest clinical feature (18 patients). Blood cultures and serum cryptococcal antigen were frequently positive. In patients with meningitis, leukocyte count, protein level, and glucose level in cerebrospinal fluid were frequently normal; cerebrospinal fluid India ink test (82%), culture (100%), and cryptococcal antigen (100%) were usually positive. Only 10 of 24 patients had no evidence of clinical activity of cryptococcal infection after completion of therapy; 6 of these 10 had relapses shown by clinical findings or at autopsy. Standard courses of amphotericin B alone or combined with flucytosine were ineffective. Cryptococcosis in patients with the syndrome is a debilitating disease that does not respond to conventional therapy; earlier diagnosis or long-term suppressive therapy may improve the prognosis.

CD4 Counts as Predictors of Opportunistic Pneumonias in Human Immunodeficiency Virus (HIV) Infection

STUDY OBJECTIVE To determine if circulating CD4+ lymphocyte counts are predictive of specific infectious or neoplastic processes causing pulmonary dysfunction. DESIGN Retrospective, consecutive sample study. SETTING Referral-based clinic and wards. PATIENTS We studied 100 patients infected with human immunodeficiency virus (HIV) who had had 119 episodes of pulmonary dysfunction within 60 days after CD4 lymphocyte determinations. MEASUREMENTS AND MAIN RESULTS Circulating CD4 counts were less than 0.200 X 10(9) cells/L (200 cells/mm3) before 46 of 49 episodes of pneumocystis pneumonia, 8 of 8 episodes of cytomegalovirus pneumonia, and 7 of 7 episodes and 19 of 21 episodes of infection with Cryptococcus neoformans and Mycobacterium avium-intracellulare, respectively. In contrast, circulating CD4 counts before episodes of nonspecific interstitial pneumonia were quite variable: Of 41 episodes, 11 occurred when CD4 counts were greater than 0.200 X 10(9) cells/L. The percent of circulating lymphocytes that were CD4+ had a predictive value equal to that of CD4 counts. Serum p24 antigen levels had no predictive value. CONCLUSIONS Pneumocystis pneumonia, cytomegalovirus pneumonia, and pulmonary infection caused by C. neoformans or M. avium-intracellulare are unlikely to occur in HIV-infected patients who have had a CD4 count above 0.200 to 0.250 X 10(9) cells/L (200 to 250 cells/mm3) or a CD4 percent above 20% to 25% in the 60 days before pulmonary evaluation. Patients infected with HIV who have a CD4 count below 0.200 X 10(9) cells/L (or less than 20% CD4 cells) are especially likely to benefit from antipneumocystis prophylaxis.

A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients with Neutropenia during Cancer Chemotherapy

BACKGROUND Among patients with fever and neutropenia during chemotherapy for cancer who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment. METHODS We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved. RESULTS A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patients inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07). CONCLUSIONS In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective.

Phase I Study of the Intravenous Administration of Attenuated Salmonella typhimurium to Patients With Metastatic Melanoma

PURPOSE A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I study of the intravenous infusion of VNP20009 to patients with metastatic cancer. PATIENTS AND METHODS In cohorts consisting of three to six patients, 24 patients with metastatic melanoma and one patient with metastatic renal cell carcinoma received 30-minute intravenous bolus infusions containing 10(6) to 10(9) cfu/m(2) of VNP20009. Patients were evaluated for dose-related toxicities, selective replication within tumors, and antitumor effects. RESULTS The maximum-tolerated dose was 3 x 10(8) cfu/m(2). Dose-limiting toxicity was observed in patients receiving 1 x 10(9) cfu/m(2), which included thrombocytopenia, anemia, persistent bacteremia, hyperbilirubinemia, diarrhea, vomiting, nausea, elevated alkaline phosphatase, and hypophosphatemia. VNP20009 induced a dose-related increase in the circulation of proinflammatory cytokines, such as interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, and IL-12. Focal tumor colonization was observed in two patients receiving 1 x 10(9) cfu/m(2) and in one patient receiving 3 x 10(8) cfu/m(2). None of the patients experienced objective tumor regression, including those patients with colonized tumors. CONCLUSION The VNP20009 strain of Salmonella typhimurium can be safely administered to patients, and at the highest tolerated dose, some tumor colonization was observed. No antitumor effects were seen, and additional studies are required to reduce dose-related toxicity and improve tumor localization.

Diagnosis of Pneumocystis carinii Pneumonia: Improved Detection in Sputum with Use of Monoclonal Antibodies

With the dramatic increase in the frequency of Pneumocystis carinii pneumonia associated with human immunodeficiency virus infection, there has been a need for more rapid and less invasive diagnostic techniques. Recent studies have shown that examination of induced sputum can establish the diagnosis of P. carinii pneumonia in about 55 percent of cases. To assess whether a recently developed indirect immunofluorescent stain using monoclonal antibodies was more sensitive than Giemsa or toluidine blue O stains in detecting P. carinii in sputum, we undertook two prospective studies. Of 63 patients at one institution from whom sputum specimens were obtained, 49 were ultimately given a diagnosis of P. carinii pneumonia, 46 of them by staining of sputum. The sensitivity of the three stains in detecting P. carinii was 45 of 49 (92 percent) for immunofluorescence; 37 of 49 (76 percent) for Diff-Quik (a Giemsa-type stain); and 39 of 49 (80 percent) for toluidine blue O. There were no false positive immunofluorescent stains. In a similar study of a series of 25 patients at another institution, a diagnosis of P. carinii pneumonia was made in 23 of 25 patients by staining of induced sputum. We conclude that examination of induced sputum is a rapid, sensitive, and inexpensive method for diagnosing P. carinii pneumonia and that indirect immunofluorescence is a practical and highly sensitive staining technique for establishing this diagnosis.

Intestinal Infections in Patients with the Acquired Immunodeficiency Syndrome (AIDS)Etiology and Response to Therapy

STUDY OBJECTIVE To determine the frequency of pathogenic gastrointestinal microorganisms in patients with the acquired immunodeficiency syndrome (AIDS) and diarrhea, and to determine if treatment for identifiable microorganisms improves symptoms. DESIGN Prospective, consecutive sample study. SETTING Referral-based clinic and wards, National Institutes of Health. PATIENTS Twenty of twenty-two consecutive homosexual males with AIDS and diarrhea, and 10 homosexual males with AIDS without diarrhea. INTERVENTIONS All patients had a complete physical examination; serial stool examinations for viral, bacterial, fungal, and protozoan pathogens; and esophagogastroduodenoscopy and colonoscopy to obtain duodenal fluid and mucosal tissue to analyze for enteric pathogens or histopathology. Patients with diarrhea had a malabsorption evaluation. Patients with treatable pathogenic microorganisms received standard antimicrobial therapy. MEASUREMENTS AND MAIN RESULTS The 20 patients with AIDS and diarrhea had greater weight loss, lower mean numbers of helper-inducer (OKT4) lymphocytes, and a higher incidence of extraintestinal opportunistic infections than the 10 patients without diarrhea. One or more enteric pathogen was identified in 17 of 20 patients (85%; 95% confidence interval [CI], 65% to 96%) with diarrhea. Only 1 patient without diarrhea was infected with an enteric pathogen. Nineteen of twenty patients with diarrhea and all 10 patients without diarrhea had chronic inflammatory changes in their intestinal biopsy specimens. Sixteen patients with identifiable enteric pathogens and diarrhea were treated; 11 (69%; 95% CI, 43% to 87%) showed microbiologic, histologic, or clinical improvement. CONCLUSIONS Thorough diagnostic evaluation can lead to the identification of enteric pathogens in a high percentage of patients with AIDS and diarrhea. Specific therapy can lead to symptomatic improvement.

Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem.

PURPOSE To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem. PATIENTS AND METHODS Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection. RESULTS Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P < .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients. CONCLUSION Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.

Development and Evaluation of a Quantitative, Touch-Down, Real-Time PCR Assay for Diagnosing Pneumocystis carinii Pneumonia

ABSTRACT A rapid (time to completion, <4 h, including DNA extraction) and quantitative touch-down (QTD) real-time diagnostic Pneumocystis carinii PCR assay with an associated internal control was developed, using fluorescence resonance energy transfer (FRET) probes for detection. The touch-down procedure significantly increased the sensitivity of the assay compared to a non-touch-down procedure. Tenfold serial dilutions of a cloned target were used as standards for quantification. P. carinii DNA has been detected in respiratory specimens from patients with P. carinii pneumonia (PCP) and from patients without clinical evidence of PCP. The latter probably represents colonization or subclinical infection. It is logical to hypothesize that quantification might prove helpful in distinguishing between infected and colonized patients: the latter group would have lower copy numbers than PCP patients. A blinded retrospective study of 98 respiratory samples (49 lower respiratory tract specimens and 49 oral washes), from 51 patients with 24 episodes of PCP and 34 episodes of other respiratory disease, was conducted. PCR-positive samples from colonized patients contained a lower concentration of P. carinii DNA than samples from PCP patients: lower respiratory tract samples from PCP and non-PCP patients contained a median of 938 (range, 2.4 to 1,040,000) and 2.6 (range, 0.3 to 248) (P < 0.0004) copies per tube, respectively. Oral washes from PCP and non-PCP patients contained a median of 49 (range, 2.1 to 2,595) and 6.5 (range, 2.2 to 10) (P < 0.03) copies per tube, respectively. These data suggest that this QTD PCR assay can be used to determine if P. carinii is present in respiratory samples and to distinguish between colonization and infection.

Improved diagnosis of Pneumocystis carinii infection by polymerase chain reaction on induced sputum and blood.

Detection of Pneumocystis carinii by the polymerase chain reaction (PCR) may facilitate non-invasive diagnosis of P carinii pneumonia and study of its epidemiology. We have compared the sensitivity and specificity of two PCR methods with those of conventional staining for detection of P carinii in induced sputum, bronchoalveolar lavage fluid (BAL), and blood. Of 71 sputum samples, 17 were from patients with microbiologically confirmed P carinii pneumonia. A nested PCR method correctly identified the presence of P carinii in all 17 (100% sensitive, 95% confidence interval [CI] 81-100%) and found no organisms in 50 of 54 microbiologically negative samples (93% specific, 95% CI 82-98%). PCR with a single primer pair was 71% sensitive (44-90%) and 94% specific (85-99%). The sensitivity of conventional staining methods (direct and indirect fluorescence antibody and toluidine-blue-O tests) was significantly less (38-53%) than that of nested PCR (p less than 0.05). In BAL, neither PCR method was significantly better than the conventional staining methods. P carinii was detected in BAL or sputum from 10 immunocompromised patients without microbiological evidence of P carinii pneumonia, which suggests that symptom-free carriers or subclinical infection can exist. P carinii was detected by nested PCR in blood from 2 of 3 patients with disseminated pneumocystosis but in only 1 of 11 patients with P carinii infection restricted to the lungs. Nested PCR on induced sputum is more sensitive than conventional staining methods for the diagnosis of P carinii pneumonia and provides a non-invasive method of detecting disseminated disease.

Bacteremia Due to Mycobacterium avium-intracellulare in the Acquired Immunodeficiency Syndrome

The presence of Mycobacterium avium-intracellulare has frequently been demonstrated in tissue specimens from patients with the acquired immunodeficiency syndrome. The importance of this mycobacterium as a cause of constitutional symptoms and organ dysfunction has been unclear, however, because of the sparse inflammatory response evoked and the frequent concurrence of other pathogenic organisms. We detected M. avium-intracellulare in blood samples from eight patients with the acquired immunodeficiency syndrome, seven of whom had a previously recognized M. avium-intracellulare infection. Blood cultures were positive on 1 to 14 occasions over 135 days using the Dupont isolator system or the Bactec 12B medium system. Cultures were positive within 14 to 51 or 7 to 14 days with the respective techniques. The ability to rapidly isolate M. avium-intracellulare from blood may provide a useful diagnostic technique for detecting disseminated mycobacterial disease in patients with the acquired immunodeficiency syndrome as well as in other patient populations. This technique may also be useful for assessing the efficacy of drug therapy.