[Human cytomegalovirus--biology and infection].
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An increasing number of antiviral agents are presently in various stages of development and testing, and an increasing number have recently been licensed for use in humans. These drugs have been used extensively to treat viral infections in immunocompromised individuals, and these studies indicate that for many antiviral agents the response to therapy is highly dependent on the integrity of the underlying host immune response. In particular, the response to zidovudine, acyclovir and ganciclovir in persons with HIV-1 infection is highly dependent upon CD4 number, which can be considered a surrogate marker for the state of host immune function in these subjects. Responses to interferons likewise can be shown to depend on the host immune response, with responses due to both direct antiviral effects of this agent as well as immunomodulatory effects mediated through interferon-induced upregulation of HLA molecule expression. The interdependence of host immunity with antiviral efficacy is underscored by the increased antiviral drug resistance in persons with advanced degrees of chronic immunosuppression, related to the higher level of viral replication and viraemia which occurs in the absence of an effective host immune response. Further definition of the precise mechanisms of these interactions should facilitate the rational design of antiviral agents and immunomodulatory therapies to improve treatment of viral infections.
Current treatment options for acquired-immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL) are unsatisfactory because of excessive toxicity rates and frequent recurrence of lymphoma. In this phase II study, we evaluated a novel 12 week chemotherapy program with respect to feasibility, toxicity and therapeutic results. Thirty HIV-seropositive patients with intermediate grade or small non-cleaved cell NHL received a 12 week program of weekly intravenous and oral chemotherapy consisting of etoposide, adriamycin, cyclophosphamide, bleomycin, vincristine, methotrexate and prednisone as well as biweekly intrathecal cytosine arabinoside. Prophylaxis against Pneumocystis carinii pneumonia (PCP) and candida were given routinely. The overall objective response rate was 73% with 33% complete responders. The time to progression for those stable or responding was 9.4 months. Five of 10 complete responders are well and free of disease 13.2 to 24.5 months from diagnosis. Median survival for the 30 patients was 8.1 months. NHL was the most common cause of death (13/22); opportunistic infection caused only one death (cryptococcal meningitis). Only 1 case of PCP occurred. The major toxicity was neutropenia. In conclusion this regimen resulted in response rates similar to other reports with acceptable toxicity and a very low incidence of PCP. Relapse of NHL remains a major challenge, however, and further studies are needed. Routine PCP prophylaxis should be incorporated into new trials of therapy for AIDS-related NHL.
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AIM: To determine the diagnostic accuracy of upper gastrointestinal endoscopy in a selected group of patients with HIV infection, who had severe symptoms unresponsive to empirical treatment. METHOD: We reviewed all patients with HIV infection, who had undergone upper gastrointestinal endoscopy at Auckland Hospital. Specific diagnoses were based on the endoscopic appearances and on the histological and microbiological examination of endoscopic biopsies taken from the oesophagus, stomach and duodenum. RESULTS: A definitive diagnosis was reached in 16 of the 21 patients endoscoped, of whom 13 had a good clinical response to treatment. The median survival was three months. The most common diagnosis was oesophageal candidiasis seen in six patients, all of whom responded to treatment with a median survival of six months. Invasive cytomegalovirus gastrointestinal disease was seen in three patients, none of whom had positive blood cultures for cytomegalovirus. All responded to intravenous ganciclovir. Three patients with severe diarrhoea had opportunistic infection of the small bowel. All three had advanced AIDS with a median survival of less than one month. CONCLUSION: Upper gastrointestinal endoscopy has a high diagnostic yield in patients with HIV infection with oesophageal symptoms which fail to respond to antifungal therapy, or with severe weight loss and diarrhoea and it should be considered in these patients because excellent palliation may be possible.
A study was performed to reveal possible differences in lymphocyte subpopulations from bronchoalveolar lavage (BAL) of acquired immunodeficiency patients with and without Pneumocystis carinii pneumonia. Forty-one consecutive human immunodeficiency virus-seropositive patients were studied. Pneumocystis carinii infection was detected in the BAL fluid from 18 patients. The BAL lymphocyte subpopulations were determined by surface marker analysis with the immunoperoxidase slide assay. No significant differences in the percentage of CD4+ and CD8+ lymphocytes were found between the two groups. The percentage of CD57+ natural killer (NK) cells was significantly higher in the Pneumocystis carinii-negative group than in the -positive group. Since NK cells protect from microbial infections, it is conceivable that the loss of CD57+ NK cells may be one of the phenomena leading to the immunodeficiency state that underlies the pulmonary complications characteristic of the acquired immunodeficiency syndrome.
Two strains of fastidious mycobacteria were isolated from two patients with AIDS and clinical disease suggestive of Mycobacterium avium complex infection. Acid-fast bacilli were isolated from blood and bone marrow of both patients in BACTEC 12B and/or 13A media. The acid-fast bacilli failed to grow on subculture to routine Löwenstein-Jensen medium containing pyruvate and egg yolk agar. After several attempts, the strain from one patient was finally cultured on Middlebrook 7H9 medium with agar, charcoal, and yeast extract 13 months after the initial specimens were received in the laboratory. The second patient's strain was cultured on the same medium 6 weeks postinoculation with fresh BACTEC fluid and 5 months after specimen collection. Routine biochemical and growth tests were performed on these isolates but failed to give definitive identifications. 16S rRNA gene sequencing suggested that the organisms share at least 98.9% homology with M. simiae. Even greater homology (99.86%) was found with the recently described species "M. genavense." Recognition of the fastidious nature of some mycobacteria that infect AIDS patients is important in the treatment of infections in these patients and in understanding the epidemiology of atypical mycobacterial infections. It is suggested that a liquid culture medium such as BACTEC be employed for primary isolation of mycobacteria from AIDS patients and that subculture to the charcoal medium described here be carried out for those organisms that fail to grow on subculture to routine media.
"Mycobacterium genavense" is a proposed new species recently reported to cause disseminated infections in 18 patients with AIDS in Europe. We have recovered "M. genavense" as slowly growing fastidious mycobacteria in blood cultures of seven patients with AIDS. In the original studies of "M. genavense," the fastidious organism grew only in BACTEC 13A vials. The Seattle, Washington, isolates of "M. genavense" also failed to grow when subcultured from 13A vials to routine solid media, but dysgonic colonies were produced on Middlebrook 7H11 agar supplemented with mycobactin J. The mycolic acid pattern of patients' isolates closely resembled that of the type strain of Mycobacterium simiae when analyzed by one- and two-dimensional thin-layer chromatography and by high-performance liquid chromatography. Whole-cell fatty acid analyses by gas-liquid chromatography distinguished the isolates from M. simiae but misidentified them as Mycobacterium fortuitum. Sequence determinations of the hypervariable regions of the 16S rRNA gene indicate that these organisms belong to the recently proposed new species "M. genavense." Growth from Middlebrook 7H11 agar supplemented with mycobactin J consistently yielded positive tests for catalase (semiquantitative and at 68 degrees C), pyrazinamidase, and urease which enable mycobacteriology laboratories to presumptively identify "M. genavense" without nucleic acid analyses. The failure of "M. genavense" to grow on conventional mycobacterial solid media suggests that mycobacterial blood cultures should include a broth medium incubated for at least 8 weeks.
Double-stranded RNA (dsRNA)-dependent protein kinase (p68) has been shown to be induced by alpha-interferon (IFN-alpha) in mammalian cells. It binds to dsRNA, and is believed to be a factor in the control of both cellular and viral protein synthesis. This report describes the use of a new monoclonal antibody (MAb) TJ4C4, to monitor levels of p68 in a patient with AIDS-associated Kaposi's sarcoma. Using a novel immunoperoxidase/iron staining method, we examined formalin-fixed, paraffin-embedded biopsies prior to, and 4 months after the initiation of IFN therapy. Immunostaining showed low levels (1+ staining) of p68 in the pretreatment tissue, whereas a marked increase (4+ staining) was noted during interferon treatment. This staining suggests an increased level of intracellular p68 expression. This patient has subsequently remained on IFN-alpha therapy and is alive with no evidence of Kaposi's sarcoma, 6 1/2 years after diagnosis. The use of MAb TJ4C4 will greatly facilitate the study of p68 kinase in clinical tissues, and may provide a way to monitor the effects of IFN therapy.
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Light and electron microscopy studies of digestive tract biopsy specimens from AIDS patients are very useful for the detection of opportunistic pathogens which may be located in: the lumen (bacteria, Candida albicans, Giardia lamblia), enterocyte brush border (Cryptosporidium sp), enterocyte cytoplasm (Enterocytozoon bieneusi), enterocyte nuclei (cytomegalovirus), or cytoplasm of lamina propria macrophages (Mycobacterium avium intracellulare). These studies may also be useful to detect combinations of morbid conditions and to evaluate the effectiveness (if any) of therapeutic agents.
We report the case of a 20-year-old homosexual man with HIV-1 infection presenting with AIDS. An erythemato-squamous, papulo-crustous, non-itching dermatosis of 4 months duration was finally diagnosed as Norwegian scabies in the immunosuppressed. For clinical and epidemiological reasons the high contagiosity of this rare entity requires an appropriate therapy without delay.
To determine the prevalence of Pneumocystis carinii in the HIV-infection department, a simultaneous survey was made of 33 HIV-infected patients at various stages of the disease, of close relatives that were nursing the patients in the unit (n-7), and of medical staff of the department (n-20). Patients with toxic infections who were on another floor of the same hospital and medical students were examined as a control group. For detection of P. carinii antigen, smears from the deep airways were tested in the immunofluorescence. P. carinii was detected in 87.7% of HIV-infected patients, in 71.4% of their relatives and in 80.0% of the medical staff, in 16.6% of control patients and 27.7% of students. The main type of the infectious process in pneumocystosis is its carriage; 2 patients at a stage of relapses (IIIB) that corresponds to AIDS were recorded as having pneumocystis pneumonia.
We worked with 51 samples, 7 bronchoalveolar lavages (BAL) and 44 sputa (S) of 31 AIDS patients with clinical and radiographic symptoms compatible with Pneumocystis pneumonia. With the aim of finding a specific sensitive methodology for the diagnosis of Pneumocystis carinii, we evaluated 4 coloration techniques (silver methenamine, its modification without gold chloride, toluidine blue and Giemsa). 35% of the patients studied were positive. P. carinii were observed in 18% of the 44 sputa. We observed that the analysis of a single sputum sample (S) has a very low sensitivity and that the processing of two or more samples is necessary since only one of the 14 patients who had sent a single sample was found P. carinii positive, while in the remaining ten who had sent more than one (S) sample, the microorganism was detected in 50%. 4 of the 7 BAL were positive. 4 BAL were preceded by the analysis of an (S) sample: in two cases the results were negative while BAL allowed us to make the diagnosis, thus demonstrating its greater efficacy. To enhance sensitivity each sample was centrifuged until exhaustion and 10 slides were prepared for coloration with the final sediment. The four techniques employed were specific and all the Pneumocystis pneumonia patients responded to the treatment. Silver methenamine, its modification without gold chloride, and toluidine blue were very sensitive, in contrast to of Giemsa. The stain to be chosen is either silver methenamine, or its modification, because both achieve the best contrast, allowing optimum P. carinii identification. We suggest the implementation of some of these techniques in laboratory routine.
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Outbreaks of tuberculosis in centres for the care of patients with AIDS, including outbreaks involving drug-resistant strains of Mycobacterium tuberculosis, have been reported from a number of countries and present special problems. Transmission of infection may be facilitated by procedures commonly used with AIDS patients, and recognition of the diagnosis in an infectious case may be delayed. Although no similar outbreaks have been identified in the United Kingdom, it may be timely to review the policy and procedures used in this country in the light of experience elsewhere.
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