Richard D. Meyer

TRANSIENT HIGH LEVELS OF VIREMIA IN PATIENTS WITH PRIMARY HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 INFECTION

BACKGROUND The rapidly evolving clinical picture of primary infection with the human immunodeficiency virus type 1 (HIV-1) suggests that a better understanding of the kinetics of viral replication in vivo during the short period before seroconversion may provide insight into the pathogenesis of the acquired immunodeficiency syndrome (AIDS). METHODS AND RESULTS Titers of infectious HIV-1 were determined by end-point-dilution culture in sequential samples of plasma and peripheral-blood mononuclear cells from four patients with primary infection, with peak titers of 1000 to 10,000 tissue-culture-infective doses per milliliter of plasma and 100 to 10,000 infective doses per 10(6) peripheral-blood mononuclear cells. The high viral burden in mononuclear cells was confirmed by quantitative studies using a polymerase-chain-reaction method. In as little as 10 days, the high HIV-1 load in both plasma and cells decreased spontaneously and precipitously, at least 100-fold, in all four patients. CONCLUSIONS Although p24 core antigenemia and viral isolation have previously been described during primary HIV-1 infection, this report documents the large viral burden during the acute phase of infection. The rapid and spontaneous decline in the viral load suggests an effective immune response in the host that, if understood, may be used to combat AIDS.

Aspergillosis complicating neoplastic disease

Abstract From 1964 to June 1971, 93 cases of aspergillosis were encountered at Memorial Sloan-Kettering Cancer Center. The 29 cases diagnosed in 1969–1970 and the 15 cases diagnosed in the first half of 1971 represented, respectively, a doubling and a quadrupling since 1964–1965. The incidence of aspergillosis in patients with leukemia was seven times greater than in patients with Hodgkins disease or lymphoma (p 3 ). Pulmonary involvement was present in 90 of 93 cases, disseminated disease in 23. The commonest clinical pattern was unremitting fever and development of pulmonary infiltrates despite broad-spectrurh antibiotic therapy. In an increasing number of cases aspergillosis followed Pseudomonas aeruginosa infections. When present, serum aspergillus precipitins correlated well with invasive disease, but a negative test result was far less reliable. In one case of acute myelogenous leukemia the patient recovered from pulmonary aspergillosis after surgical excision of the lesion and remission of her leukemia. The incidence of aspergillosis is increasing and should be considered in the setting of progressive pulmonary infiltrates in leukemic and other heavily immunosuppressed patients who respond poorly to antibacterial therapy. Earlier diagnosis may lead to more effective therapy.

A Controlled Trial of Fluconazole or Amphotericin B to Prevent Relapse of Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome

BACKGROUND After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. METHODS We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. RESULTS Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fishers exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002). CONCLUSIONS Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Phycomycosis Complicating Leukemia and Lymphoma

Abstract During the 10-year period from 1962 to 1971, 26 cases of phycomycosis were diagnosed at Memorial Hospital, New York. This large series enables us to report a significant increase in the in...

Infectious Complications of Neoplastic Disease

Progress has been made in the diagnosis and treatment of infection in patients with neoplastic disease. Among the advances is the appreciation that certain opportunistic infections occur in association with particular host immune defects and epidemiologic factors. Such immune defects are seen secondary to or as a consequence of treatment for the patients basic disease. Improved methods such as serology, open lung biopsy, and fiberoptic bronchoscopy have allowed for earlier diagnosis and treatment of opportunistic infections. The development of empiric antibiotic regimens, particularly aminoglycosides and the antipseudomonal penicillins, have improved the outcome in the febrile neutropenic patient. The benefits of protective environments have been challenged; prophylactic antibiotics and various forms of immunotherapy are of interest but remain investigational.

Evaluation of New Anti-Infective Drugs for the Treatment of Respiratory Tract Infections

Abstract These guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. Five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. A wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. Inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. Microbiologic evaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. Alternatively, surrogate markers may be used to identify the etiologic agent. The efficacy of new drugs is evaluated with reference to anticipated response rates. Establishment of the microbial etiology of respiratory tract infections is hampered by the presence of “normal flora” of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. This issue is addressed for each category of infection described. For example, it is suggested that for initial phase 2 trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collect exudate for culture. Acute exacerbations of chronic bronchitis also present difficulties in the establishment of microbial etiology. These guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. For pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. For each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. Clinical improvement is not acceptable unless quantitative response measures can be applied.

Gram-negative rod bacteremia: microbiologic, immunologic, and therapeutic considerations.

During the last 2 decades, Gram-negative rod bacteremia has become the leading infectious disease problem in American hospitals. With improvements in conventional microbiologic techniques, bacteremic infection can be diagnosed reliably within 3 days using only three sets of cultures. Clinical management still requires aggressive, presumptive use of antimicrobials in patients with the most adverse host factors. In the latter group, the use of combinations of antibiotics that interact synergistically in vitro has improved clinical results. In bacteremia due to anaerobes, particularly Bacteroides species, drainage of infected sites is probably more important than specific drug therapy. Various host defects have been associated with Gram-negative bacteremia; the most common in the nonleukopenic patient is impaired opsonization. The evidence that endotoxins are involved in the pathophysiology of Gram-negative bacillemia is inferential. Nevertheless, both clinical and experimental evidence suggest that active or passive immunization with endotoxin components or antigens similar to Gram-negative polysaccharides may be protective.

Bacterial and Fungal Infections

The rapid and thus far generally inexorable rise in HIV infections has led to a series of opportunistic infection that includes those caused by bacteria, yeasts, and members of the Eumycetes. The infections range in prevalence from occasional to highly prevalent, in severity from trivial to fatal, and in anatomic areas involved from local to disseminated. They occur as isolated, concurrent, or sequential infections with regard to other opportunistic diseases. Some vary in their geographic distribution. They may be newly acquired or reactivated and occur early or late in the course of HIV infection. Bacterial infections are usually easily treated, although they frequently disseminate and often recur after seemingly appropriate treatment. In contrast, all but the mildest fungal infections are difficult to treat and even more difficult or impossible to eradicate. The diagnosis of bacterial and fungal infections begins with clinical suspicion and involves relatively standard methodology. Treatment of the systemic mycoses and some bacterial infections in HIV infected patients is punctuated by exaggerated side effects of therapy, frequent relapses, and the need for maintenance suppressive therapy.

Pseudomonas aeruginosa Vaccine in Cancer Patients

Abstract During 1969 to 1972, 361 adult patients (176 vaccinees, 185 control patients) at a cancer center were randomized into a prospective study of the lipopolysaccharide vaccine derived from 7 s...

Coccidioidal Meningitis: AN ANALYSIS OF THIRTY-ONE CASES AND REVIEW OF THE LITERATURE

Clinical and laboratory features of 31 patients with coccidioidal meningitis seen from January 1964 through December 1976 with follow-up through 1979 are reported and data on 114 patients from the literature reviewed. History of exposure to C. immitis, a wide age range, and, in about one third, underlying conditions are noteworthy. Dissemination to the meninges usually occurs within the first few months although diagnosis is frequently delayed. Presenting symptoms and signs of coccidioidal meningitis are varied but signs of chronic meningitis or suggestion of hydrocephalus are prominent. Evidence of acute infection is unusual even with widespread disease. Diagnosis is usually made by demonstration of coccidioidal CF antibodies in the CSF although they are not found in all patients. Some show other direct evidence of C. immitis. Special diagnostic techniques such as CAT scanning for evidence of basilar meningitis or hydrocephalus are valuable. Amphotericin B remains the drug of choice despite the need for long-term therapy and the problems with intrathecal administration. Reservoirs are only occasionally useful but shunts are frequently lifesaving despite complications. Factors associated with a bad prognosis are hydrocephalus, non-Caucasian race, or presence of an underlying disease.