Scott F. Davies

An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients

With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.

Alveolar Hemorrhage Syndromes: Diffuse Microvascular Lung Hemorrhage in Immune and Idiopathic Disorders

We have reviewed the alveolar hemorrhage (AH) syndromes, defined as immune or idiopathic disorders associated with diffuse microvascular hemorrhage into the acinar portion of the lung. The disorders that are most often associated with AH include antibasement membrane antibodies (ABMA) disease, idiopathic pulmonary hemosiderosis, systemic lupus erythematosus, systemic vasculitides, and idiopathic rapidly progressive glomerulonephritis. An approach to the recognition, diagnosis, and treatment of the AH syndromes has been outlined and several illustrative case studies have been presented. Recognition of AH is not usually difficult, but does require a high index of suspicion, since many disease processes may give rise to hemoptysis with infiltrates on chest roentgenogram. Recognition of AH is aided by careful clinical and laboratory assessment for evidence of extrapulmonary disease; simple hematologic studies such as sequential hemoglobins and iron studies; and measurement of carbon monoxide uptake by the lungs. Early recognition of AH may decrease the likelihood of respiratory failure and end-stage renal disease. The specific etiology of AH is usually determined by clinical examination, serologic assay for ABMA, and percutaneous renal biopsy by immunofluorescence. Open-lung biopsy is required in a minority of cases. High-dose pulse methylprednisolone appears to effectively control AH of diverse etiology. Combined plasma exchange and immunosuppression controls AH in ABMA disease and is the treatment of choice in this disorder. Cyclophosphamide is used for Wegeners granulomatosis, and sometimes in systemic necrotizing vasculitis, in an attempt to prevent irreversible damage to the kidneys.

Disseminated histoplasmosis in immunologically suppressed patients: Occurrence in a nonendemic area

Abstract Eight immunologically suppressed (immunosuppressed) patients with disseminated histoplasmosis were seen in 36 months in a nonendemic area in which greater than 90 per cent of young adults have a negative histoplasmin skin test. Evidence suggesting endogenous reinfection as a possible mechanism for these patients include (1) virtual absence of cases in nonimmunosuppressed patients; (2) absence of cases of disseminated histoplasmosis in children during the time period of the study; (3) known previous residence in endemic areas by five of eight patients; (4) absence of an acute respiratory illness preceding dissemination; and (5) onset of disseminated disease shortly after initiation of high dose glucocorticoid therapy in very sick patients with little, if any, chance of environmental exposure. Histoplasmosis should be considered as a possible opportunist in undiagnosed febrile illnesses in compromised hosts. This is true even in nonendemic areas, especially when history of previous residence in an endemic area can be obtained. Suspicion should be greatest when high dose glucocorticoid therapy has recently been started. The clinical picture of disseminated histoplasmosis in these patients is not specific. Rapid diagnosis is often possible on bone marrow or liver biopsy once the diagnosis is considered. Cultures of these tissues usually yield the organism even when the histopathologic examination is negative. Early diagnosis is especially important because specific therapy is available. Rapid initiation of therapy can be life-saving as shown by four of our eight patients.

Prospective study of lower respiratory tract infections in an extended-care nursing home program: potential role of oral ciprofloxacin.

PURPOSE Infections of the lower respiratory tract pose an important problem in nursing homes. Despite the magnitude of this problem, few, if any, antibiotic studies have been targeted specifically at nursing home-acquired bronchopulmonary infections. Following the establishment of a teaching Extended-Care Nursing Home Program, which facilitated the early diagnosis and therapy of bronchopulmonary infections, a comparative trial of oral ciprofloxacin and intramuscular cefamandole was initiated in elderly patients with lower respiratory tract infections. In addition to assessing the relative efficacy and safety of ciprofloxacin and cefamandole, our goals were to identify problems and pitfalls associated with conducting clinical research in this nursing home setting, evaluate selected clinical and laboratory features of lower respiratory tract infection in this patient population, and measure outcomes in all study groups. PATIENTS AND METHODS During a 20-month period, 40 patients with pneumonia and 20 patients with acute bronchitis were enrolled in this randomized study. Sixty-three patients with pneumonia who were ineligible for the randomized study were also followed prospectively. The mean age of the 111 participants (123 cases) was 80.8 years; all patients had at least one chronic medical condition. RESULTS Although Streptococcus pneumoniae was the single most common isolate, gram-negative bacteria were cultured from 81 percent of the cases that yielded pathogens from a satisfactory sputum specimen. The in-hospital mortality rate was strikingly low (6.5 percent), and a large majority of patients in all study groups were discharged safely back to their nursing homes well within the Diagnosis-Related Group length of stay. CONCLUSION Ciprofloxacin appeared to be as safe and effective as cefamandole in this nursing home program; however, additional studies are needed to determine its role in the treatment of elderly patients with bronchopulmonary infections.

Disseminated histoplasmosis in renal transplant recipients

Five cases of disseminated histoplasmosis complicating renal transplantation are reported. Nine previously reported cases from the literature are reviewed. In this setting disseminated histoplasmosis usually presents as a nonspecific systemic febrile illness that may be fulminant or more subacute. Five of 14 patients presented with skin lesions; only one patient presented with primary pulmonary symptoms of cough and dyspnea. Three of our patients and three others previously reported on survived the infection and maintained good function in the transplanted kidney despite prolonged therapy with amphotericin B. Immunosuppression was the only predisposing factor that could be identified with certainty in the five patients reported on herein. However, in two of the five patients the onset of disseminated histoplasmosis coincided with a well documented cytomegalovirus infection; the viral infection may have been a factor predisposing to infection in these two cases.

Chronic blastomycotic meningitis.

Three cases of blastomycosis which presented as chronic meningitis are reported. Blastomycotic meningitis is an uncommon form of chronic fungal meningitis and is difficult to diagnose during life unless the patient has obvious systemic blastomycosis elsewhere. Evaluation of cerebrospinal fluid obtained by lumbar tap is usually not diagnostic. Obstructive hydrocephalus developed in all three patients during the course of their fungal meningitis. Culture of ventricular fluid yielded the fungus in all three patients (although only after death in one case). One patient received only minimal therapy before death whereas the third patient received a full course of amphotericin B with restoration to his premorbid state. Blastomycosis should be included in the differential diagnosis of chronic meningitis and, when suspected, the cisternal or ventricular fluid should be sampled.

In vitro suppression of erythropoiesis by bone marrow adherent cells from some patients with fungal infection

We present evidence that alterations in marrow adherent cell (Mø) function may play a role in the suppression of erythropoiesis in some patients with fungal infection. Bone marrow (BM) cells from 12 normals and 10 patients with histoplasmosis were cultured in plasma clots before and after removal of Mø. BM from five patients (Group A) produced normal numbers of erythroid colonies (EC). In the remaining patients (Group B), smaller numbers of EC were detected (P<0.01). Removal of Mø from BM of normals and Group A patients resulted in decreased growth of EC. In contrast, Mø depletion of BM from patients in Group B resulted in greater EC formation (P< 0.01). When normal Mø were admixed with normal or patients’BM‐Mø, enhanced EC formation resulted. Whereas, at similar concentrations, Mø from group B patients caused inhibition of EC formation (P< 0.005). The erythro‐regulatory function of Mø, including the inhibitory action of patients’Mø, was mediated via a soluble agent(s) since media conditioned by Mø mimicked the action of these cells. Three patients in Group B were restudied 14 months after treatment with amphotericin B, when blood parameters had returned to normal. At this time, normal patterns of EC formation and Mø activity were observed.

Evidence of subclinical blastomycosis in forestry workers in Northern Minnesota and Northern Wisconsin

PURPOSE To investigate the incidence of remote subclinical blastomycosis in a high-risk population of forestry workers. PATIENTS AND METHODS The study consisted of 39 male forestry workers from northern Minnesota and northern Wisconsin, areas endemic for blastomycosis but not for histoplasmosis. All subjects were histoplasmin skin test-negative, and none had ever been diagnosed with blastomycosis or pneumonia. An antigen-specific lymphocyte stimulation assay was performed to determine the presence of blastomycosis. RESULTS Peripheral blood lymphocytes from 12 of 39 subjects demonstrated specific antigen-induced proliferation when stimulated with a purified alkali- and water-soluble antigen derived from the cell wall of Blastomyces dermatitidis. CONCLUSION The finding that 30% of these men had evidence of previous blastomycosis suggests that subclinical cases do occur sporadically, and are probably more common than diagnosed symptomatic cases. This is similar to histoplasmosis, in which the majority of infections are subclinical. However, the reservoir of persons with previous undiagnosed blastomycosis is probably small compared to the huge number of persons (perhaps 30 million) with prior histoplasmosis.

Trephine biopsy of the bone marrow in disseminated histoplasmosis.

Twenty-two patients had bone marrow aspirates for culture and marrow trephine biopsies for histologic examination during the evaluation of an illness eventually proved to be disseminated histoplasmosis. These procedures provided evidence of involvement of the bone marrow with Histoplasma capsulatum in 19 cases. Fungi were demonstrated in trephine biopsy sections in 15 of the patients, permitting a rapid specific diagnosis. Three patterns of bone marrow morphology were observed; each reflected a variation of macrophage proliferation. In two of the patterns, diffuse macrophage proliferation and loose aggregates of macrophages, typical 2 to 4 microns intracellular hisoplasma organisms were numerous and obvious in hematoxylin and eosin-stained sections, were infrequent and were often relatively large (6 to 12 microns). There were four patients from whom H. capsulatum was cultured when organisms could not be demonstrated in either hematoxylin and eosin- or silver-stained sections. The patients with diffuse proliferation of macrophages in the marrow comprised a distinct clinical group associated with immunosuppression, a fulminant course and a fatal outcome despite therapy. Patients in the other two morphologic groups responded well to therapy even though the immune responses on many were also suppressed. Bone marrow examination is an excellent diagnostic procedure in disseminated histoplasmosis. Trephine biopsies permit a rapid diagnosis in most cases and may be of prognostic significance.

FUNGAL PULMONARY COMPLICATIONS

With AIDS has come a new level of T-cell immunosuppression, beyond that previously seen. The impact of the HIV pandemic on the field of fungal infections includes a major increase in the number of serious fungal infections, an increase in the severity of those infections, and even some entirely new manifestations of fungal illness. In this article fungal pulmonary complications of AIDS are discussed. T-cell opportunists including Cryptococcus neoformans and the endemic mycoses are the most important pathogens. Phagocyte opportunists, including Aspergillus species and agents of mucormycosis, are less important.