James H. Shelhamer

Pneumocystis carinii Pneumonia: A Comparison Between Patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies

Clinical features of 49 episodes of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome were compared with those of 39 episodes in patients with other immunosuppressive diseases. At presentation patients with the syndrome were found to have a longer median duration of symptoms (28 days versus 5 days, p = 0.0001), lower mean respiratory rate (23.4 versus 30, p = 0.005), and higher median room air arterial oxygen tension (69 mm Hg versus 52 mm Hg, p = 0.0002). The survival rate from 1979 to 1983 was similar for the two groups (57% and 50% respectively). Patients with the syndrome had a higher incidence of adverse reactions to trimethoprim-sulfamethoxazole (22 of 34 versus 2 of 17, p = 0.0007). Survivors with the syndrome at initial presentation had a significantly lower respiratory rate, and higher room air arterial oxygen tension, lymphocyte count, and serum albumin level compared to nonsurvivors. Pneumocystis carinii pneumonia presents as a more insidious disease process in patients with the syndrome, and drug therapy in these patients is complicated by frequent adverse reactions.

A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance.

We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.

Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: Heart rate as an early predictor of prognosis

Forty-eight septic shock patients with positive blood cultures had conventional serial hemodynamic evaluations until recovery or death to identify early cardiovascular variables that predicted outcome. There were 19 (40%) survivors and 29 nonsurvivors. At the initial evaluation, both survivors and nonsurvivors demonstrated an elevated cardiac index (CI), low systemic vascular resistance index (SVRI), and normal stroke volume index. However, only an initial heart rate (HR) less than 106 beat/min significantly predicted survival. Twenty-four hours after the onset of shock, both an HR less than 95 beat/min and an SVRI greater than 1529 dyne.sec/cm5.m2 predicted survival. Comparing the hemodynamic profiles from the initial to the 24 h time point, a decrease in HR greater than 18 beat/min or a decrease in CI greater than 0.5 L/min.m2 predicted survival. Twenty-two deaths occurred in the first week of study, of which 18 (82%) were due primarily to low SVRI and four (18%) to low CI. Seven deaths occurred after 1 wk, all of which were due to multiple organ failure.

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.

Adult Respiratory Distress Syndrome in Patients with Severe Neutropenia

Most investigators believe that the pulmonary endothelial damage that is characteristic of the adult respiratory distress syndrome (ARDS) requires the action of neutrophils. In a retrospective review of patients with ARDS, we looked for cases that had developed in patients who already had neutropenia. Four clinical criteria were required for the diagnosis of ARDS: the occurrence of a precipitating event, diffuse bilateral pulmonary infiltrates on a chest x-ray film, a normal intravascular volume (as reflected by a wedge pressure of less than 18 mm Hg), and arterial hypoxemia. During 2 1/2 years, 11 patients fulfilled these clinical criteria, had severe neutropenia that antedated the onset of ARDS, and had pulmonary histologic specimens obtained during the early stages (less than seven days) of clinical respiratory distress. Five of these specimens showed diffuse alveolar damage without evidence of infectious pneumonitis (the histopathological finding characteristic of ARDS), and none had a neutrophil infiltrate. We conclude that ARDS can occur in the setting of severe neutropenia, without pulmonary neutrophil infiltration.

Takayasu's Arteritis and Its Therapy

Twenty patients with Takayasus arteritis were followed prospectively for an average of 4.6 years. Sixteen patients with active inflammatory Takayasus arteritis were treated with glucocorticosteroids; eight responded to therapy. Six patients had clinical or angiographic progression of their vasculitis on daily corticosteroid therapy. These patients were then given cyclophosphamide together with prednisone on alternate days. Four of these 6 patients had no progression of vascular lesions while receiving cyclophosphamide; two had progression of vascular lesions after 30 and 48 months of therapy. Vascular reconstructive surgery was successful in 7 patients who tolerated a total of 13 vascular surgical procedures without major complications. One bypass graft occluded after 13 months and was revised. With corticosteroid therapy, cytotoxic therapy, and surgery, no deaths due to Takayasus arteritis or its treatment have occurred.

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.

Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxidedelivery

Nitric oxide (NO) may be stabilized by binding to hemoglobin, by nitrosating thiol-containing plasma molecules, or by conversion to nitrite, all reactions potentially preserving its bioactivity in blood. Here we examined the contribution of blood-transported NO to regional vascular tone in humans before and during NO inhalation. While breathing room air and then room air with NO at 80 parts per million, forearm blood flow was measured in 16 subjects at rest and after blockade of forearm NO synthesis with N(G)-monomethyl-L-arginine (L-NMMA) followed by forearm exercise stress. L-NMMA reduced blood flow by 25% and increased resistance by 50%, an effect that was blocked by NO inhalation. With NO inhalation, resistance was significantly lower during L-NMMA infusion, both at rest and during repetitive hand-grip exercise. S-nitrosohemoglobin and plasma S-nitrosothiols did not change with NO inhalation. Arterial nitrite levels increased by 11% and arterial nitrosyl(heme)hemoglobin levels increased tenfold to the micromolar range, and both measures were consistently higher in the arterial than in venous blood. S-nitrosohemoglobin levels were in the nanomolar range, with no significant artery-to-vein gradients. These results indicate that inhaled NO during blockade of regional NO synthesis can supply intravascular NO to maintain normal vascular function. This effect may have application for the treatment of diseases characterized by endothelial dysfunction.

Depressed Left Ventricular Performance: Response to Volume Infusion in Patients with Sepsis and Septic Shock

Volume infusion, to increase preload and to enhance ventricular performance, is accepted as initial management of septic shock. Recent evidence has demonstrated depressed myocardial function in human septic shock. We analyzed left ventricular performance during volume infusion using serial data from simultaneously obtained pulmonary artery catheter hemodynamic measurements and radionuclide cineangiography. Critically ill control subjects (n = 14), patients with sepsis but without shock (n = 21), and patients with septic shock (n = 21) had prevolume infusion hemodynamic measurements determined and received statistically similar volumes of fluid resulting in similar increases in pulmonary capillary wedge pressure. There was a strong trend (p = 0.004) toward less of a change in left ventricular stroke work index (LVSWI) after volume infusion in patients with sepsis and septic shock compared with control subjects. The LVSWI response after volume infusion was significantly less in patients with septic shock when compared with critically ill control subjects (p less than 0.05). These data demonstrate significantly altered ventricular performance, as measured by LVSWI, in response to volume infusion in patients with septic shock.

Effects of Arachidonic Acid, Monohydroxyeicosatetraenoic Acid and Prostaglandins on the Release of Mucous Glycoproteins from Human Airways In Vitro

Human lung explants maintained in culture for 7 d incorporate [(3)H]glucosamine into mucous glycoproteins. Ethanol-precipitable, glucosamine-labeled mucous secretion was measured, and the effects of different pharmacologic agents upon this secretion were investigated. Anaphylaxed human lung generates prostaglandin (PG) synthesis and increased mucous release. Arachidonic acid (AA), PGA(2), PGD(2), and PGF(2alpha) significantly increased mucous glycoprotein release, whereas PGE(2) significantly reduced release. Evidence which suggests that lipoxygenase products of AA augment mucous release includes the following: (a) Nonsteroidal anti-inflammatory drugs (NSAID: acetylsalicylic acid and indomethacin) increase mucous release while preventing prostaglandin formation. (b) The increase in mucous release induced by AA or NSAID is additive once the agents are combined. (c) Several nonspecific lipoxygenase inhibitors (eicosa-5,8,11,14-tetraynoic acid; vitamin E; nordihydroguaiaretic acid; and alpha-naphthol) inhibit mucous release. Three additional lines of evidence directly indicate that monohydroxyeicosatetraenoic acid (HETE) causes increased mucous release: (a) the addition of a mixture of synthetic HETE (24-600 nM) increases mucous release; (b) pure 12-HETE (1-100 nM) also increases mucous release; (c) mucous release is increased synergistically by the combination of HETE and NSIAD. These data taken together demonstrate that HETE are capable of increasing mucous release and that conditions which may influence HETE production alter mucous release. Thus, although not directly demonstrating HETE production by human airways, the data strongly suggest that lipoxygenase products of AA in airways may profoundly influence mucous release; and it seems possible that lipoxygenase inhibitors may have a role in treating bronchorrhea.