Management of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a potentially lethal disease mainly affecting young females. Although the precise mechanism of PAH is unknown, the past decade has seen the advent of many new classes of drugs with improvement in the overall prognosis of the disease. Unfortunately the therapeutic options for PAH in South Africa are severely limited. The Working Group on PAH is a joint effort by the South African Heart Association and the South African Thoracic Society tasked with improving the recognition and management of patients with PAH. This article provides a brief summary of the disease and the recommendations of the first meeting of the Working Group.

Activation of human neutrophils with chemotactic peptide, opsonized zymosan and the calcium ionophore A23187, but not with a phorbol ester, is accompanied by efflux and store-operated influx of calcium.

The objective of this study was to monitor alterations in cellular Ca2+ metabolism following activation of neutrophils with receptor- (chemotactic peptide, FMLP, 1 microM; opsonized zymosan, OZ, 0.5 mg/ml) and non-receptor (calcium ionophore, A23187, 1 microM; phorbol 12-myristate 13-acetate, PMA, 25 ng/ml)-mediated stimuli of the pro-inflammatory functions of these cells. Ca2+ fluxes in activated neutrophils were measured using a fura-2-based spectrofluorimetric method in combination with radiometric (45Ca) procedures which facilitate distinction between net efflux and net influx of the cation. Exposure of neutrophils to receptor-mediated stimuli and to A23187 was associated with an abrupt increase in cytosolic Ca2+ coincident with a rapid efflux of the cation which terminated at around 30 s. In the case of FMLP and OZ, this was followed by a delayed (30-60 s), store-operated influx of Ca2+, which was complete at around 5 min after addition of the stimulus. With A23187, however, influx of Ca2+ occurred immediately following activation of the cells. There were no detectable alterations in cytosolic Ca2+ or measurable net efflux or influx of the cation above control levels in PMA-activated neutrophils. These data demonstrate that FMLP, OZ- and A23187-mediated alterations in neutrophil cytosolic Ca2+ are due to mobilization of both intracellular and extracellular cation, while activation of neutrophils by PMA is independent of alterations in cytosolic Ca2+.

Pneumocystis carinii pneumonia in HIV infected patients from South Africa.

OBJECTIVE: To compare the spectrum of pulmonary disease in human immunodeficiency virus positive patients of African and European origin, with particular reference to Pneumocystis carinii pneumonia. DESIGN: Descriptive study with retrospective record review. SETTING: Tertiary care, university teaching hospitals in Johannesburg, South Africa. SUBJECTS: Sixty seven HIV-infected patients and 36 HIV-negative renal transplant patients (who served as controls) whose sputa were negative for tuberculosis and Pneumocystis carinii, and who had fibreoptic bronchoscopic evaluation for pulmonary disease between January 1985 and August 1992. MEASUREMENTS: Histological and cytological evaluation of pulmonary diseases. RESULTS: In the HIV infected group Pneumocystis carinii pneumonia was the most frequent disease in patients of both African and European origin but occurred less commonly in Africans than in Europeans (27.3% and 58.8%, respectively; p = 0.01). There was no statistically significant difference between patients of African and European origin in the frequency of any other diagnosis. In the renal transplant group the most frequent diagnosis was non-specific interstitial pneumonitis (Africans 33.3%, Europeans 37.0%), followed by Pneumocystis carinii pneumonia (Africans 22.2%, European 14.8%). There was no difference between HIV-infected and renal transplant patients in the frequency of any diagnosis. CONCLUSION: Pneumocystis carinii pneumonia should be considered in the diagnosis of HIV-infected African patients with pulmonary disease whose sputum smears for tuberculosis are negative.

Bacteremic pneumococcal pneumonia in HIV-seropositive and HIV-seronegative adults.

STUDY OBJECTIVES: To compare the demographic, clinical, laboratory, and microbiological data, and the hospital course and outcome of HIV-seropositive and HIV-seronegative adults with bacteremic pneumococcal pneumonia. DESIGN: Retrospective observation study conducted over a 2-year period. SETTING: Academic teaching hospital attached to the University of the Witwatersrand, Johannesburg, South Africa. PATIENTS: Consecutive patients with bacteremic pneumococcal pneumonia were identified on the basis of positive blood culture results. INTERVENTIONS: All available demographic, clinical, routine laboratory, radiographic, and microbiological data were recorded retrospectively for each of the patients, and the combined data for the HIV-seropositive patients were compared with those of the HIV-seronegative patients. MEASUREMENT AND RESULTS: A total of 112 patients (31 HIV-seropositive and 81 HIV-seronegative patients) were entered into the study. The HIV-seropositive patients were significantly younger than the HIV-seronegative patients (32.8 vs 39.6 years old) and had lower admission hemoglobin (11.8 vs 13.4 g/dL), WBC count (10.3 vs 14.3 x 10(9)/L), serum albumin (31 vs 36 g/L), sodium (129 vs 132 mmol/L), and potassium (3.0 vs 3.5 mmol/L), respectively. Although the HIV-seropositive patients appeared to have more multilobar pulmonary consolidation on the chest radiograph than the HIV-seronegative patients (60% vs 34%), this did not quite reach statistical significance. In addition, the HIV-seropositive patients had significantly more infections (48.4% vs 20.8%) with pneumococcal serogroups/serotypes (serogroups 6, 19, 23, and serotype 14) that are found more commonly in children, and they also had more penicillin-resistant isolates (13% vs 2.5%) than the HIV-seronegative patients, respectively. Similarly, it was noted that when these data were analyzed according to gender (irrespective of HIV status), women had significantly more infections than men (47% vs 21%) with serogroups/serotypes that are usually found in children, more penicillin-resistant isolates (15% vs 1%), and more co-trimoxazole-resistant isolates (21% vs 5%), respectively. There were no differences noted in any of the other parameters, including initial APACHE (acute physiology and chronic health evaluation) II score, PaO2/fraction of inspired oxygen ratio, duration of temperature, duration of IV therapy, duration of hospitalization, complications, and outcome, when comparing HIV-seropositive and HIV-seronegative patients. Two patients in each group died. CONCLUSIONS: The clinical features of bacteremic pneumococcal pneumonia are similar in HIV-seropositive and HIV-seronegative patients. Although differences are noted in various laboratory and microbiological parameters, they do not appear to have an impact on outcome.

Anti-oxidative effects of theophylline on human neutrophils involve cyclic nucleotides and protein kinase A.

The effects were studied of the non-specific phosphodiesterase inhibitor, theophylline (37.5-300 microM), on intracellular levels of cyclic adenosine monophosphate (cAMP) and superoxide generation following exposure of human neutrophils to four different stimuli of neutrophil membrane-associated oxidative metabolism, each of which utilizes a different transductional mechanism to activate NADPH-oxidase, in vitro. Exposure of neutrophils to FMLP (1 microM), the calcium ionophore A23187 (1 microM), and opsonized zymosan (OZ, 0.5 mg/ml) was accompanied by activation of superoxide production and increased concentrations of intracellular cAMP. Inclusion of theophylline resulted in augmentation of cAMP and inhibition of superoxide production by these stimuli. These negative effects of theophylline on neutrophil superoxide generation were mimicked by dibutyryl cAMP and 8-bromo-cGMP, while the inhibitory activity of all 3 agents was antagonized by the protein kinase A inhibitor KT 5720, but not by the G-kinase inhibitor KT 5823. Unlike FMLP, OZ and A23187, intracellular cAMP levels did not increase in cells activated with phorbol-12-myristate-13-acetate (PMA, 25 ng/ml), while oxidant production activated by this stimulus was insensitive to the inhibitory effects of theophylline. These observations suggest that the beneficial, anti-inflammatory interactions of theophylline with human neutrophils are related to the phosphodiesterase inhibitory properties of this agent, and are selective for those pro-inflammatory stimuli which elevate cAMP, resulting in enhanced activity of protein kinase A and inhibition of the production of potentially harmful reactive oxidants by these cells.

Study of critically ill patients with systemic lupus erythematosus.

OBJECTIVES: To determine the presenting features, prognostic factors, course, and outcome of critically ill patients with systemic lupus erythematosus admitted to the intensive care unit (ICU). DESIGN: Retrospective patient record review. SETTING: Two academic teaching hospitals. PATIENTS: All patients with systemic lupus erythematosus admitted to the ICUs between January 1982 and July 1993. MEASUREMENTS AND MAIN RESULTS: There were 28 female and two male patients. Fifteen patients were white, 11 patients were black, and four patients were Asian. The median age was 29 yrs. The reasons for admission to the ICU were multifactorial. However, most patients were admitted for infective, renal, cardiac, or coagulation complications. Despite aggressive management, 16 (53%) patients died in the ICU or shortly after discharge. The median ICU survival rate (admission to death) was 22 days. The only pretreatment factor that predicted a poor outcome was the presence of renal involvement due to systemic lupus erythematosus. CONCLUSIONS: Our study suggests that patients with systemic lupus erythematosus admitted to an ICU often have florid disease manifestations with multifactorial reasons precipitating the admission. The prognosis for such patients is poor, particularly in the presence of renal involvement.

IgG subclasses in previously healthy adult patients with acute community-acquired pneumonia.

OBJECTIVE: To measure IgG antibody subclasses in previously healthy adult patients with acute community-acquired pneumonia, and to assess any association between differences of subtype levels and severity of illness or prognosis. DESIGN: Prospective study. SETTING: The intensive care unit (ICU) and general medical wards of Hillbrow Hospital, Johannesburg, an urban general hospital. PATIENTS: Sixty-six previously healthy adult patients with acute community-acquired pneumonia, of whom 47 were considered less severely ill, while 19 were admitted to an ICU. OUTCOME MEASURES: Measurement of IgG subclass levels and determination of any association between differences in subtype levels and various poor prognostic factors in pneumonia, need for ICU admission, complications of illness, and APACHE II score of ICU cases or outcome of patients. RESULTS: A number of statistically significant differences (P < 0.05) were noted between the two groups of patients (critically ill v. others) representing well-known negative prognostic factors in pneumonia. A greater degree of tachycardia and tachypnoea and extremes of white cell count, a higher serum urea concentration and multilobar pulmonary consolidation characterised the patients in the ICU. In addition, the mortality rate in the ICU patients was significantly greater (P < 0.0001). Similar findings were noted when survivors and non-survivors were compared. Few abnormalities of IgG subclass levels were noted in the various patient groups, which did not allow adequate analysis of their clinical significance. CONCLUSION: This study demonstrated a small number of abnormalities in IgG subclass levels in previously healthy adult patients with acute community-acquired pneumonia.

The aetiology of severe community-acquired pneumonia and its impact on initial, empiric, antimicrobial chemotherapy.

Of 259 patients admitted to an intensive care unit with severe acute community-acquired pneumonia, 173 had primary infections and 86 had secondary infections. The commonest organism isolated in each group was Streptococcus pneumoniae (51.3 and 36.6% of known isolates in each group respectively). Klebsiella pneumoniae was the next most common isolate (31.9 and 29.3% respectively). A variety of other Gram-negative organisms and Staphylococcus aureus accounted for most of the remaining pathogens. Based on retrospective analysis of data, there appeared to be no difference in the alcohol consumption of patients with infection due to S. pneumoniae and K. pneumoniae. The overall mortality rate for the primary infections was 47.4%, with 68.4% of these infections due to K. pneumoniae and 33.9% due to the pneumococcus (P < 0.002). Among the secondary infections, the overall mortality rate was 40.8% (not significantly different to that of primary infections) with 45.5% due to K. pneumoniae and 23.1% due to the pneumococcus (not significantly different on statistical analysis, probably due to low patient numbers). Our investigation confirms that severe community-acquired pneumonia due to K. pneumoniae is extremely common, even in patients without obvious risk factors for Gram-negative colonization. This organism is contributing to the high mortality rate seen in our intensive care unit among patients with pneumonia, and our empiric therapy for such cases routinely includes a combination of agents active against this organism (e.g. a cephalosporin and an aminoglycoside).