[Psychogenic cough: Another etiology for persistent cough]. / Tos psicógena: una causa de tos crónica.

The most common causes of persistent cough are upper respiratory tract disease (postnasal drip syndrome, infections) and asthma. In the last year, six patients (four boys and two girls), aged 7-12 years old, with a diagnosis of hard-to-manage asthma and/or persistent cough were referred to our department. All the patients had undergone treatment with multiple drugs for long periods without favorable clinical response. The findings of physical examination, radiology, basal pulmonary function and post-bronchodilation and fibrobronchoscopy were normal. Organic disease was ruled out and a psychiatric evaluation was performed. Intelligence quotient was in the lower normal range and generalized anxiety order was identified, thus establishing a diagnosis of psychogenic cough. Treatment consisted of relaxation techniques and psychopedagogic support with favorable outcome. To avoid diagnostic errors and inappropriate treatment, psychogenic cough should be included in the differential diagnosis of persistent cough and hard-to-manage asthma.

Treatment of recurrent cytomegalovirus disease in patients receiving solid organ transplants.

Tissue-invasive cytomegalovirus (TI-CMV) disease occurs commonly after solid organ transplantation and has been associated with increased allograft loss and patient mortality. Although ganciclovir has been demonstrated to be an effective form of treatment for TI-CMV disease, therapy may be followed by recurrence. The purpose of this study was to determine the impact of recurrent TI-CMV disease on patient and allograft survival. We studied 619 patients who underwent solid organ transplantation (535 kidney transplants [253 from living related donors and 282 from cadavers] and 84 combined cadaveric kidney-pancreas transplants) during a 3 1/2-year period. One hundred fourteen patients (18.4%) developed TI-CMV disease and were treated with a standardized regimen of intravenous ganciclovir for 14 to 21 days. Of the 114 patients in whom primary TI-CMV disease developed, 28 (24.6%) developed recurrent TI-CMV disease more than 30 days after the initial episode, and these patients were retreated with ganciclovir. Cure rates at 30 days were 98.9% in patients with primary TI-CMV disease and 100% in patients with recurrent TI-CMV disease. Patients who underwent cadaveric kidney or kidney-pancreas transplantation were more likely to develop recurrent TI-CMV disease than were recipients of kidney transplants from living related donors; antirejection therapy also was associated with a higher incidence of recurrent TI-CMV disease. Patients who developed TI-CMV disease exhibited lower rates of graft and patient survival at 3 years than patients without TI-CMV disease or with solely asymptomatic CMV infection, although recurrent TI-CMV disease did not appear to exacerbate morbidity or mortality. We conclude that recurrent episodes of TI-CMV disease do not appear to further adversely affect patient or graft survival in comparison with primary TI-CMV disease in ganciclovir-treated patients.

Protective anti-lipopolysaccharide monoclonal antibodies inhibit tumor necrosis factor production.

Elevated systemic levels of tumor necrosis factor (TNF) have been directly correlated with increased mortality during experimental gram-negative bacterial sepsis. Although monoclonal antibodies (mAbs) directed against gram-negative bacterial lipopolysaccharide (endotoxin, LPS) decrease TNF production in vitro and enhance survival in vivo, the precise relationship between inhibition of TNF secretion and protective capacity has not been defined. We hypothesized that protective anti-LPS mAbs inhibited LPS-stimulated TNF production. To test this hypothesis, we first produced and characterized three anti-LPS mAbs. We then examined the ability of these mAbs to decrease TNF secretion in an in vitro assay using cells from the murine macrophage cell line RAW 264.7. Subsequently, we assessed the protective capacities of these anti-LPS mAbs in a murine mucin peritonitis model of sepsis using live Escherichia coli 0111:B4 bacterial challenge. Our results demonstrated that those anti-LPS mAbs that decreased LPS-stimulated TNF secretion in vitro were protective in vivo. We concluded that inhibition of TNF secretion in vitro reflected protective capacity and that anti-LPS mAbs may confer protection via abrogation of macrophage TNF secretion. Inhibition of TNF production in vitro may provide a valuable test that may facilitate the selection of protective anti-LPS mAbs.

Diagnosis and treatment of cytomegalovirus disease in transplant patients based on gastrointestinal tract manifestations.

Infection due to cytomegalovirus is a substantial cause of morbidity and mortality in immunocompromised patients. In particular, cytomegalovirus infection has been associated with a significant detrimental effect on patient and allograft survival after solid-organ transplantation. We are evaluating a new antiviral agent, ganciclovir 9-[1,3-dihydroxy-2-2 propoxymethyl] guanine (DHPG), used in solid-organ transplant recipients who developed life-threatening cytomegalovirus infections. Between March 1, 1987, and June 30, 1989, we treated 93 solid-organ transplant patients who developed tissue-invasive cytomegalovirus disease. From this group of patients we have identified 14 patients with primary gastrointestinal cytomegalovirus disease who received treatment with DHPG. Tissue diagnosis was made by endoscopy of the upper gastrointestinal tract (11 patients) or colonoscopy (three patients). Invasive cytomegalovirus disease was identified prior to severe complications of the gastrointestinal tract in all but one patient, who suffered colonic perforation prior to treatment with DHPG and subsequently died of bacterial sepsis. While 13 of the 14 patients improved after treatment with DHPG, four patients required additional treatments for recurrent cytomegalovirus disease and recovered. No DHPG toxicity was observed. We believe treatment with DHPG is indicated in this patient population, but that further studies are indicated to fully define the impact of this recommendation on both patient and allograft survival after solid-organ transplantation.

Evidence that combined procurement of pancreas and liver grafts does not affect transplant outcome.

We compared outcome after pancreas and liver transplantation when both organs were retrieved from the same donor to outcome when only one or the other organ was retrieved. A total of 166 cadaver pancreata were transplanted at our institution between November 1984 and August 1989; 64 were obtained from donors in whom the liver was also donated (LD), and 102 were retrieved from non-liver donors (non-LD). Of the 64 LD pancreata, 53 were the entire organ with a segment of duodenum and 11 were segmental. Both the superior mesenteric artery (SMA) and celiac axis (CA) were retained with the pancreas in 13, while in 40 pancreata the CA was retrieved with the liver and the blood supply to the pancreas was reconstructed [end-to-side anastomosis of splenic artery (SA) to SMA in 11 and a Y-graft of donor iliac bifurcation to SA and SMA in 29]; a graft of common iliac vein was used to extend the portal vein in 10. The technical failure rate was 8/64 (12%) in LD pancreata, and 13/102 (13%) in non-LD pancreata (P greater than 0.1). The overall pancreas allograft survival rate at 1 year was 76% for pancreata obtained from LD (n = 64) and 64% for technically successful transplanted pancreata obtained from non-LD (n = 102, P greater than 0.1). One-year actuarial patient survival was 95% in the LD group and 90% in the non-LD group (P greater than 0.1). Among the 64 livers from pancreas donors (PD), 20 were transplanted at our hospital, 42 were transported to other institutions, and 2 were not transplanted. Follow-up information regarding 47 primary orthotopic adult, whole liver PD recipients (18 at our hospital, 29 at other institutions) was available for analysis and was compared with information concerning 62 adult recipients of primary orthotopic whole livers from non-PD transplanted during the same period at our institution. The total PNF rate among 47 PD liver allografts was 2/47 (4%), compared with 1/62 (1%) for the livers from non-PD (P greater than 0.1). The technical failure rate for the PD group was 1/47 (2%) versus 5/62 (8%) in the non-PD group (P greater than 0.1). The overall liver allograft survival rate at 1 year was 75% for livers obtained from PD (n = 47) and 81% for livers obtained from non-PD (n = 62, P greater than 0.1). One-year actuarial patient survival was 88% in the PD group and 81% in the non-PD group (P greater than 0.1). We concluded that simultaneous procurement of liver and pancreas grafts had no significant detrimental effect on the rate of technical failure, or on allograft or patient survival after either pancreas or liver transplantation.

Resistance to graft-versus-host disease following small bowel transplantation.

Transplantation of a Lewis rat small bowel allograft (SBTx) into Lewis x Brown Norway F1 (LBNF1) hybrid recipients provokes lethal graft-versus-host disease. GVHD in F1 hybrid rats inoculated with large number of parental lymphocytes may be abrogated by prior treatment of F1 hybrids with a sublethal dose (SLD) of the same parental lymphocytes. Therefore, we sought to determine whether this type of immunomodulation would prevent GVHD after SBTx. We examined whether pretreatment of LBNF1 recipients with a SLD of parental lymphocytes, or with a revascularized segment of parental small bowel, might ameliorate GVHD following transplantation of the entire parental small bowel. Nonpretreated LBNF1 recipients died of GVHD after entire Lew SBTx; 95% of LBNF1 recipients pretreated with SLD of Lew lymphocytes and 84% of LBNF1 recipients first transplanted with a segment of Lew small bowel survived GVHD induced by entire Lew SBTx 10 days later. Of LBNF1 recipients pretreated with SLD of Brown Norway lymphocytes or first transplanted with a segment of BN small bowel, none were protected from GVHD induced by entire Lew SBTx 10 days later. We concluded that pretreatment of LBNF1 recipients either with an SLD of parental lymphocytes or with a segment of parental small bowel provides profound protection from the effects of GVHD following transplantation of an entire small bowel of the same parental strain specificity.

Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir.

The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.

Cross-reactive murine monoclonal antibodies directed against the core/lipid A region of endotoxin inhibit production of tumor necrosis factor.

Two murine monoclonal antibodies (mAbs) directed against the core/lipid A moiety of lipopolysaccharide (endotoxin, LPS) were derived from mice immunized with either Escherichia coli J5 or Salmonella minnesota Ra, Rb, Rc, or Re heat-killed organisms or LPS. These mAbs were selected on the basis of their ability to cross-react against a panel of gram-negative bacterial LPS using Western immunotransblot analysis. We hypothesized that these anti-LPS mAbs directed against the conserved core region of LPS would inhibit LPS-induced macrophage tumor necrosis factor (TNF) production by neutralizing LPS derived from different gram-negative bacteria. To test this hypothesis, unelicited peritoneal macrophages were treated with either mAb 5G11 (deep core/lipid A specificity, broad LPS cross-reactivity) or mAb 5B11 (intermediate core specificity, limited LPS cross-reactivity). Macrophages were then challenged with a panel of LPS, and TNF activity was measured by the use of the L929 cytotoxicity assay. MAb 5G11 significantly inhibited TNF production against a panel of different types of LPS, but mAb 5B11 did not. In addition, mAb 5G11 did not inhibit TNF production due to isolated lipid A stimulation, suggesting that mAb 5G11 neutralized LPS by binding primarily to the deep core region of LPS. MAb 5G11 was also able to inhibit TNF production if added within 10 min of LPS stimulation but had no effect at 30 min, suggesting that macrophage stimulation may be irreversible during even the early stages of the response to LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased tumor necrosis factor production during the initial stages of infection correlates with survival during murine gram-negative sepsis.

Secretion of tumor necrosis factor (TNF)/cachectin occurs during gram-negative bacterial sepsis in response to macrophage stimulation by lipopolysaccharide (endotoxin) and may play an early pivotal role in the subsequent host response. We sought to determine whether administration of: (1) murine monoclonal antibody directed against endotoxin, (2) steroids, or (3) antimicrobial agents would abrogate TNF production and whether the protective capacity would correlate with TNF levels in an experimental model of murine gram-negative bacterial sepsis. Mice were pretreated with anti-lipopolysaccharide monoclonal antibody, gentamicin sulfate, hydrocortisone, or saline and were then challenged with a lethal dose of intraperitoneal Salmonella minnesota. Murine serum TNF levels were measured by the L929 fibroblast cytotoxicity assay. Both gentamicin and anti-lipopolysaccharide monoclonal antibody significantly enhanced survival, and TNF activity at 1.5 and 3 hours was significantly suppressed in animals receiving these agents compared with animals that received either steroids or saline. We conclude that agents such as gentamicin, which inhibits bacterial replication, or monoclonal antibodies, which may neutralize lipopolysaccharide, indeed enhance survival, and survival was correlated with a significant reduction in circulating TNF during the early stages of infection.