Pulmonary Capillary Leak Syndrome Research Articles

Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) gL-1 , P<0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

FLT-3 ITD Positive Acute Basophilic Leukemia with Rare Complex Karyotype Presenting with Acute Respiratory Failure: Case Report

AbstractBackground: Acute basophilic leukemia is a rare subtype of acute myeloid leukemia, as categorized by the 2008 World Health Organization classification of myeloid neoplasms. Acute basophilic leukemia diagnosis requires thorough morphological, cytochemical, immunophenotypic, molecular, and cytogenetic studies and exclusion of other hematological neoplasms associating basophilia. The disease course is defined by histamine driven, occasionally life-threatening respiratory, cardiovascular, cutaneous or digestive complications, as well as primary refractoriness to standard therapy. Clinical presentation: We herein report a case of a 63-year-old asthmatic female patient diagnosed with acute basophilic leukemia, associated with previously unpublished cytogenetic features and FLT-3 ITD mutation, pulmonary leukostasis and spontaneous pulmonary capillary leak syndrome, which worsened immediately following chemotherapy initiation. Respiratory complications were successfully managed, but recrudesced upon emergence of refractory disease and were ultimately fatal. We highlight the likelihood of pulmonary complications induced by basophil degranulation and tumor lysis in hypercellular acute basophilic leukemia and the potential benefit of histamine receptor blockade in this setting.

Sargramostim (GM-CSF) for induction of remission in Crohn's disease

Crohn's disease is an inflammatory condition of the gut, thought to involve an overactive immune response to gut flora. A novel theory postulates possible immunodeficiency as a cause, and aims to use sargramostim (granulocyte macrophage colony stimulating factor, GM-CSF) to boost the immune system in an effort to test this hypothesis. The primary objectives were to determine the efficacy and safety of sargramostim for induction of remission in patients with clinically active Crohn's disease. A systematic search of MEDLINE, EMBASE, and CENTRAL was conducted from inception to April 2011. Reference lists of relevant review articles were also searched. Trial registries and abstract databases including Digestive Diseases Week (1980-2010) and United European Gastroenterology Week (2005-2009) were searched to identify studies published in abstract form. Randomized controlled trials of sargramostim for the treatment of patients with active Crohn's disease were considered for inclusion. Data from selected articles were extracted and the Cochrane Risk of Bias tool applied independently by two authors. The primary outcome was induction of clinical remission as defined by a Crohn's Disease Activity Index (CDAI) of < 150 at the end of treatment. Secondary outcomes included clinical responses measures on the CDAI and safety outcomes. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes, in most cases using a random effects model due to high heterogeneity. Three studies were identified, 2 published as full papers and one in abstract form (537 patients). The risk of bias was low for the 3 included studies. There was no statistically significant difference in the proportion of patients (GM-CSF 25.3% versus placebo 17.5%) who achieved clinical remission (RR 1.67; 95% CI 0.80 to 3.50; P = 0.17; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 38.3% versus placebo 24.8%) who achieved a 100-point clinical response (RR 1.71 95% CI 0.98 to 2.97; P = 0.06; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 54.3% versus placebo 44.2%) who achieved a 70 point clinical response (RR 1.23; 95% CI 0.83 to 1.82; P = 0.30; 1 study; 124 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 95.8% versus placebo 89.3%) who experienced at least one adverse event (RR 1.07; 95% CI 0.99 to 1.16; P = 0.08; 2 studies; 251 patients), or serious adverse events (GM-CSF 12.0% versus placebo 4.8%; RR 2.21; 95% CI 0.84 to 5.81; P = 0.11; 2 studies; 251 patients). The incidence of bone pain, musculoskeletal chest pain, and dyspnea were higher in patients treated with sargramostim compared to placebo. Other adverse events commonly associated with sargramostim such as pulmonary capillary leak syndrome, pulmonary edema, heart failure, fever, and neurotoxicity were not reported in these studies. Sargramostim does not appear to be more effective than placebo for induction of clinical remission or clinical improvement in patients with active Crohn's disease. However, the GRADE analysis indicates that the overall quality of the evidence for the primary (clinical remission) and secondary outcomes (clinical response) was low indicating that further research is likely to have an impact on the effect estimates.

Pulmonary Capillary Leak Syndrome as a Result of OKT-3 Therapy

Pulmonary Capillary Leak Syndrome as a Result of OKT-3 Therapy

Convalescent Pulmonary Dysfunction Following Hantavirus Pulmonary Syndrome in Panama and the United States

The objective of this study was to document persistent pulmonary symptoms and pulmonary function abnormalities in adults surviving hantavirus pulmonary syndrome (HPS). Acute infection by most hantaviruses result in mortality rates of 25–35%, while in Panama the mortality rate of 10% is contrasted by an unusually high incidence. In all types of HPS, the viral prodrome, cardiopulmonary phase due to massive pulmonary capillary leak syndrome, and spontaneous diuresis are followed by a convalescent phase with exertional dyspnea for 3–4 weeks, but the frequency of persistent symptoms is not known. In this observational study of a convenience sample, 14 survivors of HPS caused by Choclo virus infection in Panama and 9 survivors of HPS caused by Sin Nombre virus infection in New Mexico completed a questionnaire and pulmonary function tests up to 8 years after infection. In both groups, exertional dyspnea persisted for 1–2 years after acute infection in 43% (Panama) and 77% (New Mexico) of survivors surveyed. Reduction in midexpiratory flows (FEF25–75%), increased residual volume (RV), and reduced diffusion capacity (DLCO/VA) also were common in both populations; but the severity of reduced expiratory flow did not correlate with exertional dyspnea. Symptoms referable to previous hantavirus infection had resolved within 3 years of acute infection in most but not all patients in the Panama group. Temporary exertional dyspnea and reduced expiratory flow are common in early convalescence after HPS but resolves in almost all patients.

Pulmonary capillary leak syndrome after influenza A (H1N1) virus infection

Pulmonary capillary leak syndrome after influenza A (H1N1) virus infection

Acute pulmonary capillary leak syndrome during elective surgery under general anesthesia

A 75-year-old previously healthy man presented for elective resection of rectal cancer under general anesthesia. Six days before the operation, he had a high-grade fever, and elevated leukocyte count and C-reactive protein concentration, but this was resolved by an intravenous antibiotic. His condition was well controlled before the operation. Soon after the operation started, severe hypoxemia emerged, with low arterial pressure. Fiberoptic bronchoscopy demonstrated a massive amount of plasma-like edema fluid; the total amount of suctioned fluid was approximately 800 ml at the end of the surgery. This acute pulmonary edema appeared to be due to increased permeability rather than pulmonary congestion as indicated by chest radiography, pulmonary artery occlusion pressure, echocardiogram, and the protein-rich edema fluid. Elevated concentrations of the proinflammatory cytokines, interleukin (IL)-6 and IL-8, in both plasma and the pulmonary edema fluid, suggested a possible role of systemic and pulmonary inflammation in the development of this acute pulmonary capillary leak. According to the "two-hit" hypothesis, the bacterial infection preceding the operation may have primed the immune cells, and the following surgical stress may have then triggered rapid progression of acute respiratory distress syndrome. We should keep in mind that, especially following sepsis, sudden massive pulmonary capillary leak can occur during elective surgery, even though the patient's condition is well controlled.

Hantavirus Cardiopulmonary Syndrome

Hantavirus cardiopulmonary syndrome (HCPS) is caused by infection with multiple types of hantaviruses throughout the Americas. All strains induce a pulmonary capillary leak syndrome with cardiogenic shock in severe cases, and almost all strains have an overall mortality rate of 35%. Some strains in South America are commonly associated with either mild disease without pulmonary edema or severe disease with pulmonary hemorrhage. Early recognition during the thrombocytopenic prodrome phase and transport to intensive care improve survival, due to very rapid progression of respiratory failure and shock in some patients. Limited fluid replacement, early inotropic therapy, and mechanical ventilation also improve survival. Extracorporeal membrane oxygenation (ECMO) has been life saving for patients with refractory shock. Ribavirin does not appear to reduce mortality, but hyperimmune serum offers a promising future therapy because survival is correlated with higher neutralizing antibody titers at admission.

Analysis of therapeutic and immunologic effects of R24 anti‐GD3 monoclonal antibody in 37 patients with metastatic melanoma

BACKGROUND Antitumor effects of antibodies against ganglioside antigens of melanoma have been reported, but neither optimal doses nor mechanisms have been established. METHODS This Phase IB trial of the murine immunoglobulin IgG3 monoclonal antibody R24 against disialoganglioside GD3 was conducted with 37 patients to define better the dose-response relation and mechanism of action of R24 in patients with metastatic melanoma. RESULTS Dose-limiting toxicity consisted of a pulmonary capillary leak syndrome in 3 of 5 patients in the 80 mg/M2/day dosage tier. Serial blood and tumor biopsy samples were obtained prior to therapy and on Days 5, 9, and 22 following R24 infusion. Tumor biopsy-infiltrating lymphocytes were enumerated in peritumoral, endotumoral, and perivascular compartments: endotumoral CD4+ and CD8+ T cells and HLA-DR+ T cells increased over time on R24 antibody. Endotumoral CD4 lymphoid infiltrate activation (DR expression) and antibody-dependent cytotoxicity were the greatest in the one patient who achieved a complete response. CONCLUSIONS Clinical response was associated with depression in natural killer (CD56+ and CD56+DR+) blood cells (P = 0.03) and was associated with R24 dosage (P = 0.01). A complete response that lasted 2 years and a partial response that lasted 2 months occurred at a dose of 1 mg/M2/day. The limited number of clinical responses observed in this trial hampered the correlation of antitumor and immune parameters but provided a rational foundation for the future evaluation of antiganglioside antibodies. Cancer 2000;88:2693–702. © 2000 American Cancer Society.

Analysis of therapeutic and immunologic effects of R24 anti-GD3 monoclonal antibody in 37 patients with metastatic melanoma

Antitumor effects of antibodies against ganglioside antigens of melanoma have been reported, but neither optimal doses nor mechanisms have been established. This Phase IB trial of the murine immunoglobulin IgG(3) monoclonal antibody R(24) against disialoganglioside GD3 was conducted with 37 patients to define better the dose-response relation and mechanism of action of R(24) in patients with metastatic melanoma. Dose-limiting toxicity consisted of a pulmonary capillary leak syndrome in 3 of 5 patients in the 80 mg/M(2)/day dosage tier. Serial blood and tumor biopsy samples were obtained prior to therapy and on Days 5, 9, and 22 following R(24) infusion. Tumor biopsy-infiltrating lymphocytes were enumerated in peritumoral, endotumoral, and perivascular compartments: endotumoral CD4(+) and CD8(+) T cells and HLA-DR(+) T cells increased over time on R(24) antibody. Endotumoral CD4 lymphoid infiltrate activation (DR expression) and antibody-dependent cytotoxicity were the greatest in the one patient who achieved a complete response. Clinical response was associated with depression in natural killer (CD56(+) and CD56(+)DR(+)) blood cells (P = 0.03) and was associated with R(24) dosage (P = 0.01). A complete response that lasted 2 years and a partial response that lasted 2 months occurred at a dose of 1 mg/M(2)/day. The limited number of clinical responses observed in this trial hampered the correlation of antitumor and immune parameters but provided a rational foundation for the future evaluation of antiganglioside antibodies.

Hantavirus pulmonary syndrome

<h2>Abstract</h2> The number of known HPS cases in the United States is now more than 150, and the illness has occurred in all geographic areas of the country. Though the incidence of the disease is low, the mortality rate remains at 50%, owing to the difficulty in treating a simultaneous severe pulmonary capillary leak syndrome and cardiogenic shock. Adequate treatment of severe cases requires experienced critical care physicians and nurses, as well as advanced facilities. Although nosocomial transmission appears unlikely in North America, universal precautions must be used, and some consideration may be given to the use of respiratory isolation.

Critical care issues in the patient with hematologic malignancy

Patients with lymphomas, multiple myeloma, and leukemia are often at risk for life-threatening complications. Complications include viral infections (eg, herpes zoster, herpes simplex, cytomegalovirus) and hemolytic anemia, which are related to the hematologic origin of the malignancy. Life-threatening disorders related to amount of tumor burden are leukostasis and hyperviscosity. Complications related to therapy include pulmonary capillary leak syndrome and tumor lysis syndrome. Good assessment skills assist in early identification of individuals at risk and initiation of preventive measures.

Clinical and Immunologic Effects of Prolonged Infusion of Low-Dose Recombinant Interleukin-2 After Autologous and T-Cell-Depleted Allogeneic Bone Marrow Transplantation

Bone marrow transplantation (BMT) can produce prolonged clinical remission in some patients with hematologic malignancies. Unfortunately, disease relapse may occur despite BMT. Studies in animal models and clinical experience have provided evidence that immunologic factors play an important role in preventing relapse post-BMT. To stimulate immunologic activity in patients post-BMT, we administered prolonged uninterrupted continuous infusions of low-dose recombinant interleukin-2 (rIL-2). Thirteen marrow recipients (seven autologous BMT, six CD6 T-depleted allogeneic BMT) received rIL-2 at a dose of 2 x 10(5) U/m2/d for a scheduled period of 90 days. rIL-2 was administered through a Hickman catheter with a portable pump beginning a median of 85 days after BMT. Toxicity was minimal and all treatment could be undertaken in the outpatient setting. No patient developed any signs of graft-versus-host disease, hypotension, or pulmonary capillary leak syndrome. Treatment did not affect the absolute neutrophil count or hemoglobin level, but eosinophils increased substantially in most patients. Platelet counts decreased by 20% in 10 of 13 individuals within 2 weeks, but stabilized thereafter. Despite the low dose of rIL-2 administered, significant immunologic changes were noted. Specifically, all 13 patients experienced a marked increase (fivefold to 40-fold) in natural killer (NK) cell number. Phenotypic characterization showed that the majority of NK cells were CD56bright+ CD16+ CD3-. In contrast, a minor increase in T-cell number was noted in only 4 of 13 patients. Low-dose rIL-2 treatment resulted in augmentation of in vitro cytotoxicity against K562 and COLO tumor targets. This cytotoxic activity could be dramatically enhanced by incubation with additional rIL-2 in vitro. The immunologic effects of rIL-2 treatment were similar in both autologous and allogeneic marrow recipients. Our data suggest that prolonged infusion of rIL-2 at low doses is safe and can selectively increase NK cell number and activity after BMT. Further studies to assess the impact these changes may have on disease relapse post-BMT will be undertaken.

Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation

Bone marrow transplantation (BMT) can produce prolonged clinical remission in some patients with hematologic malignancies. Unfortunately, disease relapse may occur despite BMT. Studies in animal models and clinical experience have provided evidence that immunologic factors play an important role in preventing relapse post-BMT. To stimulate immunologic activity in patients post-BMT, we administered prolonged uninterrupted continuous infusions of low-dose recombinant interleukin-2 (rIL-2). Thirteen marrow recipients (seven autologous BMT, six CD6 T-depleted allogeneic BMT) received rIL-2 at a dose of 2 x 10(5) U/m2/d for a scheduled period of 90 days. rIL-2 was administered through a Hickman catheter with a portable pump beginning a median of 85 days after BMT. Toxicity was minimal and all treatment could be undertaken in the outpatient setting. No patient developed any signs of graft-versus-host disease, hypotension, or pulmonary capillary leak syndrome. Treatment did not affect the absolute neutrophil count or hemoglobin level, but eosinophils increased substantially in most patients. Platelet counts decreased by 20% in 10 of 13 individuals within 2 weeks, but stabilized thereafter. Despite the low dose of rIL- 2 administered, significant immunologic changes were noted. Specifically, all 13 patients experienced a marked increase (fivefold to 40-fold) in natural killer (NK) cell number. Phenotypic characterization showed that the majority of NK cells were CD56bright+ CD16+ CD3-. In contrast, a minor increase in T-cell number was noted in only 4 of 13 patients. Low-dose rIL-2 treatment resulted in augmentation of in vitro cytotoxicity against K562 and COLO tumor targets. This cytotoxic activity could be dramatically enhanced by incubation with additional rIL-2 in vitro. The immunologic effects of rIL-2 treatment were similar in both autologous and allogeneic marrow recipients. Our data suggest that prolonged infusion of rIL-2 at low doses is safe and can selectively increase NK cell number and activity after BMT. Further studies to assess the impact these changes may have on disease relapse post-BMT will be undertaken.

Pulmonary capillary leak syndrome complicating generalized pustular psoriasis: possible role of cytokines

Two cases are reported of generalized pustular psoriasis complicated by profound alterations in pulmonary capillary permeability. Several features suggest the involvement of cytokines in the pathogenesis of this condition.