ABSTRACT
Acanthamoeba is the most common cause of granulomatous amebic encephalitis, a typically fatal condition that is classically described as indolent and slowly progressive. We report a case of Acanthamoeba encephalitis in a kidney transplant recipient that progressed to death within 3 days of symptom onset and was diagnosed at autopsy. We also review clinical characteristics, treatments, and outcomes of all published cases of Acanthamoeba encephalitis in solid organ transplant (SOT) recipients. Ten cases were identified, and the infection was fatal in 9 of these cases. In 6 patients, Acanthamoeba presented in a fulminant manner and death occurred within 2 weeks after the onset of neurologic symptoms. These acute presentations are likely related to immunodeficiencies associated with solid organ transplantation that result in an inability to control Acanthamoeba proliferation. Skin lesions may predate neurologic involvement and provide an opportunity for early diagnosis and treatment. Acanthamoeba is an under-recognized cause of encephalitis in SOT recipients and often presents in a fulminant manner in this population. Increased awareness of this disease and its clinical manifestations is essential to attain an early diagnosis and provide the best chance of cure.
Subject(s)
Acanthamoeba/isolation & purification , Amebiasis/parasitology , Encephalitis/parasitology , Kidney Transplantation/adverse effects , Encephalitis/diagnosis , Fatal Outcome , Humans , Male , Middle AgedABSTRACT
Plasmapheresis (PP) is often employed in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the renal allograft, where it appears to be effective in the pediatric population. The efficacy of PP in adults and predictors of response are not well documented. We analyzed the records of 13 adult patients from three transplant centers who underwent PP for recurrent FSGS between 1993 and 1999. One patient (8%) had a complete response, one (8%) had a partial response, and 3 (23%) partially responded but remain PP-dependent. All 5 responders were started on PP within 30 days of recurrence, while 7 of the 8 non-responders initiated PP after a delay of at least 42 days (p = 0.0047). FSGS recurred within 30 days of transplantation in all 5 responders, while 4 of 8 non-responders had no evidence of recurrence until 42-150 days after transplantation (p = 0.098). Post-transplant biopsies were examined in 10 patients and revealed either cellular (6) or collapsing (4) variants of FSGS. We conclude PP is less effective in adults than in children as a treatment for recurrent FSGS in the renal allograft. Predictors of response to PP include early initiation of treatment after recurrence and possibly an early recurrence of disease.
Subject(s)
Glomerulosclerosis, Focal Segmental/etiology , Glomerulosclerosis, Focal Segmental/therapy , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , Plasmapheresis , Adult , Female , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kidney/pathology , Kidney/surgery , Kidney Failure, Chronic/pathology , Kidney Transplantation/pathology , Male , Middle Aged , Recurrence , Remission Induction , Retrospective Studies , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: To determine the relationship of hypolipidemia to cytokine concentrations and clinical outcomes in critically ill surgical patients. DESIGN: Consecutive, prospective case series. SETTING: Surgical intensive care unit of an urban university hospital. PATIENTS: Subjects were 111 patients with a variety of critical illnesses, for whom serum lipid, lipoprotein, and cytokine concentrations were determined within 24 hrs of admission to a surgical intensive care unit. Controls were 32 healthy men and women for whom serum lipid, lipoprotein, and cytokine concentrations were determined. INTERVENTIONS: Blood samples were drawn on admission to the intensive care unit. Predetermined clinical outcomes including death, infection subsequent to intensive care unit admission, length of intensive care unit stay, and magnitude of organ dysfunction were monitored prospectively. MEASUREMENTS AND MAIN RESULTS: Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoproteins A-I and B, phospholipid, triglyceride, interleukin-6, interleukin-10, soluble interleukin-2 receptor, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptors p55 and p75. Mean serum lipid concentrations were extremely low: total cholesterol, 127 +/- 52 mg/dL; low-density lipoprotein cholesterol, 75 +/- 41 mg/dL; high-density lipoprotein cholesterol, 29 +/- 15 mg/dL. Total, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations and apolipoprotein concentrations inversely correlated with interleukin-6, soluble interleukin-2 receptor, and interleukin-10 concentrations, whereas the triglyceride concentration correlated positively with tumor necrosis factor soluble receptors p55 and p75. Clinical outcomes were related to whether the admission cholesterol concentration was above (n = 56) or below (n = 55) the median concentration of 120 mg/dL. Each of the clinical end points occurred between 1.9- and 3.5-fold more frequently in the very low cholesterol (<120 mg/dL) group. Nine patients (8%) died during the hospitalization. Seven of the nine patients who died had total cholesterol concentrations below the median concentration of 120 mg/dL. CONCLUSIONS: Low cholesterol and lipoprotein concentrations found in critically ill surgical patients correlate with interleukin-6, soluble interleukin-2 receptor, and interleukin-10 concentrations and predict clinical outcomes.
Subject(s)
Cytokines/biosynthesis , Lipids/blood , APACHE , Adult , Aged , Aged, 80 and over , Cholesterol, HDL/blood , Critical Care , Cytokines/blood , Female , Humans , Intensive Care Units , Interleukins/blood , Length of Stay , Linear Models , Lipids/deficiency , Male , Middle Aged , Postoperative Period , Prospective Studies , Treatment OutcomeABSTRACT
The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9-center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.
Subject(s)
Blood Component Removal , Cholesterol/blood , Hyperlipoproteinemia Type II/therapy , Adolescent , Adult , Aged , Child , Child, Preschool , Dextran Sulfate , Female , Follow-Up Studies , Humans , Hyperlipoproteinemia Type II/blood , Lipoproteins, LDL/blood , Male , Middle Aged , Treatment Outcome , Triglycerides/bloodABSTRACT
The United States Liposorber Study was a 22 week randomized controlled study of low-density lipoprotein (LDL) apheresis with an optional follow-up phase. The procedure was found to acutely lower LDL cholesterol by up to 81%, have good tolerability, and produce a reduction in the frequency of cardiovascular events. Studies outside the United States have found therapy with LDL apheresis to be associated with a favorable clinical outcome including improved myocardial perfusion, but variable regression of coronary artery disease (CAD). Improvement in blood viscosity and endothelial function may help explain the symptomatic benefits observed with relatively small changes in angiography. Based upon favorable clinical experience, LDL apheresis using dextran sulfate cellulose columns has recently received approval for commercialization in the United States in patients with inadequate responses to diet and drug therapy and LDL levels > or = 200 mg with CAD present or LDL levels > or = 300 mg/dl without CAD.
Subject(s)
Blood Component Removal/trends , Lipoproteins, LDL/blood , Blood Component Removal/instrumentation , Coronary Disease/blood , Coronary Disease/prevention & control , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/therapy , Randomized Controlled Trials as TopicABSTRACT
The use of LDL-apheresis to treat patients with severe hypercholesterolemia has gained wider clinical acceptance during the past 2-3 years, particularly in patients with coronary artery disease. Systems utilizing immunoadsorption columns, dextran sulfate cellulose columns and heparin precipitation have been most commonly employed. New or improved technologies include whole-blood compatible columns, double-filtration plasmapheresis and lipoprotein (a)-apheresis. The mechanisms for clinical improvement extend beyond simple regression of atherosclerotic plaque.
Subject(s)
Blood Component Removal , Hypercholesterolemia/therapy , Lipoproteins, LDL/isolation & purification , Clinical Trials as Topic , Humans , Lipoproteins, LDL/blood , Treatment OutcomeABSTRACT
OBJECTIVES: To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients. SETTING: Surgical intensive care unit (ICU) of a large urban university hospital. DESIGN: Prospective case series. PATIENTS: A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production. INTERVENTIONS: Blood samples were drawn on admission to the ICU and over a subsequent 8-day period. MEASUREMENTS AND MAIN RESULTS: Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p = .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation. CONCLUSIONS: Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted high-density lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia.
Subject(s)
Endotoxins/blood , Lipids/blood , Toxemia/blood , Adult , Aged , Analysis of Variance , Apolipoproteins/isolation & purification , Apolipoproteins/therapeutic use , Critical Illness , Female , Humans , Lipoproteins/blood , Lipoproteins, HDL/isolation & purification , Lipoproteins, HDL/therapeutic use , Male , Middle Aged , Prospective Studies , Toxemia/drug therapy , Toxemia/prevention & control , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
A subset of patients with familial hypercholesterolemia (FH) have an inadequate lipid-lowering response to diet and drug treatment and should be considered for low-density lipoprotein (LDL)-apheresis therapy. This procedure selectively removes apolipoprotein B-containing particles [LDL, very-low-density lipoprotein, lipoprotein(a)] from plasma independent of diet and drug therapy. Methods for performing LDL-apheresis include dextran sulfate cellulose adsorption, immunoadsorption, and heparin-induced extracorporeal precipitation. The Liposorber Study Group evaluated LDL removal using the Liposorber LA-15 LDL-apheresis System in 64 patients with FH who had not responded adequately to diet and maximal drug therapy. Mean acute reductions in LDL cholesterol (LDL-C) were 76% in heterozygous FH (HtFH) patients and 81% in homozygous FH (HoFH) patients. Time-averaged levels of LDL-C were lowered 41% in HtFH and 53% in HoFH patients. Hypotension was the most frequent side effect, occurring in 3% of procedures. The Liposorber LA-15 System has been approved by the Food and Drug Administration and is recommended for 1) patients with functional homozygous FH (LDL-C level > 500 mg/dL; 2) patients with coronary artery disease (CAD) and LDL-C levels > or = 200 mg/dL; 3) patients without CAD, but an LDL-C level > or = 300 mg/dL.
Subject(s)
Blood Component Removal/methods , Hypercholesterolemia/therapy , Lipoproteins, LDL/isolation & purification , Plasmapheresis/methods , Cellulose , Dextran Sulfate , Humans , Hypercholesterolemia/bloodABSTRACT
Aclear relationship between the development of coronary artery disease (CAD) and elevated levels of low-density lipoprotein cholesterol (LDL-C) has been established. The benefits of reducing LDL-C on cardiac and overall mortality have also been shown. The second report of the National Cholesterol Education Program Expert Panel has recommended an LDL-C goal of 100 mg/dL in patients with CAD. Accordingly, cholesterol lowering has become an important strategy for reducing the incidence and progression of CAD.
ABSTRACT
LDL-apheresis is an extracorporeal plasma-perfusion method that selectively removes apolipoprotein B-containing lipoproteins from the blood. It is indicated for patients with homozygous and drug-resistant heterozygous familial hypercholesterolemia. Clinical and angiographic regression of coronary artery disease has been demonstrated in patients treated with cholesterol-lowering programs that include LDL-apheresis.
Subject(s)
Apolipoproteins B/blood , Blood Component Removal , Hyperlipoproteinemia Type II/therapy , Lipoproteins, LDL/blood , Blood Component Removal/methods , Cholesterol, LDL/metabolism , Clinical Trials as Topic , Coronary Disease/therapy , HumansSubject(s)
Blood Component Removal/methods , Hypercholesterolemia/therapy , Immunosorbent Techniques , Adult , Aged , Blood Component Removal/adverse effects , Blood Component Removal/instrumentation , Child , Cholesterol/analysis , Cholesterol, LDL , Cholestyramine Resin/therapeutic use , Coronary Disease/therapy , Dextran Sulfate , Humans , Lovastatin/therapeutic use , Middle Aged , Niacin/therapeutic use , Pilot ProjectsABSTRACT
Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.
Subject(s)
Calcium Channel Blockers/therapeutic use , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , Adult , Antibodies, Monoclonal/therapeutic use , Azathioprine/therapeutic use , Cadaver , Cyclosporine/therapeutic use , Drug Therapy, Combination , Female , Graft Rejection/prevention & control , Humans , Male , Middle Aged , Nifedipine/therapeutic use , Prednisone/therapeutic use , Survival Rate , Transplantation, Homologous/mortalityABSTRACT
Low-density lipoprotein apheresis (LDL-apheresis) is an extracorporeal procedure that preferentially removes LDL cholesterol from the blood. One of the primary techniques for performing this procedure uses immunoadsorption columns containing monospecific polyclonal sheep antibodies to human LDL covalently coupled to a gel filtration medium. LDL-apheresis has generally been well-tolerated, with chills, fever, or flushing occurring rarely. The possibility of an immune reaction was investigated as a basis for these reactions observed in 12 of the 1312 procedures performed. Antibodies to sheep IgG developed in 12 of the 15 patients treated with LDL-apheresis as a result of the shedding of small quantities of the sheep immunoglobulin from the columns. A column acid-washing procedure minimized the quantity of shed antibody but did not prevent immunization of the patient. The clinical reactions were probably unrelated to shedding and immunization, as the reactions occurred even in patients who were not immunized to the sheep IgG. Immunization to ethylene oxide was not the cause, as determined by a radioallergosorbent test. The reactions were more likely related to the activation of complement, as indicated by the generation of C3a des Arg by the columns and an increase in C3a des Arg levels systemically.
Subject(s)
Blood Component Removal , Hypercholesterolemia/therapy , Lipoproteins, LDL/blood , Antibody Formation , Complement Activation , Humans , Hypercholesterolemia/immunology , Immunosorbent Techniques , Radioallergosorbent TestABSTRACT
The direct relationship between hypercholesterolemia and atherosclerosis has resulted in formal cholesterol-lowering recommendations for patients at increased risk. The incomplete response to therapy of some forms of hypercholesterolemia as well as not uncommon drug intolerance prompted the development of extracorporeal techniques to reduce serum cholesterol levels. Nonhuman primate data and an analysis of human cholesterol epidemiology and reduction trials were used to establish guidelines that would maximize the likelihood of stabilizing or regressing established coronary artery atherosclerosis. These goals are a total cholesterol (TC) level of less than or equal to 150 mg/dL (3.9 mmol/L) and a ratio of TC to high-density lipoprotein cholesterol (HDL) of less than 2.8. Selective, extracorporeal removal of LDL cholesterol (LDL-pheresis) was combined with diet and hypolipidemic drugs in a pilot study at The Rogosin Institute to achieve these lipid end-points. Technical aspects of LDL-pheresis, the background rationale for its use as part of a combined hypolipidemic therapy, the initial experience at The Rogosin Institute, and plans for future studies and applications are presented.
Subject(s)
Blood Component Removal , Cholesterol, LDL/blood , Coronary Artery Disease/prevention & control , Hypercholesterolemia/therapy , Animals , Blood Component Removal/methods , Humans , Hypercholesterolemia/diet therapy , Hypercholesterolemia/drug therapyABSTRACT
A new technique called LDL-pheresis was used in patients to lower low-density lipoprotein cholesterol levels. This procedure combines continuous extracorporeal plasma separation with immunoadsorption of low-density lipoprotein on columns containing monospecific antibody to human apolipoprotein B. Six patients underwent a total of 164 procedures without significant side effects or nonspecific protein depletion. Acutely, LDL-pheresis lowered plasma cholesterol levels by removing up to 82 percent of the circulating low-density lipoprotein. Weekly LDL-pheresis combined with a portacaval shunt in a patient with homozygous familial hypercholesterolemia resulted in normalization of plasma cholesterol levels and rapid regression of skin xanthomata. Three of four patients with atherosclerotic coronary artery disease have noted improvement in their angina. LDL-pheresis appears to be a promising new technique capable of safely and efficiently lowering plasma low-density lipoprotein cholesterol levels.
Subject(s)
Hypercholesterolemia/metabolism , Immunosorbent Techniques , Lipoproteins, LDL/analysis , Adult , Child , Female , Humans , Hypercholesterolemia/therapy , Immunosorbent Techniques/standards , Male , Middle Aged , Plasma ExchangeABSTRACT
Plasma high density lipoprotein (HDL) concentrations were increased in five hypercholesterolemic normoglyceridemic patients after removal of plasma low density lipoprotein (LDL) by LDL-pheresis. In each patient up to 80% of circulating LDL was removed by passing plasma through immunoadsorption columns containing antibody to apolipoprotein B immobilized to Sepharose. Rebound of LDL was slow after the procedure: 5-7 days in four non-familial hypercholesterolemic patients and greater than 14 days in one patient with homozygous familial hypercholesterolemia. Plasma HDL rose above the pretreatment baseline during the interval between treatments in four of the five patients. When treatments were repeated weekly, time-averaged plasma LDL was lowered by 40-70%, while plasma HDL cholesterol and apolipoprotein AI were increased up to 2-fold, depending on the degree of LDL lowering. Plasma HDL concentrations fell back to their baseline values when LDL-pheresis was stopped and rose again when treatment was restarted. Thus, LDL-pheresis may augment the therapeutic effectiveness of LDL lowering by raising plasma HDL levels and the concentration of HDL relative to LDL.
Subject(s)
Blood Component Removal , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Adult , Child , Female , Humans , Hyperlipoproteinemia Type II/blood , Immunosorbent Techniques , Lipoproteins, VLDL/blood , Male , Middle AgedABSTRACT
Protein A-positive or -negative Staphylococcus aureus preparations were used in an extracorporeal system to treat dogs with spontaneously occurring cancers. Tumor regression was seen in 4 of 7 dogs treated by reinfusion of plasma that had been incubated with protein A-positive S. aureus Cowan I strain (SAC). Therapy was associated with fever, liver enzyme abnormalities, and hypocomplementemia. Tumor response and toxicity could be diminished by more extensive washing of the SAC preparation. Tumor regression was also seen in 2 of 2 animals treated with protein A-negative S. aureus Wood strain 46. In addition, tumors regressed in 3 of 4 dogs treated with infusions of protein A-free saline extracts from S. aureus. These results suggest that the release of a non-protein A bacterial product contributes to tumor regression following incubation of plasma with S. aureus.
Subject(s)
Breast Neoplasms/therapy , Lymphoma/therapy , Staphylococcal Protein A/administration & dosage , Staphylococcal Vaccines/administration & dosage , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Animals , Antigen-Antibody Complex/analysis , Breast Neoplasms/pathology , Complement System Proteins/analysis , Creatinine/blood , Dogs , Extracorporeal Circulation , Fever/etiology , Immunosorbent Techniques , Infusions, Parenteral , Injections, Intravenous , Lymphoma/pathology , Neoplasms, Experimental/therapy , Staphylococcal Protein A/adverse effects , Staphylococcal Vaccines/adverse effectsABSTRACT
A patient with steroid resistant, allergen related angioimmunoblastic lymphadenopathy underwent a course of six plasmaphereses during a three-week period. A 75% reduction in lymph node size along with the disappearance of her night sweats occurred. Immunologic abnormalities prior to plasmapheresis included the presence of elevated levels of circulating immune complexes, high levels of spontaneous mononuclear cell blastogenesis and abnormal mitogen responses to Conconavalin A and phytohemagglutinin. Following plasmapheresis there was a marked reduction in immune complex levels, and return of spontaneous blastogenesis and mitogen responses to normal levels. Mechanisms for the beneficial effect seen in this patient include removal of: (1) the antigenic stimulus; (2) antigen antibody complexes; and (3) other humoral factors which may modulate lymphocyte or macrophage function. Additional studies of plasmapheresis are warranted in selected patients with allergen related AIL.