Pulmonary Adverse Reactions Research Articles

Endoalveolar haemorrhage due to methotrexate overdosage in a patient treated for psoriatic arthritis

There are no previous reports of adverse pulmonary reactions in psoriatic patients treated for a long time with low dosages of methotrexate (MTX). We successfully treated a 57-year-old woman, affected with psoriasis and psoriatic arthritis, with 7.5 mg/week MTX for 24 months. One year later the patient herself, without any medical supervision, took 7.5 mg MTX every day instead of once a week, for a period of 15 days, after which she developed a nonproductive cough, increasing dyspnoea and fever. We discontinued MTX and introduced antibiotic therapy. The clinical course was unchanged. Chest radiograph, HRCT, bronchoalveolar lavage and transbronchial biopsy demonstrated haemosiderosis and focal mild fibrosis. The diagnosis was pulmonary adverse reaction to MTX. Corticosteroid therapy was introduced which produced a rapid clinical improvement. We describe this side-effect, never seen before, emphasizing that it occurred as a result of excessiveovertreatment.

Hyperventilation induces release of cytokines from perfused mouse lung.

Artificial mechanical ventilation represents a major cause of iatrogenic lung damage in intensive care. It is largely unknown which mediators, if any, contribute to the onset of such complications. We investigated whether stress caused by artificial mechanical ventilation leads to induction, synthesis, and release of cytokines or eicosanoids from lung tissue. We used the isolated perfused and ventilated mouse lung where frequent perfusate sampling allows determination of mediator release into the perfusate. Hyperventilation was executed with either negative (NPV) or positive pressure ventilation (PPV) at a transpulmonary pressure that was increased 2.5-fold above normal. Both modes of hyperventilation resulted in an approximately 1.75-fold increased expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) mRNA, but not of cyclooxygenase-2 mRNA. After switching to hyperventilation, prostacyclin release into the perfusate increased almost instantaneously from 19 +/- 17 pg/min to 230 +/- 160 pg/min (PPV) or 115 +/- 87 pg/min (NPV). The enhancement in TNFalpha and IL-6 production developed more slowly. In control lungs after 150 min of perfusion and ventilation, TNFalpha and IL-6 production was 23 +/- 20 pg/min and 330 +/- 210 pg/min, respectively. In lungs hyperventilated for 150 min, TNFalpha and IL-6 production were increased to 287 +/- 180 pg/min and more than 1,000 pg/min, respectively. We conclude that artificial ventilation might cause pulmonary and systemic adverse reactions by inducing the release of mediators into the circulation.

The incidence of adverse pulmonary reactions to mitomycin was low

The incidence of adverse pulmonary reactions to mitomycin was low

Neutrophil Activation Mediates Protamine-Induced Pulmonary Hypertension

Protamine reversal of heparin anticoagulation can cause catastrophic pulmonary hypertension, systemic hypotension, and hypoxemia. This reaction is thought to be associated with pulmonary sequestration of activated neutrophils. To examine whether this reaction could be prevented by blocking neutrophil activation with NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl)-l-leucine), an inhibitor of Mac-1 adhesion molecule up-regulation, we gave 12 piglets a heparin bolus (300 IU/kg iv) followed by protamine (3 mg/kg iv over 90 sec) 15 min later. Six of the piglets received NPC 15669 (10 mg/kg iv bolus, then 6 mg/kg/hr iv infusion) 15 min before the heparin bolus. Two minutes after protamine administration, CD18 (β-sub-unit of Mac-1) expression measured by immunofluorescence flow cytometry increased 128 ± 9% (mean ± SEM) over preprotamine levels in control piglets but remained unchanged in NPC piglets (99 ± 2%, P < 0.05). Fifteen minutes after protamine, lung myeloperoxidase activity, an index of neutrophil degranulation, was significantly lower in the NPC group (87.83 ± 10.04 versus 57.23 ± 2.59 μmol/10 mg; P < 0.005). NPC 15669 also prevented postreversal pulmonary artery hypertension (158 ± 30, 150 ± 20, and 140 ± 13 versus 91 ± 7, 91 ± 18, and 85 ± 9% preprotamine at Minutes 2, 5, and 10; P < 0.05). Systemic arterial pressure, cardiac output, and circulating neutrophil counts were not different between groups. These results demonstrate that (1) neutrophil activation occurs following protamine reversal of heparin anticoagulation and (2) inhibition of neutrophil activation prevents pulmonary hypertension after protamine reversal, suggesting an important role for neutrophils in the adverse pulmonary hypertensive reactions related to protamine reversal of heparin.

Pulmonary reactions to tartrazine

In this report we have reviewed the medical literature and outlined the history of, support for and prior conclusions about adverse pulmonary reactions to tartrazine. Data obtained during oral tartrazine challenges, conducted at Scripps Clinic and Research Foundation, revealed the following: in 194 aspirin (ASA)‐sensitive asthmatic patients, asthmatic attacks, occurring after ingestion of tartrazine, occurred in only one patient. Since this patient has not been available for rechallenge, using double blind protocol, we cannot definitively conclude that this patient has tartrazine induced asthmatic cross‐reactivity. In the remaining six patients with initial single‐blind positive challenges to tartrazine, repeat double blind challenges were subsequently negative. In 43 asthmatic patients, proven to be insensitive to ASA during oral challenges, none reacted to single blind challenges with tartrazine 50 mg.

THE HARD METAL DISEASES

Hard metal is a mixture of tungsten carbide and cobalt, to which small amounts of other metals may be added. It is widely used for industrial purposes whenever extreme hardness and high temperature resistance are needed, such as for cutting tools, oil well drilling bits, and jet engine exhaust ports. Cobalt is the component of hard metal that can be a health hazard. Respiratory diseases occur in workers exposed to cobalt--either in the production of hard metal, from machining hard metal parts, or from other sources. Adverse pulmonary reactions include asthma, hypersensitivity pneumonitis, and interstitial fibrosis. A peculiar, almost unique form of lung fibrosis, giant cell interstitial pneumonia, is closely linked with cobalt exposure.

High Incidence of Bronchospasm with Regular Administration of Aerosolized Pentamidine

A systematic evaluation of changes in pulmonary status by objective spirometric assessment and subjective rating using visual analog scale was performed in a cohort of 134 patients receiving aerosolized pentamidine (AP) for the prevention of Pneumocystis carinii pneumonia. Significant bronchospasm defined as greater than or equal to 15 percent reduction in the forced expiratory volume in 1 s was noted in 26 of 100 (26 percent) of patients receiving AP alone. Despite the use of salbutamol (albuterol) as concurrent aerosolized treatment in 34 subjects, bronchospasm developed in 9 of 34 (26 percent) of the patients. The subjective respiratory status rating scale was found to be unreliable in correctly predicting the development of bronchospasm. We conclude that a high incidence of bronchospasm is present in patients receiving regular AP administration using an ultrasonic nebulizer as studied, and concurrent administration of salbutamol is not fully protective of this acute adverse pulmonary reaction.

Delayed Pulmonary Fibrosis after Nitrosourea Therapy

Adverse pulmonary reactions resulting from the use of chemotherapeutic agents are a life-threatening complication of modern cancer therapy. Their recognition and differentiation from lung injuries with infectious or other causes present a continuing diagnostic challenge to physicians treating patients with cancer. Many commonly used chemotherapeutic agents cause pulmonary injury and fibrosis. Until now, bleomycin has been the prototype, with fibrosis occurring in approximately 10 percent of patients receiving this agent, in whom it is fatal in roughly 10 percent.1 Adverse pulmonary reactions have also been associated with other cytotoxic agents, including busulfan, cyclophosphamide, chlorambucil, methotrexate, cytarabine, and the nitrosourea compounds; . . .

Reduced lipid peroxidation in dilated hearts of cardiomyopathy turkeys

Adverse pulmonary reactions to some nitrofuran antibiotics are thought, in part, to involve production of reactive oxygen radicals. Furazolidone, a nitrofuran antibiotic, causes a dilated cardiomyopathy in domestic turkeys. The mechanism of this drug induced cardiomyopathy is unknown. We investigated the possible role of free radical injury in this heart failure model. Left ventricular lipid peroxidation capacity, assessed by two methods (the thiobarbituric acid reactive substances and lipid hydroperoxides assays respectively), was investigated in five 5-8 week old cardiomyopathic turkeys with severe cardiac dilatation, left ventricular dysfunction and systemic hypotension, and in five control birds. Superoxide dismutase activity, total and manganese, was also measured in the crude left ventricular homogenates. Both lipid peroxidation products were reduced in the myopathic hearts: thiobarbituric acid reactive substances (malondialdehyde) 70(SEM 4) v 86(3) nmol.100 mg protein-1 in controls, p less than 0.02; and lipid hydroperoxides 29(7) v 74(14) nmol.100 mg protein-1, p less than 0.02. Total superoxide dismutase activity was similar in cardiomyopathic and control hearts: 670(26) v 657(105) nitrite units.100 mg protein-1. Although total superoxide dismutase activity was unchanged, we found decreased manganese superoxide dismutase in the dilated hearts compared with controls (54% v 84% of total activity, p less than 0.02). In separate in vitro experiments furazolidone (2-10 mg.g wet weight-1) did not increase malondialdehyde production in turkey (or rat) left ventricular homogenates. These results indicate that cardiomyopathy induced by furazolidone is associated with decreased myocardial lipid peroxidation. Although as yet unexplained, the decrease may be due to a diminished amount of heart lipid susceptible to peroxidation accompanying the process of cardiac hypertrophy and dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal responses to aspirin of leukocyte oxygenation of arachidonic acid in adults with aspirin intolerance

The effect of 1 μ and 5 μ aspirin on oxygenation of arachidonic acid in vitro by basophils stimulated with anti-IgE was assessed with basophil-enriched suspensions of mononuclear leukocytes from five patients with asthma and hypertrophic allergic rhinitis and one patient with rhinitis alone who had recent adverse pulmonary reactions to aspirin, four aspirin-tolerant patients with asthma receiving therapy similar to that of the aspirin-sensitive patients, and eight normal subjects who resembled the patients with respect to sex and age. As quantified by the combined application of high-performance liquid chromatography and radioimmunoassays, the generation of the principal products prostaglandin E 2 (PGEZ 2) and leukotriene D 4 was modified differently by aspirin but not sodium salicylate in the aspirin-sensitive patients. The alterations of PGE 2 generation and of the ratio of leukotriene D 4 to PGE 2 generation by aspirin were much greater for basophil-containing leukocytes of aspirin-sensitive patients than those of the nvo control groups. Although the basic mechanism and relevance to pulmonary reactions 9f the observed effects of aspirin were not elucidated, aspirin clearly modifies the leukocyte oxygenation of arachidonic acid differently in aspirin-sensitive patients.

Pulmonary Disease in the Immunocompromised Host (First of Two Parts)

With few exceptions, pulmonary complications in the immunocompromised host will proceed to death unless the clinician intercedes. The differential diagnosis of diffuse pulmonary disease in this setting includes (1) infection, most commonly from opportunistic organisms; (2) recurrence or extension of the basic underlying disease process to involve the lungs; (3) adverse pulmonary reaction to drugs; (4) a new, unrelated disease process such as cardiac pulmonary edema or pulmonary emboli; and (5) any combination of these categories. Up to a third of these patients have two or more complications, such as pneumonitis from two different opportunistic organisms or an opportunistic infection and a drug-induced pulmonary complication. An understanding of the host defense that is compromised enables the clinician to narrow the differential diagnosis. The most common types of impairment of defense mechanisms are reductions in the number of granulocytes, B-lymphocytes, or T-lymphocytes, and not uncommonly, two or all three of these types of cells are involved. Impairment of each of these cell types is associated with an increased frequency of infection by a particular group of organisms. Consequently, the clinician can be somewhat selective if empiric therapy is being considered. In the immunocompromised patient, most pulmonary complications, including drug-induced pulmonary disease and pulmonary emboli, are associated with fever that mimics an infection. Up to 25% of the pulmonary complications in these patients are noninfectious.

Serious adverse effects of amiodarone.

Amiodarone is an effective antiarrhythmic drug which has been used successfully to treat a variety of cardiac arrhythmias. Early reports emphasized both the striking efficacy of this agent and the relative paucity of side effects necessitating discontinuing treatment with this drug. As amiodarone has been used more widely and in more diverse patient populations, reports of serious thyroid, pulmonary, cardiovascular, and other adverse reactions have appeared in the literature. In this paper, we review the serious adverse effects that have been reported to date. The incidence of these reactions varies considerably in different series, and cannot be explained solely by different doses employed or by varying methods of drug administration. The final role of amiodarone in the therapy of cardiac arrhythmias cannot be determined until the long-term toxicity has been more thoroughly investigated.

Activation of Plasma Complement by Perfluorocarbon Artificial Blood: Probable Mechanism of Adverse Pulmonary Reactions in Treated Patients and Rationale for Corticosteroid Prophylaxis

Abstract Perfluorocarbons have shown promise as clinical blood substitutes. Although early experience in Japan with one such product--Fluosol-DA-- has been uncomplicated, we observed an adverse pulmonary reaction in the first American patient to receive it and know of similar reactions in two other Americans so treated. Postulating that activation of plasma complement (C) by the perfluorocarbon emulsion might have caused the reaction, we tested the product to determine if it is an activator of complement. Incubation of Fluosol with plasma led to C3 conversion, decrement in CH50, and generation of C5a-related PMN aggregating activity; EDTA prevented such activation, while EGTA did not, suggesting that it proceeded via the alternative C pathway. Infusion of Fluosol into rabbits produced hypoxemia, neutropenia, thrombocytopenia, and pulmonary leukostasis, mimicking abnormalities previously demonstrated in rabbits receiving infusions of zymosan-activated plasma C. These deleterious responses to Fluosol were diminished by premedicating rabbits with corticosteroids (which had seemed to benefit when used empirically in our patient). In vitro and in vivo, Fluosol's effects were reproduced by Pluronic F-68, the nonionic detergent used to maintain the emulsion stability of Fluosol-DA. We conclude that adverse reactions to Fluosol are probably mediated by C activation and that steroid premedication may prevent them in susceptible patients.

Activation of plasma complement by perfluorocarbon artificial blood: probable mechanism of adverse pulmonary reactions in treated patients and rationale for corticosteroids prophylaxis

Perfluorocarbons have shown promise as clinical blood substitutes. Although early experience in Japan with one such product--Fluosol-DA--has been uncomplicated, we observed an adverse pulmonary reaction in the first American patient to receive it and know of similar reactions in two other Americans so treated. Postulating that activation of plasma complement (C) by the perfluorocarbon emulsion might have caused the reaction, we tested the product to determine if it is an activator of complement. Incubation of Fluosol with plasma led to C3 conversion, decrement in CH50, and generation of C5a-related PMN aggregating activity; EDTA prevented such activation, while EGTA did not, suggesting that it proceeded via the alternative C pathway. Infusion of Fluosol into rabbits produced hypoxemia, neutropenia, thrombocytopenia, and pulmonary leukostasis, mimicking abnormalities previously demonstrated in rabbits receiving infusions of zymosan-activated plasma C. These deleterious responses to Fluosol were diminished by premedicating rabbits with corticosteroids (which had seemed to benefit when used empirically in our patient). In vitro and in vivo, Fluosol's effects were reproduced by Pluronic F-68, the nonionic detergent used to maintain the emulsion stability of Fluosol-DA. We conclude that adverse reactions to Fluosol are probably mediated by C activation and that steroid premedication may prevent them in susceptible patients.

Pulmonary complications of drug therapy.

Adverse pulmonary reaction to systemically administered drugs is a common occurrence. The roentgen patterns produced by adverse drug reactions can be grouped into five major categories. Agents known to cause pleuropulmonary complications are listed. A careful drug history should be as much a part of the evaluation of a patient with disseminated or recurrent pulmonary disease as is the occupational history.