Diagnosis: Chronic eosinophilic bronchitis/bronchiolitis (clinical diagnosis: asphyxic asthma)

Comment: The progressive dyspnea preceding the terminal respiratory arrest and the prominent mucous plugs found at autopsy indicate that the death was not a sudden asphyxic attack [1] but rather one of gradual onset, for which the patient did not seek medical help.


Asthma

Definition: Asthma is characterized by widespread narrowing of airways in response to various stimuli. It remits spontaneously or with treatment. An expanded definition currently in use states that asthma is a chronic inflammatory disorder of the airways. The affected persons have recurrent episodes of wheeze, breathlessness, and cough, especially at night or in the early morning. The episodes are associated with airflow obstruction that is reversible either spontaneously or with treatment. Patients also have an increase in bronchial hyperresponsiveness to many stimuli [2].

Clinical features: Asthma has been divided into allergic (extrinsic) and nonallergic (intrinsic) types. The allergic type usually begins in childhood, is often seasonal, and is accompanied by an elevated, allergen-specific IgE level. Risk factors include a hereditary predisposition, respiratory illness (adenovirus, respiratory syncytial virus, rhinovirus, influenza virus [3,4]) before the age of 2, and exposure to common allergens (house dust mites, animal danders, or cockroaches). The nonallergic type usually begins in adults, is more severe, and has no elevation of serum IgE. Asthma has also been subclassified according to substances or conditions that cause it: aspirin [5], occupational inhalants such as toluene diisocyanate, ABPA, or exercise [6]. Smoking crack cocaine may be a factor that exacerbates asthma and may contribute to the death of these patients [7,8]. In all cases the patient complains of episodic breathlessness, wheezing, or tightness in the chest ± cough. Nocturnal symptoms are very common [9]. Symptoms may be accompanied by tachypnea, tachycardia, and use of accessory muscles of respiration. Peak expiratory flow is decreased, and hypoxemia and hypercarbia occur in severe episodes. Blood eosinophilia is frequent and sputum often contains eosinophils, Charcot-Leyden crystals, Curschmann's spirals, or Creola bodies--rounded balls of sloughed epithelial cells. Fungi may be present. PMNs suggest infection. Progressive disease is the exception. Treatment includes anti-inflammatory medications (corticosteroids, cromolyn) and bronchodilators. As a result of treatment with corticosteroids, numbers of mast cells, eosinophils, and CD4+ T cells decrease in the bronchial mucosa [10].

Prevalence: Asthma is increasing in many countries. This increase in prevalence was studied in a large HMO in Portland, OR. Based on clinic visits from 1967-1987, it was found that significant increases occurred in all groups except in men over age 65 (Table). Increases have been related to increased concentrations of indoor allergens, changes in immune responses to infection, diet, health care delivery systems, and adverse drug effects [11].

Table: Change in Percentage of Patients in HMO Treated for Asthma Over a Twenty-Year Period by Age and Sex

Age group

Sex

1967-69

1985-87

Fraction change: 85-87/67-69

0-14

M

1.25*

3.6

2.88

F

0.6

2.2

3.7

15-64

M

1.0

1.6

1.6

F

0.75

1.7

1.25

65+

M

2.1

1.8

0.86

F

0.7

3.2

4.6

* % of members treated for asthma per year

Histologic features--Summary

Histologic features: Asthma has been characterized as an eosinophilic bronchitis/bronchiolitis [12]. However, even in patients dying of asthma, airways are not uniformly involved, although bronchi are more uniformly involved than bronchioles. Study of bronchial biopsies has shown that inflammation is present even in mild or asymptomatic asthmatics [13].

Mural changes include edematous thickening and infiltration by eosinophils, mast cells, lymphocytes, and plasma cells. In the absence of infection, PMNs appear to be a feature of acute, severe disease [14]. Lymphoid aggregates are prominent and may infiltrate mucous glands. Bronchial arteries and veins are increased in number. Smooth muscle is hypertrophied and hyperplastic, and its contraction in the inflamed wall produces more narrowing than similar contraction in a non-inflamed wall [15]. Bronchial glands are enlarged and may show an increased percentage of mucus-producing cells. Epithelium is hyperplastic with goblet cell or squamous metaplasia. Eosinophils and mast cells also infiltrate the epithelial layer. Groups of sloughed epithelial cells round up to form Creola bodies, which can be seen in the sputum. They are distinguished from adenocarcinoma by their small nucleoli and the presence of cilia. The epithelial basement membrane appears thickened in H&E-stained sections, but ultrastructurally, it is normal. The apparent thickening (better termed collagenosis) noted by light microscopy is a deposition by myofibroblasts of types 3 and 5 collagen and fibronectin on the abluminal side of the basement membrane [13,16]. Scarring is usually absent, but with prolonged, severe disease, bronchiectasis and peribronchiolar fibrosis occur and help to account for persistent declines in FEV1 [17,18]. Medial thickening of the pulmonary arteries and right ventricular hypertrophy, indicating pulmonary hypertension, can also occur.

Mucous plugs, which are sometimes absent even in patients dying of asthma [19,20], result from a combination of fluid and cellular exudate from the airway wall and mucus from goblet cells and bronchial glands.

Airway remodeling: All of the mural changes together constitute airway remodeling, which includes inflammatory cells, connective tissue cells and matrix, and vascular changes. The changes are mediated by cytokines and chemokines that sustain the inflammation [21]. In contrast to other inflammatory conditions in the lung, inflammation tends to persist, but dense scar is unusual.

Pathogenesis: Asthma, a syndrome with many different causes and pathogenetic mechanisms, has at its basis airway hyperresponsiveness. A distinctive inflammatory component that waxes and wanes depending on extrinsic (allergen, cold, exercise) and intrinsic (emotional) factors is an integral part of the disease. The inflammatory component can be marked or very minimal as noted in some cases of sudden death with no mucous plugs and little inflammation. Therapy, besides bronchodilators, targets the inflammatory component in an attempt to diminish the airway narrowing of clinical attacks [22].

Hyperresponsiveness is believed to be a T-cell-mediated response that may, in part, be genetically induced, or develop in response to allergens, infections, drugs, or chemicals. In a mouse model, CD4-T cells and antigen can produce hyperresponsiveness and inflammation in animals genetically lacking T and B cells [23]. Further, eosinophils do not appear to be required [24]. Nevertheless, many types of cells, including eosinophils, are involved in the inflammation in humans. When allergens are presented to T cells (probably the TH-2 type T cells), they produce IL-4, IL-5, and IL-13, which recruit eosinophils and induce IgE formation [25]. As seen in the table, mast cells, basophils, and T lymphocytes produce similar mediators that are probably the link between acute T-cell mediated events, inflammation that causes the late phase reaction (see physiology below), and the chronic, low-grade inflammation that persists in airways and causes remodeling. Therapeutic drugs, such as steroids, are effective because they inhibit cytokine production by many cell types. In both allergic and non-allergic individuals, other triggers of bronchospasm have been identified, and these include neutrophil products, insect venoms, radiocontrast solutions, cold, and narcotics [26].

Table: Mast Cell, Basophil, and T Lymphocyte Products [26,27]

Mast cells

Basophils

T Lymphocytes

Granule products

Histamine, heparin/chondroitin sulfate, tryptase, chymase

Histamine, chondroitin sulfate

----

Cytokines

IL-4, IL-5, IL-13, TNF alfa

IL-4, 1L-13

IL-4, IL-5, IL-10, IL-13

Arachidonic acid metabolites

LTC4, PGD2

LTC4

----

Results of transplantation: Asthma has been noted to develop in recipients of bone marrow transplants [28]. More recently, two non-smoking patients in their 20s received heart-lung transplants for severe asthma. Both were asthma-free 3 years after receiving organs from nonasthmatic donors. Responses to histamine challenge were normal. Transbronchial biopsies did not show features of asthma. In contrast, two nonasthmatic patients, who received single lungs from mildly asthmatic donors, developed asthma-like symptoms in the first week after transplantation and required bronchodilator therapy. These cases suggest that asthma is organ specific, and innervation and atopy are not requisites [29].

Physiology: Airway bronchoconstrictive responses to allergen occur early (minutes), but may remit only to recur again as a late response (beginning at 3-4 hr after challenge). Whereas the early response is reversed by beta-agonists and prevented by anti-inflammatory drugs, the late response is only partially reversed by beta-agonists, but prevented by anti-inflammatory drugs [30]. This late response, which does not occur in all asthmatics, is thought to result from continued recruitment of inflammatory cells that was initiated during the acute response. It dissipates over days.

Course: As a result of airway remodeling, pulmonary function declines more rapidly than normal. In a non-industrial town in Australia, pulmonary function (FEV1 standardized for height and age), which was measured at least 4 times over a period of 18 years, declined at a significantly greater rate in asthmatics than in normal persons (e.g., for male nonsmokers of 1.7 m height, decline was 50 ml/y compared with 35 ml/y for normal nonsmokers). Further, initial lung function was significantly worse in asthmatics than normal subjects for both mean FEV1/FVC and mean percent predicted FEV1 [31].

Outcome: Of the estimated 10 million asthmatics in the US, about 4000 die each year. Most of these persons die out of hospital because of undertreatment or lack of availability of medical care [32]. Acute deaths occurring in the hospital have been attributed to respiratory failure and not cardiac events. This finding supports undertreatment and delay in seeking treatment, and not cardiac arrhythmia, as the cause of death in these patients [33]. In defense of the patient, a study of asthmatics with past episodes of near-fatal asthma, who were examined during a stable period, showed reduced ventilatory responses to hypoxia and decreased perception of dyspnea compared to normal subjects. These findings may account for delay in seeking help [34].

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Clinical summary

Comments: mw6825@itsa.ucsf.edu

Last revised 6/26/98

Copyright 1998 by Martha L. Warnock. All rights reserved.

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