Postviral Bronchial Hyperreactivity Syndrome: Recognizing Asthma's

• Postviral bronchial hyperreactivity syndrome: Recognizing asthmas great mimic

DAVID OSTRANSKY, DO FRANCIS X. BLAIS, DO

Although there are no prospec- (Key words: Viral infections, asthma, tive studies regarding the frequency of respiratory tract infections, postviral postviral bronchial hyperreactivity syn- bronchial hyperreactivity syndrome) drome, it is a common complication of upper and lower respiratory tract viral Viral respiratory tract infections frequently infections. The respiratory symptoms cause wheezing and other asthmalike symp- closely resemble those of asthma, but they toms. Several investigators have demonstrated are present for only 3 weeks to 3 months pertinent features of this abbreviated form of following the acute infection phase. Defin- asthma, including early response phase, late ing the mechanisms of this syndrome may response phase, and bronchial hyperreac- provide insight into the pathogenesis of tivity. 1-5 Understanding the mechanisms by asthma. Postviral bronchial hyperreac- which viral respiratory tract infections precipi- tivity syndrome is frequently misdiag- tate the airway abnormalities of asthma may nosed and inappropriately managed be- be a potential key to the pathogenesis of cause many physicians are unfamiliar asthma, although whether viral respiratory with this illness. Because of its character- tract infections truly cause asthma is un- istic history, diagnosis is straightforward proved.6 when the physician knows what to look The symptom complex following viral up- for, and response to therapy is excellent. per or lower respiratory tract infections (or This report presents a case history fol- both) has not been formally identified. It is fre- lowed by a review of the proposed mecha- quently misdiagnosed by physicians who then nisms of bronchial hyperreactivity follow- institute inappropriate diagnostic studies and ing viral respiratory infections. The clini- ineffective antibiotic therapy. This article dis- cal features and criteria for diagnosing cusses the proposed mechanisms of "viral postviral bronchial hyperreactivity syn- asthma" as well as its clinical description and drome are also discussed. criteria for the diagnosis of this disorder, re- ferred to as the postviral bronchial hyperreactivity syndrome (PVBHS). From the Texas College of Osteopathic Medicine, Fort Worth, where, at the time this article was written, Dr Ostransky was associate professor of medicine, Division Report of case of Pulmonary and Critical Care Medicine; Dr Blais is A 38-year-old woman had a persistent cough. One associate professor of medicine, Division of Infectious Dis- month previously, she had had a viral upper respi- eases. Dr Ostransky is a physician specialist in private ratory tract infection with accompanying symptoms practice in the Dallas–Forth Worth area. Reprint requests to David Ostransky, DO, 1236 S of sore throat, cough, malaise, myalgias, and low- Ridge Ct, Suite 200, Hurst, TX 76053. grade fever. After resolution of the acute symptoms,

Clinical practice • Ostransky and Blais JAOA • Vol 91 • No 5 • May 1991 • 465 the cough had persisted with occasional scant Proposed mechanisms of hyperreactivity expectoration of clear mucus. The coughing oc- The proposed mechanisms of virus-induced curred frequently, it was often paroxysmal, and it asthma discussed in several reviews include continued at night. After nighttime coughing, the epithelial inflammation or damage with en- patient was short of breath and often wheezed. Dur- ing the daytime, coughing and shortness of breath hanced airway cholinergic sensitivity,3 stimu- were precipitated by exposure to household clean- lation of peptidergic nerve fibers 11 or loss of ing materials, perfume, gasoline fumes, and ciga- "epithelial relaxant factor," 12,13 diminished rette smoke. 13-adrenergic function, enhanced mediator The patient was not able to participate in aero- release,4 and stimulation of virus-specific IgE bics because of dyspnea and coughing. Use of an antibody production.4,14-18 over-the-counter cold formula and prescribed eryth- Ramphal and coworkers, 19 using scanning romycin had not alleviated the symptoms. She also and transmission electron microscopy in a mur- complained of anterior chest wall discomfort. The ine model of influenza virus infection, have patient was a nonsmoker. Her medical history was shown that viruses damage airway epithelium. significant for a benign breast biopsy several years The series of scanning electron micrographs earlier. She had no history of asthma, sinusitis, (Figs 1 through 4) show tracheal epithelium allergies, or symptoms of gastroesophageal reflux. Her family history was positive only for breast car- before infection and at 36 hours, 5 days, and cinoma. 10 days after infection. Desquamative changes On physical examination, the patients vital begin approximately 12 hours following inocu- signs were as follows: pulse, 92 beats per minute; lation and are virtually complete in 48 to 72 respiratory rate, 24 per minute; blood pressure, 120/ hours. 19 The serous and ciliated cells of the 65 mm Hg, and temperature, 37.4°C. Physical ex- pseudostratified columnar epithelium are af- amination was significant for mild erythema of the fected with sparing of the regenerative layer.9 posterior pharynx and prolonged expiration on aus- Regeneration begins 5 days after infection and cultation of the chest. Results of spirometry were recovery is complete in 2 weeks.19 normal. A chest roentgenogram was also normal. Such dysfunctional or absent respiratory After evaluation, albuterol therapy administered tract epithelium may cause or potentiate bron- by metered-dose inhaler (two puffs four times daily) chial hyperreactivity by multiple mechanisms, was started, with instructions on the proper use of the medication. Symptoms were improved mark- including sensitization of rapidly adapting va- edly within 2 days, and the patient was asympto- gal sensory afferent nerve endings, 3 preven- matic in 1 week. tion of the protective release of large concentrations of prostaglandin E2,2021 generation of Discussion 15-lipoxygenase pathway products,22 and the Many clinical and epidemiologic observations deficiency or absence of epithelium-derived "re- suggest that viral infections cause asthma for laxant factor."23 In humans, the duration of reasons outlined by Busse": bronchial hyperreactivity closely parallels the • Patients with recurrent wheezing or asthma time needed for epithelial repair. 24 This pa- can date the onset of their symptoms to an thogenetic schema is similar to that described acute febrile illness with catarrhal features by McIntosh,25 who surmised that there was of viral infection. a clinical continuum of infant bronchiolitis to • Viral infections cause 11% to 42% of exacer- childhood asthma. bations of asthma.? Clinical expression is thought to be deter- • Small airway abnormalities and exaggerated mined by the virulence of the particular vi- bronchial hyperreactivity occur in normal in- rus, its affinity for a specific part of the respi- dividuals during and after viral respiratory ratory tract epithelium, and host response— tract infections.3,5,8 immunologic and other—to the infection.26 • Individuals with allergic diatheses suffer However, bronchial epithelial damage is not more severe symptoms following viral respi- necessary for enhanced cholinergic sensitivity ratory tract infections.9 because bronchial hyperreactivity and wheez- • Viruses are intensely inflammatory.1° ing occur following upper respiratory tract in-

466 • JAOA • Vol 91 • No 5 • May 1991 Clinical practice • Ostransky and Blais fection, that is, parainfluenza virus infec- pable of in iating production of virus-specific tions. 1315 Thus, cholinergic reflex bronchocon- IgE ant ody was advanced by Welliver and striction can arise from upper respiratory tract colleagues and supported by others. 4,14-18 In stimulation. Also, cholinergic hypersensi- studies of respiratory syncytial virus (RSV)4,18 tivity following viral respiratory tract infec- and parainfluenza virus infections, 15,17 many tion is suggested by bronchial hyperreactivity subjects demonstrated cell-bound IgE during to carbachol,2 histamine, citric acid, and cold acute and convalescent phases of viral ill- air, each of which is blocked by inhaled atro- ness.4,18 Significantly greater titers of IgE were pine sulfate.3 found in those individuals with subsequent Viral infections may cause asthma by al- wheezing or bronchiolitis. 4 Additionally, there tering the response of the peptidergic nerve was a direct relationship between the degree fibers, which are located beneath the respira- of arterial hypoxemia and histamine concen- tory tract epithelium. 1,11 Peptidergic nerve trations in nasal secretions to the level of virus- fibers release tachykinins in response to numer- specific IgE.4 ous stimuli—such as viruses, ozone, and al- Viral-induced airway inflammation may in- lergens—with resultant bronchial hyperreac- crease epithelial permeability and permit tivity.11 Usually, the tachykinins are modu- greater influx of the virus and its products lated by membrane-bound enzymes, enkephal- with subsequent IgE sensitization. The logi- inases, which inactivate the tachykinins.23 cal progression of reasoning is that virus-spe- Studies12,13 show that respiratory tract viruses cific IgE is capable of attaching to the mast cause tachykinin release with bronchial cell and precipitating the release of its numer- smooth-muscle contraction. In the presence of ous mediators. These mast cell products may viral-induced epithelial damage or inflamma- provoke immediate bronchospasm but, more tion, concentrations of enkephalinase may be importantly, they play a major role in the late- inadequate, with the bronchomotor tone set by phase reaction, the probable key to understand- the unopposed action of tachykinins. 12,13 In- ing asthma with its delayed inflammation and deed, enkephalinase may be the "epithelial re- bronchial reactivity. laxant factor."23 Mediator release certainly occurs in viral Beta-adrenergic responsiveness is probably infections with their inflammatory and destruc- diminished in asthma, 27 causing bronchocon- tive potentia1. 3° The integral role of mediators striction, decreased mucociliary clearance, and in the pathogenesis of asthma is the subject enhanced mediator release. 28 Circulating neu- of several recent reviews.31 Mediators con- trophils from patients with asthma demon- tained within inflammatory cells, such as mast strate diminished response to p-adrenergic cells, are purported to cause all the pathologic stimulation. 21 Further p-adrenergic impair- changes of asthma, that is, bronchospasm, base- ment occurs during viral infections associated ment membrane thickening, desquamation, mu- with wheezing21 and, experimentally, when cosal edema, inflammatory cell infiltration, neutrophils are incubated with infectious vi- and hypersecretion of mucus. 32 The aforemen- ral particles or interferon. 18 The relevance of tioned studies of Welliver 4,15-17 demonstrate decreased p-adrenergic function of circulating that the production of virus-specific IgE in- neutrophils to airway disease is speculative, duces the release of histamine, capable of pro- although impaired (3-receptor activity has been ducing bronchospasm.4 reported in airway smooth muscle from anti- Ida and associates18 demonstrated that leu- gen-sensitive dogs.29 kocytes incubated with infectious viruses, in- The exact mechanism of diminished p-ad- terferon, and inducers of interferon produced renergic sensitivity in asthma is unknown. an enhancement of histamine release when ex- Studies of inflammatory cells collected by bron- posed to ragweed antigen IgE or anti-IgE. choalveolar lavage are necessary to further re- These investigators speculated that interferon fine this pathogenetic mechanism. may be one of the cofactors responsible for pre- The theory that viruses are antigenically ca- cipitating or potentiating attacks of wheezing

Clinical practice • Ostransky and Blais JAOA • Vol 91 • No 5 • May 1991 • 467 during asthma. Studies investigating the role should be investigated. The cough may be se- of other mediators—such as platelet activat- vere and paroxysmal with consequent chest dis- ing factor, leukotrienes, prostaglandins, and comfort. thromboxanes—in viral respiratory tract in- Patients with posterior pharyngeal irrita- fections are the subject of future investiga- tion should be evaluated for the simultaneous tion.26 presence of upper respiratory tract illnesses causing postnasal drainage, that is, sinusitis Clinical description and rhinitis. Dyspnea occurs with exertion, Postviral bronchial hyperreactivity syndrome exposure to nonspecific irritants, or following is a benign, self-limited syndrome of persis- coughing. Decreased exercise tolerance is com- tent asthmalike symptoms of cough, wheezing, mon. A minority of patients report the sudden and shortness of breath following viral respi- onset of significant dyspnea relieved by expecto- ratory tract infections. It affects young and old ration of a mucous plug. Diaphoresis and fe- alike, and there is significant variability of air- ver secondary to underlying inflammation way response. In patients with atopy, positive may be present. Quite commonly, patients self- allergen skin tests, and a family history of administer antibiotics without gaining relief. asthma, more severe and persistent symptoms While under the supervision of the referral phy- develop after respiratory tract infections. sician, these patients often undergo multiple Usually, the specific virus is not a signifi- and inappropriate diagnostic tests and ther- cant factor, although the type of virus is age- apy. Some patients continue to work or per- specific.3 For example, infections caused by form their usual duties. RSV lead to more significant symptoms in The physical examination is characteristic young children owing to the patients smaller for its paucity of findings. Generally the pa- airway diameter, because airflow resistance is tient has frequent cough, lassitude, and pal- inversely proportional to the radius of the air- lor. Occasionally, patients may have a low- way to the fourth power.33 Specifically, respi- grade fever (usually less than 38.5°C) with ratory tract infections precipitating asthma mild tachypnea, tachycardia, and hyperten- symptoms on the basis of age groups are as sion. Examination of the posterior aspect of follows34-37 : preschool-aged children—RSV, the pharynx may reveal erythema and post- parainfluenza, and adenovirus; school-aged chil- nasal drainage. Auscultation of the lungs dem- dren—rhinovirus, Mycoplasma pneumoniae, onstrates either bronchovesicular, prolonged parainfluenza, and RSV; adolescents—M pneu- expiratory, or harsh breath sounds with occa- moniae, rhinovirus, parainfluenza, and RSV; sional rales and wheezing. Tenderness to pal- adults—influenza viruses, rhinovirus, herpes pation at the costochondral junctions is com- simplex, M pneumoniae, coronovirus, and monly found in association with severe cough- RSV. Also, the more severe the viral infection, ing. the more significant the symptoms of PVBHS. Laboratory findings and chest roent- Usually, there is initial resolution of the vi- genogram results are usually normal; mild leu- ral illness in 7 to 10 days. Subsequently, one kopenia, leukocytosis, or relative lymphocyto- or more respiratory tract symptoms—most com- sis may be present. Occasionally, findings of monly cough, wheezing, and shortness of increased bronchovascular markings or mild breath—persist up to 3 months. These symp- hyperinflation are noted. Chest x-ray films are toms may be precipitated by exposure to in- useful in eliminating other causes. Spirometry haled particles; fumes; aerosols; or cold, dry results are usually normal, except for small air. Symptoms often occur nocturnally, prevent- airway abnormalities such as a decrease in the ing restful sleep and resulting in irritability FEF25%-75% If PVBHS is suspected and the di- and malaise. The cough is occasionally produc- agnosis is equivocal, a bronchoprovocation test tive of scant amounts of clear or white mucus using methacholine, hyperpnea, or cold air will and, rarely, mucus that is blood-streaked. If demonstrate an exaggerated asthmatic-type re- significant hemoptysis is present, other causes sponse or bronchial hyperreactivity. (continued on page 471)

468 • JAOA • Vol 91 • No 5 • May 1991 Clinical practice • Ostransky and Blais Diseases to consider in diagnosing PVBHS Table 1 are listed in Table 1. Viral bronchiolitis and Differential Diagnosis of Postviral pneumonia are characterized by greater sever- Bronchial Hyperreactivity Syndrome ity of symptoms than PVBHS with signs of tox- icity. Symptoms are continuous, including sig- • Viral bronchiolitis/pneumonia • Sinusitis/postnasal drip nificant respiratory distress manifested by • Gastroesophageal reflux dyspnea, tachypnea, wheezing, use of acces- • Chronic bronchitis sory muscles, and diminished breath sounds • Occupational asthma in association with hypoxemia.38 The usual reso- • Occult asthma lution of acute symptoms seen in PVBHS does not occur. The wheezing associated with bron- history of pyrosis, belching, abdominal bloat- chiolitis is unresponsive to bronchodilator ther- ing, waterbrash, and regurgitation." Cough apy. Fever, chills, rigors, myalgia, and arthral- may be the sole presenting manifestation of gia are common. Gastrointestinal symptoms— gastroesophageal reflux as in 28% of the pa- including nausea, diarrhea, and vomiting— tients in a recent study41 on chronic cough. How- may occur, depending on the viral pathogen. ever, cough, wheezing, and shortness of breath The chest x-ray film shows profound hyper- are not always temporally associated with the inflation and diffuse haziness in bronchiolitis gastrointestinal symptoms. Wheezing may oc- and interstitial infiltrates often involving multi- cur in the absence of aspiration as stimula- ple lobes in pneumonia. Coalescence of the in- tion of the vagal afferents in the lower aspect filtrate may lend an alveolar characteristic to of the esophagus by acid reflux causes reflex the infiltrate. 38 Viral bronchiolitis is an ex- bronchospasm.41 tremely common illness in early childhood and Chronic bronchitis can be recognized by a decreases in incidence with increasing age; it significant smoking history and productive is rare in adults. 38 Respiratory syncytial virus daily cough of at least 2 years duration. 43 To is the most frequent cause of bronchiolitis in confuse the picture, viral infections often ex- children, whereas the most common causes of acerbate chronic bronchitis with resultant adult viral pneumonia in the normal host are wheezing. 43 Chronic bronchitics may also have influenza, parainfluenza, varicella, rubeola, an exaggerated response to methacholine.44 and rhinovirus.38 Adult respiratory distress syn- These patients may develop PVBHS with pro- drome and secondary bacterial pneumonia are found sputum production. Rhonchi and breath serious complications of viral pneumonia and sounds with prolonged expiration are present require prompt diagnosis.38 on auscultation of the lungs.43 Postnasal drainage from sinus infections, Occupational asthma (OA) manifests as new- rhinitis, and occasionally carious teeth are onset asthma in adults caused by specific causes of chronic, persistent cough. 39 Stimu- agents in the workplace. More than 100 sub- lation of cholinergic afferent nerve fibers in stances have been identified in the workplace the posterior aspect of the pharynx and the to cause 0A,45 but many more are likely to larynx cause cough and bronchospasm. Asso- be identified in the future. Variable degrees ciated symptoms of nasal drainage and con- of exposure, short- and long-term, can lead to gestion, maxillary or frontal tenderness to pal- development of OA. Symptoms of wheezing pation, sore throat, hoarseness, and symptoms and chest tightness occurring primarily at of ear fullness or discomfort suggest sinusitis.4° work with abatement during weekends and va- Physical examination of the posterior aspect cations are classic symptoms of 0A.45 Several of the pharynx reveals erythema and postna- variations of OA exist. Some patients initially sal drainage. Coexistence of postnasal drain- have a productive or dry cough that is not nec- age may confound the diagnosis of PVBHS and essarily temporally related to exposure. aggravate cough and wheezing. Bronchodila- Asthma may be occult, because it is often tor therapy may be ineffective. not recognized by the patient or the physician Gastroesophageal reflux is identified by a for several reasons, including its episodic na-

Clinical practice • Ostransky and Blais JAOA • Vol 91 • No 5 • May 1991 • 471 Figure 1. Normal, nonin- fected mouse tracheal epithelium ( original magnification x 1050). Reprinted with permission of the Ameri- can Review of Respiratory Disease, Ramphal R, et al: 1979;120:1313-1324.

Figure 2. Scanning electron micrograph of mouse tracheal epithelium 36 hours after infection. Few desqua- mating cells remain and the basal layer is exposed ( original magnification x 2000). Reprinted with permission of the American Review of Respiratory Disease, Ram- phal R, et al: 1979;120: 1313-1324.

472 • JAOA • Vol 91 • No 5 • May 1991 Clinical practice • Ostransky and Blais Figure 3. Scanning electron micrograph of mouse tracheal epithelium 5 days after infection. Short and long microvilli appear on cell surfaces I arrows/ (original magnification x 4000). Reprinted with permission of the American Review of Respiratory Disease, Ram- phal R, et al: 1979;120: 1313-1324.

Figure 4. Scanning electron micrograph of mouse tracheal epithelium shows cilia formation 10 days after infection (arrow) ( original magnification x 2000). Reprinted with permission of the American Review of Respiratory Disease, Ram- phal R, et al: 1979; 120: 1313 -1324.

Clinical practice • Ostransky and Blais JAOA • Vol 91 • No 5 • May 1991 • 473 ics if sinusitis is present. In the face of severe, Table 2 Criteria for Diagnosis of Postviral persistent symptoms or failure of conservative Bronchial Hyperreactivity Syndrome therapy, careful reevaluation is suggested before the use of systemic corticosteroids. The • History of prior viral respiratory tract infection prevention of a significant percentage of with initial recovery • Appropriate intermittent and nocturnal PVBHS can be easily accomplished by the ap- symptom complex propriate administration of influenza vaccine • Nonspecific bronchial hyperreactivity or amantadine hydrochloride. • Paucity of physical, laboratory, spirometric, and radiologic findings • Positive cold air or methacholine challenge test Summary • Self-limited illness The diagnosis of PVBHS usually is easily es- tablished on the basis of history and response to a clinical trial of bronchodilator therapy. ture, variant manifestation as cough, 46 and Proposed criteria for diagnosis are listed in Ta- mild severity. It is also frequently misdiag- ble 2. Prospective studies regarding the fre- nosed as "bronchitis." A careful history will quency of PVBHS have not been done, but the reveal the classic features of asthma, includ- condition is probably common. Prompt diag- ing episodic bronchial hyperreactivity, chron- nosis by the primary care physician is essen- icity, and positive family history. tial in reducing the morbidity of this syndrome. In addition, physician recognition will Management prevent the use of inappropriate laboratory The management of PVBHS is subdivided into studies and antibiotics. Increased awareness categories of pharmacotherapy, supportive of this disease will provide data regarding its measures, and prevention. Supportive meas- frequency, and more careful study may lead ures include reassuring the patient of the be- to a better understanding of the pathogenesis nign nature of the illness, and advising the of asthma. patient of prophylactic measures—rest, hydra- tion, appropriate diet, and avoidance of bronchial irritants. Often, a good nights rest fol- 1.Busse WW: The contribution of viral respiratory infections lowing reassurance and institution of appro- to the pathogenesis of airway hyperreactivity. Chest priate drug therapy is extremely beneficial. 1988;93:1076-1082. 2. Little JW, Hall WJ, Douglas RG: Airway hyperreactivity and Drug therapy for PVBHS is identical to that peripheral airways dysfunctions in influenza A infection. Am for asthma, with initial use of p-adrenergic Rev Respir Dis 1978;118:295-303. agents. These drugs usually alleviate symp- 3. Empey DW, Laitinen LA, Jacobs L, et al: Mechanisms of bron- toms within a few days. Some patients report chial hyperreactivity in normal subjects after upper respiratory tract infections. Am Rev Respir Dis 1976;113:131-138. equal relief from theophylline or ipratropium 4. Welliver RC, Wong DT, Sun M, et al: The development of bromide. respiratory syncytial virus-specific IgE and the release of his- In the absence of prompt relief (more than tamine in nasopharyngeal secretions after infection. N Engl J Med 1981;305:841-846. 48 to 72 hours), a combination of these agents 5. Hall W, Hall C: Clinical significance of pulmonary function is appropriate. If coughing is recalcitrant, cro- tests: Alterations in pulmonary function following respiratory molyn sodium or corticosteroids by inhalation viral infections. Chest 1979;76:458-465. may be useful. Cromolyn and corticosteroids 6. Sherter CB, Polnitsky CA: The relationship of viral infections to subsequent asthma. Clin Chest Med 1981;2:67-78. are effective in the prevention of bronchial hy- 7. Beasley R, Coleman ED, Hermon Y, et al: Viral respiratory perreactivity, with little or no immediate bron- tract infections and exacerbations of asthma in adult patients. chodilation. Both drugs have a delayed onset Thorax 1988;43:679-683. 8. Aquilina AT, Hall WJ, Douglas RG, et al: Airway reactivity of action and require a week or longer to be- in subjects with viral upper respiratory tract infections: The come effective. effect of exercise and cold air. Air Rev Respir Dis 1980;122:3- Patients with associated symptoms of post- 10. nasal drainage benefit from an antihistamine 9. Rooney JC, Wolmans HE: The relationship between proved viral bronchiolitis and subsequent wheezing. J Pediatr or nasal corticosteroid (or both) plus antibiot- 1971;79:744-747.

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