Postviral bronchial hyperreactivity syndrome: Recognizing

Postviral bronchial hyperreactivitysyndrome: Recognizing asthma'sgreat mimicDAVID OSTRANSKY, DO

FRANCIS X. BLAIS, DO

•

Although there are no prospec-tive studies regarding the frequency ofpostviral bronchial hyperreactivity syn-drome, it is a common complication ofupper and lower respiratory tract viralinfections. The respiratory symptomsclosely resemble those of asthma, but theyare present for only 3 weeks to 3 monthsfollowing the acute infection phase. Defin-ing the mechanisms of this syndrome mayprovide insight into the pathogenesis ofasthma. Postviral bronchial hyperreac-tivity syndrome is frequently misdiag-nosed and inappropriately managed be-cause many physicians are unfamiliarwith this illness. Because of its character-istic history, diagnosis is straightforwardwhen the physician knows what to lookfor, and response to therapy is excellent.This report presents a case history fol-lowed by a review of the proposed mecha-nisms of bronchial hyperreactivity follow-ing viral respiratory infections. The clini-cal features and criteria for diagnosingpostviral bronchial hyperreactivity syn-drome are also discussed.

From the Texas College of Osteopathic Medicine, FortWorth, where, at the time this article was written, DrOstransky was associate professor of medicine, Divisionof Pulmonary and Critical Care Medicine; Dr Blais isassociate professor of medicine, Division of Infectious Dis-eases. Dr Ostransky is a physician specialist in privatepractice in the Dallas–Forth Worth area.

Reprint requests to David Ostransky, DO, 1236 SRidge Ct, Suite 200, Hurst, TX 76053.

(Key words: Viral infections, asthma,respiratory tract infections, postviralbronchial hyperreactivity syndrome)

Viral respiratory tract infections frequentlycause wheezing and other asthmalike symp-toms. Several investigators have demonstratedpertinent features of this abbreviated form ofasthma, including early response phase, lateresponse phase, and bronchial hyperreac-tivity. 1 -5 Understanding the mechanisms bywhich viral respiratory tract infections precipi-tate the airway abnormalities of asthma maybe a potential key to the pathogenesis ofasthma, although whether viral respiratorytract infections truly cause asthma is un-proved.6

The symptom complex following viral up-per or lower respiratory tract infections (orboth) has not been formally identified. It is fre-quently misdiagnosed by physicians who theninstitute inappropriate diagnostic studies andineffective antibiotic therapy. This article dis-cusses the proposed mechanisms of "viralasthma" as well as its clinical description andcriteria for the diagnosis of this disorder, re-ferred to as the postviral bronchial hyperreac-tivity syndrome (PVBHS).

Report of caseA 38-year-old woman had a persistent cough. Onemonth previously, she had had a viral upper respi-ratory tract infection with accompanying symptomsof sore throat, cough, malaise, myalgias, and low-grade fever. After resolution of the acute symptoms,

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the cough had persisted with occasional scantexpectoration of clear mucus. The coughing oc-curred frequently, it was often paroxysmal, and itcontinued at night. After nighttime coughing, thepatient was short of breath and often wheezed. Dur-ing the daytime, coughing and shortness of breathwere precipitated by exposure to household clean-ing materials, perfume, gasoline fumes, and ciga-rette smoke.

The patient was not able to participate in aero-bics because of dyspnea and coughing. Use of anover-the-counter cold formula and prescribed eryth-romycin had not alleviated the symptoms. She alsocomplained of anterior chest wall discomfort. Thepatient was a nonsmoker. Her medical history wassignificant for a benign breast biopsy several yearsearlier. She had no history of asthma, sinusitis,allergies, or symptoms of gastroesophageal reflux.Her family history was positive only for breast car-cinoma.

On physical examination, the patient's vitalsigns were as follows: pulse, 92 beats per minute;respiratory rate, 24 per minute; blood pressure, 120/65 mm Hg, and temperature, 37.4°C. Physical ex-amination was significant for mild erythema of theposterior pharynx and prolonged expiration on aus-cultation of the chest. Results of spirometry werenormal. A chest roentgenogram was also normal.

After evaluation, albuterol therapy administeredby metered-dose inhaler (two puffs four times daily)was started, with instructions on the proper useof the medication. Symptoms were improved mark-edly within 2 days, and the patient was asympto-matic in 1 week.

DiscussionMany clinical and epidemiologic observationssuggest that viral infections cause asthma forreasons outlined by Busse":• Patients with recurrent wheezing or asthma

can date the onset of their symptoms to anacute febrile illness with catarrhal featuresof viral infection.

• Viral infections cause 11% to 42% of exacer-bations of asthma.?

• Small airway abnormalities and exaggeratedbronchial hyperreactivity occur in normal in-dividuals during and after viral respiratorytract infections.3,5,8

• Individuals with allergic diatheses suffermore severe symptoms following viral respi-ratory tract infections.9

• Viruses are intensely inflammatory.1°

Proposed mechanisms of hyperreactivityThe proposed mechanisms of virus-inducedasthma discussed in several reviews includeepithelial inflammation or damage with en-hanced airway cholinergic sensitivity,3 stimu-lation of peptidergic nerve fibers 11 or loss of"epithelial relaxant factor," 12,13 diminished13-adrenergic function,' enhanced mediatorrelease,4 and stimulation of virus-specific IgEantibody production.4,14-18

Ramphal and coworkers, 19 using scanningand transmission electron microscopy in a mur-ine model of influenza virus infection, haveshown that viruses damage airway epithelium.The series of scanning electron micrographs(Figs 1 through 4) show tracheal epitheliumbefore infection and at 36 hours, 5 days, and10 days after infection. Desquamative changesbegin approximately 12 hours following inocu-lation and are virtually complete in 48 to 72hours. 19 The serous and ciliated cells of thepseudostratified columnar epithelium are af-fected with sparing of the regenerative layer.'9Regeneration begins 5 days after infection andrecovery is complete in 2 weeks.19

Such dysfunctional or absent respiratorytract epithelium may cause or potentiate bron-chial hyperreactivity by multiple mechanisms,including sensitization of rapidly adapting va-gal sensory afferent nerve endings, 3 preven-tion of the protective release of large concen-trations of prostaglandin E2,2021 generation of15-lipoxygenase pathway products, 22 and thedeficiency or absence of epithelium-derived "re-laxant factor."23 In humans, the duration ofbronchial hyperreactivity closely parallels thetime needed for epithelial repair. 24 This pa-thogenetic schema is similar to that describedby McIntosh,25 who surmised that there wasa clinical continuum of infant bronchiolitis tochildhood asthma.

Clinical expression is thought to be deter-mined by the virulence of the particular vi-rus, its affinity for a specific part of the respi-ratory tract epithelium, and host response—immunologic and other—to the infection.26However, bronchial epithelial damage is notnecessary for enhanced cholinergic sensitivitybecause bronchial hyperreactivity and wheez-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-tions. 1 '3 ' 15 Thus, cholinergic reflex bronchocon-striction can arise from upper respiratory tractstimulation.' Also, cholinergic hypersensi-tivity following viral respiratory tract infec-tion is suggested by bronchial hyperreactivityto carbachol,2 histamine, citric acid, and coldair, each of which is blocked by inhaled atro-pine sulfate.3

Viral infections may cause asthma by al-tering the response of the peptidergic nervefibers, which are located beneath the respira-tory tract epithelium. 1,11 Peptidergic nervefibers release tachykinins in response to numer-ous stimuli—such as viruses, ozone, and al-lergens—with resultant bronchial hyperreac-tivity. 11 Usually, the tachykinins are modu-lated by membrane-bound enzymes, enkephal-inases, which inactivate the tachykinins.23Studies 12,13 show that respiratory tract virusescause tachykinin release with bronchialsmooth-muscle contraction. In the presence ofviral-induced epithelial damage or inflamma-tion, concentrations of enkephalinase may beinadequate, with the bronchomotor tone set bythe unopposed action of tachykinins. 12,13 In-deed, enkephalinase may be the "epithelial re-laxant factor."23

Beta-adrenergic responsiveness is probablydiminished in asthma, 27 causing bronchocon-striction, decreased mucociliary clearance, andenhanced mediator release. 28 Circulating neu-trophils from patients with asthma demon-strate diminished response to p-adrenergicstimulation. 21 Further p-adrenergic impair-ment occurs during viral infections associatedwith wheezing21 and, experimentally, whenneutrophils are incubated with infectious vi-ral particles or interferon. 18 The relevance ofdecreased p-adrenergic function of circulatingneutrophils to airway disease is speculative,although impaired (3-receptor activity has beenreported in airway smooth muscle from anti-gen-sensitive dogs.29

The exact mechanism of diminished p-ad-renergic sensitivity in asthma is unknown.Studies of inflammatory cells collected by bron-choalveolar lavage are necessary to further re-fine this pathogenetic mechanism.

The theory that viruses are antigenically ca-

pable of in iating production of virus-specificIgE ant ody was advanced by Welliver andcolleagues and supported by others. 4,14-18 Instudies of respiratory syncytial virus (RSV)4,18and parainfluenza virus infections, 15,17 manysubjects demonstrated cell-bound IgE duringacute and convalescent phases of viral ill-ness.4,18 Significantly greater titers of IgE werefound in those individuals with subsequentwheezing or bronchiolitis. 4 Additionally, therewas a direct relationship between the degreeof arterial hypoxemia and histamine concen-trations in nasal secretions to the level of virus-specific IgE.4

Viral-induced airway inflammation may in-crease epithelial permeability and permitgreater influx of the virus and its productswith subsequent IgE sensitization. The logi-cal progression of reasoning is that virus-spe-cific IgE is capable of attaching to the mastcell and precipitating the release of its numer-ous mediators. These mast cell products mayprovoke immediate bronchospasm but, moreimportantly, they play a major role in the late-phase reaction, the probable key to understand-ing asthma with its delayed inflammation andbronchial reactivity.

Mediator release certainly occurs in viralinfections with their inflammatory and destruc-tive potentia1. 3° The integral role of mediatorsin the pathogenesis of asthma is the subjectof several recent reviews.31 Mediators con-tained within inflammatory cells, such as mastcells, are purported to cause all the pathologicchanges of asthma, that is, bronchospasm, base-ment membrane thickening, desquamation, mu-cosal edema, inflammatory cell infiltration,and hypersecretion of mucus. 32 The aforemen-tioned studies of Welliver 4,15- 17 demonstratethat the production of virus-specific IgE in-duces the release of histamine, capable of pro-ducing bronchospasm.4

Ida and associates18 demonstrated that leu-kocytes incubated with infectious viruses, in-terferon, and inducers of interferon producedan enhancement of histamine release when ex-posed to ragweed antigen IgE or anti-IgE.These investigators speculated that interferonmay be one of the cofactors responsible for pre-cipitating or potentiating attacks of wheezing


during asthma. Studies investigating the roleof other mediators—such as platelet activat-ing factor, leukotrienes, prostaglandins, andthromboxanes—in viral respiratory tract in-fections are the subject of future investiga-tion.26

Clinical descriptionPostviral bronchial hyperreactivity syndromeis a benign, self-limited syndrome of persis-tent asthmalike symptoms of cough, wheezing,and shortness of breath following viral respi-ratory tract infections. It affects young and oldalike, and there is significant variability of air-way response. In patients with atopy, positiveallergen skin tests, and a family history ofasthma, more severe and persistent symptomsdevelop after respiratory tract infections.

Usually, the specific virus is not a signifi-cant factor, although the type of virus is age-specific. 3 For example, infections caused byRSV lead to more significant symptoms inyoung children owing to the patients' smallerairway diameter, because airflow resistance isinversely proportional to the radius of the air-way to the fourth power. 33 Specifically, respi-ratory tract infections precipitating asthmasymptoms on the basis of age groups are asfollows34-37 : preschool-aged children—RSV,parainfluenza, and adenovirus; school-aged chil-dren—rhinovirus, Mycoplasma pneumoniae,parainfluenza, and RSV; adolescents—M pneu-moniae, rhinovirus, parainfluenza, and RSV;adults—influenza viruses, rhinovirus, herpessimplex, M pneumoniae, coronovirus, andRSV. Also, the more severe the viral infection,the more significant the symptoms of PVBHS.

Usually, there is initial resolution of the vi-ral illness in 7 to 10 days. Subsequently, oneor more respiratory tract symptoms—most com-monly cough, wheezing, and shortness ofbreath—persist up to 3 months. These symp-toms may be precipitated by exposure to in-haled particles; fumes; aerosols; or cold, dryair. Symptoms often occur nocturnally, prevent-ing restful sleep and resulting in irritabilityand malaise. The cough is occasionally produc-tive of scant amounts of clear or white mucusand, rarely, mucus that is blood-streaked. Ifsignificant hemoptysis is present, other causes

should be investigated. The cough may be se-vere and paroxysmal with consequent chest dis-comfort.

Patients with posterior pharyngeal irrita-tion should be evaluated for the simultaneouspresence of upper respiratory tract illnessescausing postnasal drainage, that is, sinusitisand rhinitis. Dyspnea occurs with exertion,exposure to nonspecific irritants, or followingcoughing. Decreased exercise tolerance is com-mon. A minority of patients report the suddenonset of significant dyspnea relieved by expecto-ration of a mucous plug. Diaphoresis and fe-ver secondary to underlying inflammationmay be present. Quite commonly, patients self-administer antibiotics without gaining relief.While under the supervision of the referral phy-sician, these patients often undergo multipleand inappropriate diagnostic tests and ther-apy. Some patients continue to work or per-form their usual duties.

The physical examination is characteristicfor its paucity of findings. Generally the pa-tient has frequent cough, lassitude, and pal-lor. Occasionally, patients may have a low-grade fever (usually less than 38.5°C) withmild tachypnea, tachycardia, and hyperten-sion. Examination of the posterior aspect ofthe pharynx may reveal erythema and post-nasal drainage. Auscultation of the lungs dem-onstrates either bronchovesicular, prolongedexpiratory, or harsh breath sounds with occa-sional rales and wheezing. Tenderness to pal-pation at the costochondral junctions is com-monly found in association with severe cough-ing.

Laboratory findings and chest roent-genogram results are usually normal; mild leu-kopenia, leukocytosis, or relative lymphocyto-sis may be present. Occasionally, findings ofincreased bronchovascular markings or mildhyperinflation are noted. Chest x-ray films areuseful in eliminating other causes. Spirometryresults are usually normal, except for smallairway abnormalities such as a decrease in theFEF25%-75%* If PVBHS is suspected and the di-agnosis is equivocal, a bronchoprovocation testusing methacholine, hyperpnea, or cold air willdemonstrate an exaggerated asthmatic-type re-sponse or bronchial hyperreactivity.

(continued on page 471)


Diseases to consider in diagnosing PVBHSare listed in Table 1. Viral bronchiolitis andpneumonia are characterized by greater sever-ity of symptoms than PVBHS with signs of tox-icity. Symptoms are continuous, including sig-nificant respiratory distress manifested bydyspnea, tachypnea, wheezing, use of acces-sory muscles, and diminished breath soundsin association with hypoxemia.38 The usual reso-lution of acute symptoms seen in PVBHS doesnot occur. The wheezing associated with bron-chiolitis is unresponsive to bronchodilator ther-apy. Fever, chills, rigors, myalgia, and arthral-gia are common. Gastrointestinal symptoms—including nausea, diarrhea, and vomiting—may occur, depending on the viral pathogen.

The chest x-ray film shows profound hyper-inflation and diffuse haziness in bronchiolitisand interstitial infiltrates often involving multi-ple lobes in pneumonia. Coalescence of the in-filtrate may lend an alveolar characteristic tothe infiltrate. 38 Viral bronchiolitis is an ex-tremely common illness in early childhood anddecreases in incidence with increasing age; itis rare in adults. 38 Respiratory syncytial virusis the most frequent cause of bronchiolitis inchildren, whereas the most common causes ofadult viral pneumonia in the normal host areinfluenza, parainfluenza, varicella, rubeola,and rhinovirus. 38 Adult respiratory distress syn-drome and secondary bacterial pneumonia areserious complications of viral pneumonia andrequire prompt diagnosis.38

Postnasal drainage from sinus infections,rhinitis, and occasionally carious teeth arecauses of chronic, persistent cough. 39 Stimu-lation of cholinergic afferent nerve fibers inthe posterior aspect of the pharynx and thelarynx cause cough and bronchospasm. Asso-ciated symptoms of nasal drainage and con-gestion, maxillary or frontal tenderness to pal-pation, sore throat, hoarseness, and symptomsof ear fullness or discomfort suggest sinusitis.4°Physical examination of the posterior aspectof the pharynx reveals erythema and postna-sal drainage. Coexistence of postnasal drain-age may confound the diagnosis of PVBHS andaggravate cough and wheezing. Bronchodila-tor therapy may be ineffective.

Gastroesophageal reflux is identified by a

Table 1Differential Diagnosis of Postviral

Bronchial Hyperreactivity Syndrome

• Viral bronchiolitis/pneumonia• Sinusitis/postnasal drip• Gastroesophageal reflux• Chronic bronchitis• Occupational asthma• Occult asthma

history of pyrosis, belching, abdominal bloat-ing, waterbrash, and regurgitation.'" Coughmay be the sole presenting manifestation ofgastroesophageal reflux as in 28% of the pa-tients in a recent study41 on chronic cough. How-ever, cough, wheezing, and shortness of breathare not always temporally associated with thegastrointestinal symptoms. Wheezing may oc-cur in the absence of aspiration as stimula-tion of the vagal afferents in the lower aspectof the esophagus by acid reflux causes reflexbronchospasm.41

Chronic bronchitis can be recognized by asignificant smoking history and productivedaily cough of at least 2 years' duration. 43 Toconfuse the picture, viral infections often ex-acerbate chronic bronchitis with resultantwheezing. 43 Chronic bronchitics may also havean exaggerated response to methacholine.44These patients may develop PVBHS with pro-found sputum production. Rhonchi and breathsounds with prolonged expiration are presenton auscultation of the lungs.43

Occupational asthma (OA) manifests as new-onset asthma in adults caused by specificagents in the workplace. More than 100 sub-stances have been identified in the workplaceto cause 0A,45 but many more are likely tobe identified in the future. Variable degreesof exposure, short- and long-term, can lead todevelopment of OA. Symptoms of wheezingand chest tightness occurring primarily atwork with abatement during weekends and va-cations are classic symptoms of 0A.45 Severalvariations of OA exist. Some patients initiallyhave a productive or dry cough that is not nec-essarily temporally related to exposure.

Asthma may be occult, because it is oftennot recognized by the patient or the physicianfor several reasons, including its episodic na-


Figure 1. Normal, nonin-fected mouse tracheal epithe-lium ( original magnifica-tion x 1050). Reprintedwith permission of the Ameri-can Review of RespiratoryDisease, Ramphal R, et al:1979;120:1313-1324.

Figure 2. Scanning elec-tron micrograph of mouse tra-cheal epithelium 36 hours af-ter infection. Few desqua-mating cells remain and thebasal layer is exposed ( origi-nal magnification x 2000).Reprinted with permissionof the American Review ofRespiratory Disease, Ram-phal R, et al: 1979;120:1313-1324.

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Clinical practice • Ostransky and Blais

Figure 3. Scanning elec-tron micrograph of mousetracheal epithelium 5 daysafter infection. Short andlong microvilli appear oncell surfaces I arrows/ (origi-nal magnification x 4000).Reprinted with permissionof the American Review ofRespiratory Disease, Ram-phal R, et al: 1979;120:1313-1324.

Figure 4. Scanning elec-tron micrograph of mousetracheal epithelium showscilia formation 10 days af-ter infection (arrow) ( origi-nal magnification x 2000).Reprinted with permissionof the American Review ofRespiratory Disease, Ram-phal R, et al: 1979; 120:1313 -1324.


Table 2Criteria for Diagnosis of Postviral

Bronchial Hyperreactivity Syndrome

• History of prior viral respiratory tract infectionwith initial recovery

• Appropriate intermittent and nocturnalsymptom complex

• Nonspecific bronchial hyperreactivity• Paucity of physical, laboratory, spirometric, and

radiologic findings• Positive cold air or methacholine challenge test• Self-limited illness

ture, variant manifestation as cough, 46 andmild severity. It is also frequently misdiag-nosed as "bronchitis." A careful history willreveal the classic features of asthma, includ-ing episodic bronchial hyperreactivity, chron-icity, and positive family history.

ManagementThe management of PVBHS is subdivided intocategories of pharmacotherapy, supportivemeasures, and prevention. Supportive meas-ures include reassuring the patient of the be-nign nature of the illness, and advising thepatient of prophylactic measures—rest, hydra-tion, appropriate diet, and avoidance of bron-chial irritants. Often, a good night's rest fol-lowing reassurance and institution of appro-priate drug therapy is extremely beneficial.Drug therapy for PVBHS is identical to thatfor asthma, with initial use of p-adrenergicagents. These drugs usually alleviate symp-toms within a few days. Some patients reportequal relief from theophylline or ipratropiumbromide.

In the absence of prompt relief (more than48 to 72 hours), a combination of these agentsis appropriate. If coughing is recalcitrant, cro-molyn sodium or corticosteroids by inhalationmay be useful. Cromolyn and corticosteroidsare effective in the prevention of bronchial hy-perreactivity, with little or no immediate bron-chodilation. Both drugs have a delayed onsetof action and require a week or longer to be-come effective.

Patients with associated symptoms of post-nasal drainage benefit from an antihistamineor nasal corticosteroid (or both) plus antibiot-

ics if sinusitis is present. In the face of severe,persistent symptoms or failure of conservativetherapy, careful reevaluation is suggested be-fore the use of systemic corticosteroids. Theprevention of a significant percentage ofPVBHS can be easily accomplished by the ap-propriate administration of influenza vaccineor amantadine hydrochloride.

SummaryThe diagnosis of PVBHS usually is easily es-tablished on the basis of history and responseto a clinical trial of bronchodilator therapy.Proposed criteria for diagnosis are listed in Ta-ble 2. Prospective studies regarding the fre-quency of PVBHS have not been done, but thecondition is probably common. Prompt diag-nosis by the primary care physician is essen-tial in reducing the morbidity of this syn-drome. In addition, physician recognition willprevent the use of inappropriate laboratorystudies and antibiotics. Increased awarenessof this disease will provide data regarding itsfrequency, and more careful study may leadto a better understanding of the pathogenesisof asthma.

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Postviral bronchial hyperreactivity syndrome: Recognizing