OVERVIEW: What every practitioner needs to know

Are you sure your patient has croup? What are the typical findings for this disease?

The classic triad of symptoms in viral croup include stridor, a barking (deep) cough, and laryngitis. Stridor is a harsh, almost crowing sound made during inspiration, distinguishing it from expiratory sounds such as wheezing and rhonchi. The cough is somewhat variable, but the brassy sound resembling that of an ocean seal is characteristic if the child has an adequate tidal volume. Laryngitis will be more obvious in the child who is verbal, but hoarseness can be identified in children of any age with careful listening.

Most children with viral croup have a 2- to 3-day prodrome of symptoms of a minor upper respiratory tract infection (rhinorrhea and cough) before stridor develops. Fever is frequently absent, and, if present to a high degree, may suggest bacterial secondary infection. The general appearance of the child is a nontoxic one (unlike epiglottitis). Wheezing is occasionally present simultaneously with stridor in children with a predisposition to wheezing.

What other disease/condition shares some of these symptoms?

The differential diagnosis of croup comprises a long list of entities. The condition most commonly confused with croup is possibly laryngomalacia, which also presents with stridorous breathing, either when the child has a viral infection or is simply upset. In contrast to the child with croup, the child with laryngomalacia does not have a hoarse voice, and the stridor is present intermittently over many months (not just with an acute viral infection). Stridor with laryngomalacia is positional, being more prominent when the child lies on the back.

Epiglottitis also presents with stridor but generally occurs with high fever and toxicity. The child with epiglottitis usually positions himself or herself so that the epiglottis is pulled forward from the pharynx. Thus the child will be sitting up with the jaw extended forward. Drooling is also evident, since the child avoids swallowing and therefore closing the larynx. Fortunately, epiglottitis is now uncommon in children who have received the routine vaccination against Haemophilus influenzae type b.

Aspirated foreign body is an important possible diagnosis in the child with stridorous breathing. These children are afebrile and nontoxic in appearance but lack hoarseness. Although they may cough frequently, the cough does not have the brassy quality of the cough in croup. If the foreign body is in the esophagus, the child may be drooling and gagging. Breath sounds may be asymmetric on auscultation of the lungs.

Peritonsillar and retropharyngeal abscesses may present with stridor, although these children are usually febrile and appear more toxic than children with croup. The onset of abscess is more gradual than the fairly rapid onset of croup, which progresses from a mild upper respiratory tract infection to stridor, often within a few hours. Deviations of the uvula, muffled (“hot potato”) voice, and protrusions of the tonsils into the airway are often noticeable.

Stridor may also be present when the child has an anatomic anomaly that compresses or obstructs the airway near the larynx. These entities include webs, hemangiomas, vascular rings, and congenital subglottic stenosis. Evidence of stridor should be present intermittently over the entire lifetime of the child who has one of these fixed anatomic conditions.

Spasmodic croup is an entity essentially identical to more conventional croup, except that episodes are frequent and there is no prodrome. The same respiratory viral precipitants are recovered from children with conventional croup and those with spasmodic croup.

Diphtheria may present with stridor, but these children are toxic in appearance, have marked neck swelling, and a dense fibrotic membrane in the posterior pharynx.

Bacterial croup occurs when pyogenic bacteria invade an airway already inflamed by infection with the viruses that commonly cause croup. These children appear more toxic than those with conventional croup, have higher fevers, and do not respond to therapeutic measures that are usually effective in viral croup. The diagnosis of bacterial croup is often made when a child is being intubated for conventional croup that is unresponsive to usual therapies.

What caused this disease to develop at this time?

Episodes of croup represent an unusual host response to common respiratory viral infections. Croup is most commonly caused by the parainfluenza viruses (PIV), especially type 1. This virus appears in biannual epidemics beginning in late summer and autumn. PIV-1 is the cause of most cases of severe croup. PIV-3 generally causes milder cases, with the peak of activity in spring and early summer. Influenza virus is not a common cause of croup, but when it is the cause, the episodes may be unusually severe. Respiratory syncytial virus (RSV), adenovirus, and rhinovirus are other occasional causes of croup, but essentially any respiratory virus can cause croup.

There do not appear to be genetic or nutritional factors predisposing to croup that are of any importance. Immunodeficient children may not experience croup as frequently as their immunocompetent peers, although immunocompromised children may experience severe and protracted pneumonia with PIV infections.

The child presenting with croup has usually been healthy until the time of presentation and, with the possible exception of reactive airway disease or asthma, is no more likely to have underlying conditions than the general pediatric population. In general, a 2- to 3-day history of rhinorrhea and mild cough can be elicited, following which the characteristic brassy cough and stridor rapidly develop. This rapid progression of symptoms usually occurs after nightfall, with the child awakening from sleep in various degrees of respiratory distress. The child is understandably frightened, and consoling and reassuring the child is an important step in relieving the respiratory distress.

On examination of the child, stridor is usually quite evident, masked only if there is an inability to generate substantial airflow. Suprasternal, subcostal, and intercostal chest wall retractions are easily recognizable. Auscultation of the chest reveals inspiratory stridor and, occasionally, wheezing. Otherwise the breath sounds are equal throughout the lungs, with no crackles.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The results of complete blood counts and chemistry panels are nonspecific. Blood gas determinations are not necessary unless there is suspicion of respiratory failure. Since the alveolar spaces are usually unaffected in croup, and ventilation-perfusion abnormalities are uncommon, hypoxia is not observed in croup unless the child tires and subsequently underventilates. Carbon dioxide retention may precede the development of hypoxia. Therefore oxygen saturation values will be in the normal range in the vast majority of croup cases; normal oxygen saturation values also may distract the clinician from considering whether carbon dioxide retention is occurring. To summarize, monitoring for hypoxia and carbone dioxide retention is only necessary in children with croup who appear to be tiring as a result of their work of breathing.

Would imaging studies be helpful? If so, which ones?

Radiographic studies are usually unnecessary in croup, since the diagnosis is usually made clinically and the development of secondary bacterial pneumonia is distinctly unusual. Airway films may, however, reveal the smooth subglottic narrowing that is characteristic of croup i.e., as the airway is followed superiorly from the carina, there is gradual tapering of the air column approaching the larynx (“steepling”). This finding is highly suggestive of croup. Airway films may occasionally be useful in distinguishing croup from retropharyngeal abscesses, but croup can usually be differentiated from other entities on a clinical basis alone.

Confirming the diagnosis

Croup is a clinical diagnosis, occasionally assisted by airway radiographs. The classic triad of laryngitis, stridor, and barking cough is usually enough to establish the diagnosis. Patients with intermittent stridor and no respiratory distress probably will not require hospitalization unless other mitigating factors are present. Subjects with stridor at rest, reduced air entry, or any degree of pronounced chest wall retractions are candidates for therapy (see below). Patients with cyanosis, reduced level of consciousness, and fatigue from the effort of respiration should be referred to intensive care areas for management.

If you are able to confirm that the patient has croup, what treatment should be initiated?

The treatment of choice for croup is dexamethasone. When given intramuscularly to patients with moderate to severe forms of croup, dexamethasone reduces the overall severity of illness and reduces the need for hospitalization and intubation. In mild to moderate croup, the use of dexamethasone reduces the need for return visits to medical facilities over the next week. Dexamethasone is equally effective when given orally or intramuscularly. Although most studies, particularly those involving patients with more severe croup, have been carried out using a dose of 0.6 mg/kg of dexamethasone, it nevertheless appears that a dose of 0.15 mg/kg is equally effective, especially in milder cases.

Oral therapy may not be possible in the chid with severe respiratory distress. Because of the long half-life of dexamethasone effects (>50 hours), a single dose is usually sufficient. Once benefits from dexamethasone become apparent, they are generally well sustained, so repeated doses are not required. Nebulized betamethasone has been demonstrated to be effective in croup, but this modality is neither more effective nor less toxic than dexamethasone in croup. Also, administration by aerosol is more complicated than simple oral or intramuscular administration of a single dose of dexamethasone.

Since the effects of dexamethasone do not become apparent for several hours after its administration, patients with moderate to severe croup are candidates for further forms of therapy while waiting for dexamethasone to take effect. Controlled studies indicate that inhalation of racemic epinephrine aerosols provides substantial temporary benefit in croup. Patients characteristically have reduced work of breathing nearly immediately and lasting for up to 2 hours after inhaling 2.25% aerosols of racemic epinephrine, after which the effects of the drug wear off. Repeated doses can be administered until more long-term benefit from dexamethasone administration occurs.

Fears of a “rebound” response to racemic epinephrine treatment have proved unfounded. Patients who have begun to respond to combined therapy with dexamethasone and racemic epinephrine can be discharged home 2 hours after the time of the last racemic epinephrine dose, after which no further deterioration should occur.

Helium-oxygen (heliox) mixtures have gained some popularity in the treatment of croup. However the use of these gases provides only minimal or no additional benefit in patients hospitalized with croup and treated with dexamethasone. Oxygen concentrations greater than 30%-40% cannot be achieved using heliox mixtures, so therapy is limited to patients requiring only this amount of supplemental oxygen. The use of heliox also requires special equipment, and administration has not been demonstrated to reduce mortality or the need for intubation.

Although it was long believed that inhaling cool mist is beneficial in croup, controlled studies have not demonstrated any benefit from this measure.

The most serious complication of viral croup is secondary bacterial invasion of the damaged airway. Bacterial croup may be suspected when patients have unusually high fever and are not responsive to dexamethasone and racemic epinephrine. However the diagnosis is rarely secure until the patient is intubated for respiratory failure and purulent secretions are noted in the airway lumen in the subglottic region. The usual invading bacteria are Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pneumoniae, and Haemophilus species. An appropriate first choice of antibiotics is therefore vancomycin and ceftriaxone. Clindamycin can be substituted for vancomycin in regions where staphylococci remain susceptible to clindamycin, but resistance is becoming more common.

What are the adverse effects associated with each treatment option?

Short-term dexamethasone use can be accompanied by fluid retention, hyperglycemia, and mood alterations, but these should be transient or nonexistent given the limited duration of therapy required for successful management of croup.

Racemic epinephrine use can cause tachycardia and anxiety, but these are generally mild and temporary.

Heliox mixtures are essentially free from harmful effects.

Vancomycin can result directly in histamine release from mast cells, inducing flushing and pruritus in recipients (red man syndrome). Vancomycin use has been temporally associated with the development of ototoxicity and nephrotoxicity. When used alone, and in the absence of coadministration of nephrotoxic agents, renal toxicity from vancomycin is negligible.

Ceftriaxone may cause mild diarrhea frequently, and can cause allergic responses including anaphylaxis in patients allergic to β-lactam compounds.

Cindamycin is generally a benign drug. Although it can precipitate pseudomembranous colitis, this is uncommon in otherwise healthy children.

What are the possible outcomes of croup?

The prognosis of croup is excellent, with no long-term complications in the vast majority of cases. Repeated episodes of croup may occur in some individuals, but recurrent croup in these patients is more likely a result of a hereditary tendency toward constriction of the subglottic area in response to a variety of viruses and nonspecific stimuli, rather than of damage to the airway as a result of croup.

When intubation of the patent is necessary in the management of croup, it is normally required for only a few days, so subglottic stenosis is unlikely to occur. Only in patients with severe bacterial croup requiring prolonged intubation is there a likelihood (albeit a small one) that tracheal hemorrhage or fibrosis may occur, resulting in a fixed narrowing of the airway. This is a very uncommon event, however.

What causes this disease and how frequent is it?

Croup is most frequently caused by PIV-1 infection, followed in frequency by PIV-3, RSV, influenza A, and (less commonly) a variety of other viruses. PIV-1 and PIV-3 cause 60%-80% of severe cases of croup. Croup can occur at any time during the year, but epidemics are most likely to be seen in late summer to early autumn (PIV-1) and in late spring (PIV-3). The activity of PIV-1 tends to occur in an biannual fashion, whereas PIV-3 epidemics are annual.

Croup most commonly presents between 6 months and 3 years of age. The disease is uncommon after approximately 6 years of age but has been observed even in early adolescence. Males with croup outnumber females in almost a 2:1 ratio. The prevalence of croup is approximately 60 cases/100 child-years of observation, and croup occurs in approximately 3% of all children less than 6 years of age.

The mode of transmission of parainfluenza viruses has not been studied extensively. Infection with parainfluenza viruses, like that of RSV, is probably transmitted most frequently by contact with respiratory secretions of infected individuals, including older children with only minor “colds” and asymptomatic adults. Influenza virus can be transmitted by aerosols and by direct contact with secretions of infected individuals.

There are no known predisposing exposures that increase the likelihood of the croup developing. The influence of exposure to cigarette smoke or environmental pollution on the development of croup has not been determined.

How do these pathogens/genes/exposures cause the disease?

Little is known about the pathogenesis of croup, other that it can be induced by a variety of respiratory viruses. Therefore a unique pathogen-specific disease mechanism is unlikely. However, most cases of severe croup are caused by PIV-1, followed by PIV-3. These viruses may have a proclivity for infecting the airway epithelium in the subglottic area, since autopsy studies of fatal croup cases suggest that inflammation is maximal in this area.

The response of croup to racemic epinephrine and dexamethasone suggests that airway smooth muscle constriction and mucosal edema contribute to the subglottic narrowing noted in croup cases. Histamine challenge studies of patients having had recurrent episodes of croup reveal that they have hyperreactivity of the subglottic area, in a fashion analogous to bronchial hyperreactivity in asthmatic individuals.

Individuals with immune deficiency states do not experience especially severe forms of croup; therefore croup is unlikely to be a result of inadequate immune responses. PIV-specific IgE antibody responses in respiratory secretions have been reported to be greater in patients with PIV-related croup than in those with only upper respiratory tract infections caused by PIV infection, suggesting that a type 1 hypersensitivity mechanism may be involved in the pathogenesis of croup..

What complications might you expect from the disease or treatment of the disease?

As noted above, viral croup essentially always resolves without sequelae. Cases of bacterial croup that result in prolonged intubation can uncommonly result in airway strictures, but this is a decidedly uncommon outcome.

How can croup be prevented?

Although work is ongoing, there is no licensed PIV vaccine. There currently are no measures that have been demonstrated to be effective in the prevention of croup.

There is no evidence that behavioral factors lead to the development of croup. Existing studies have not established any effect of passive exposure to cigarette smoke and environmental pollution on the outcome of croup.

What is the evidence?

Edwards, KM, Dundon, MC, Altemeier, WA. “Bacterial tracheitis as a complication of viral croup”. Pediatr Infect Dis J. vol. 2. 1983. pp. 390-1. (This article establishes the existence and hazard of bacterial croup.)

Bjornson, CL, Klassen, TP, Williamson, J. “A randomized trial of a single dose of oral dexamethasone for mild croup”. N Engl J Med. vol. 351. 2004. pp. 1306-13. (This study demonstrates the effectiveness of oral dexamethasone in croup.)

Colletti, JE. “Myth: cool mist is an effective therapy in the management of croup”. CJEM. vol. 6. 2004. pp. 357-8. (This article demonstrates the lack of effect of cool mist in croup, thereby streamlining therapy.)

Cruz, MN, Stewart, G, Rosenberg, N. “Use of dexamethasone in the outpatient management of acute laryngotracheitis”. Pediatrics. vol. 96(2 Pt 1). 1995. pp. 220-3. (This article establishes the effectiveness of dexamethasone in croup.)