Vol. 12 •Issue 8 • Page 16
Allergy & Asthma
Examining How Infections Influence Asthma
A 22 year-old female patient with childhood onset asthma has disabling symptoms despite the use of high-dose inhaled corticosteroids, long-acting beta2-agonists, cromolyn sodium, theophylline and albuterol. For the last 13 years, only oral corticosteroids have controlled her symptoms. Dyspnea and wheezing ensue when steroids are tapered.
She is evaluated with a bronchoscopy and endobronchial biopsies. Surprisingly, this demonstrates the presence of intraluminal Mycoplasma pneumoniae. Is it possible that this patient’s severe asthma is related to chronic mycoplasma infection? If so, how should she be treated? Examining how infections influence the inception, exacerbation and chronicity of asthma is a provocative topic.
In the last 50 years, there has been a marked increase in the incidence of asthma and allergy in the United States and other industrialized nations. During the same time, improved hygiene, better socioeconomic conditions, the widespread availability of antibiotics and the effective use of vaccines have led to a vast decrease in childhood infections.
In 1989, a researcher reported that the incidence of allergic rhinitis in British children was inversely related to family size and the number of older siblings.1 He hypothesized that children with older siblings were exposed to a greater number of infections and that this exposure protected against the development of allergic disease.
Subsequent investigators have demonstrated lower rates of asthma and allergic diseases in children who are raised on farms, those who have multiple pets, and those who attend day care in the first six months of life.2-4 It’s assumed that these children are exposed to infectious agents or endotoxins at a greater level than their counterparts. The apparent protective effect of early childhood infection against allergic disease and asthma has been termed the “hygiene hypothesis.”
The critical immune cells involved in the hygiene hypothesis are the T-helper lymphocytes. Two subsets of T-helper cells exist: Th1 and Th2. Th2 lymphocytes regulate the production of IgE and promote the allergic inflammatory response. Their counterparts, Th1 lymphocytes, are involved in cell-mediated immunity against intracellular pathogens and delayed-type hypersensitivity reactions. They also suppress IgE.
In simplistic terms, Th2 cells are involved in allergic responses and Th1 lymphocytes fight infection. Activation of one system suppresses the other. Therefore, children who have few infections develop a robust Th2 system and are prone to allergic disease. In contrast, children who are frequently exposed to infectious agents have a vigorous Th1 system and a suppressed responsiveness to allergens.
The hygiene hypothesis has been verified in the laboratory by a study using a mouse model.5 Researchers divided mice into two groups.
The first group was given a mixture of aerosolized saline and M. pneumoniae to create a low-grade respiratory tract infection. These mice were then sensitized to an antigen. Four weeks later, they were challenged with the antigen, and airway hyperresponsiveness was assessed using plethysmography. In addition, bronchoalveolar lavage was used to assess the levels of Th1 and Th2 cytokines. A similar process was used in the second group of mice except that they were antigen sensitized and antigen challenged prior to infection with mycoplasma.
As predicted by the hygiene hypothesis, the group that was infected prior to the antigen exposure had decreased airway inflammation, reduced bronchial hyperresponsiveness, increased levels of Th1-related cytokines and decreased levels of Th2 cytokines. Mice that were infected after antigen sensitization and challenge had decreased bronchial hyperresponsiveness immediately after infection but then displayed increased airway hyperresponsiveness by day five in conjunction with an increased Th2 response.
Are all infections protective against asthma? Probably not. Epidemiologic studies suggest that tuberculosis, hepatitis A virus, measles and gastrointestinal parasites may have a protective effect, while lower respiratory infections with respiratory syncytial virus (RSV) and rhinovirus may be causative.6-8 Nearly all children are infected with RSV by age 2, so the severity of infection, the child’s age at first infection, or the timing of infection in relation to allergen exposure may be important.
ACUTE ASTHMA EXACERBATIONS
There’s clear evidence that respiratory viruses cause most asthma exacerbations. Hospital admissions for asthma correlate closely with the seasonal patterns of upper respiratory virus infections, and viral DNA can be detected in the upper airways of up to 50 percent of adults and 85 percent of children with acute asthma symptoms.9,10
The exact mechanisms by which asthmatic patients develop lower airway symptoms have not yet been established. Concomitant allergic exposure almost certainly plays a role as demonstrated by a recent case-controlled study in which patients with the combination of viral infection, allergic sensitivity and allergic exposure were 5.8 times more likely to be hospitalized than case-controls.11
New evidence suggests that acute myco-plasma infection also may play a role in asthma exacerbation. In a prospective study of 100 patients hospitalized with asthma, researchers found serologic evidence of M. pneumoniae infection in 18 percent.12 Interestingly, more than half of these patients had a concurrent viral infection. The patients with mycoplasma infection tended to be sicker than their counterparts, were more likely to require mechanical ventilation, and were readmitted to the hospital at a greater rate.
Despite these findings, most guidelines don’t recommend the routine use of antibiotics for the treatment of acute asthma exacerbations.13
Bacterial infections impair mucociliary clearance and increase mucous production in the lungs. Thus, it has been hypothesized that chronic bacterial infection may contribute to lower airway inflammation and chronic asthma symptoms. The strongest evidence exists for infection with Chlamydia pneumoniae and M. pneumoniae.
However, study of these pathogens has been hindered by the availability of sensitive and specific tests. Both chlamydia and mycoplasma species are intracellular pathogens and are difficult to grow in culture. Serologic tests are similarly unreliable. Members of the general population develop seropositivity to chlamydia throughout life and by middle age more than 50 percent are seropositive.14
In addition, antibodies to the various chlamydia species cross-react, further limiting their utility. While chlamydia serologies lack specificity, mycoplasma serologies lack sensitivity. In fact, it isn’t uncommon for antibody responses to be absent even after pneumonia.15 In chronic infections, the bacterial load may be low, further limiting the antibody response.
In recent years, polymerase chain reaction (PCR) has emerged as a specific method for the detection of chlamydia and mycoplasma. One study investigating these pathogens compared 55 patients with chronic stable asthma to 11 control subjects.16 Nasal swabs, endobronchial biopsies, brushings and alveolar lavage were obtained from all patients and processed for culture and PCR.
Thirty-one (55 percent) of the asthmatic patients had positive PCR results for mycoplasma or chlamydia as compared to only one (9 percent) of the control patients. Cultures were negative in both groups.
While the work of other investigators supports the presence of chlamydia and mycoplasma in patients with chronic asthma, the role that these bacteria play in asthma pathogenesis is still unclear. It’s possible that they induce chronic airway inflammation, thus increasing the susceptibility to other exacerbating stimuli such as viruses, allergens, or both.
On the other hand, if infection precedes allergic sensitization, the immune system may be shifted toward a Th1 response as suggested by the hygiene hypothesis. More research is needed in this area.
At the current time, antibiotics aren’t recommended for acute exacerbations of asthma; most acute exacerbations are due to the combined effect of allergic exposure and viral infections. The cornerstone of therapy remains inhaled beta2-agonists, and inhaled or systemic corticosteroid therapy.
The role of antibiotics in the management of chronic asthma also is under investigation. Macrolide antibiotics are known to have good activity against mycoplasma and chlamydia species, and several investigators have used this class of antibiotics in treatment of patients with chronic asthma. One such study randomized patients to receive either placebo or oral clarithromycin for six weeks.17 Overall, there was no significant change in lung function between the two groups.
However, when the group that received antibiotic therapy was further analyzed, patients who had been PCR positive for mycoplasma or chlamydia prior to therapy had a significant improvement in FEV1, while PCR-negative patients didn’t. (See Figure.) These findings suggest that a select group of patients with chronic airway colonization by mycoplasma or chlamydia may benefit from antibiotic therapy.
The patient described earlier has been treated with long-term clarithromycin. She has been successfully weaned from steroids and has demonstrated dramatic improvement in her lung function.
Dr. Janssen is a pulmonary fellow at the University of Colorado/National Jewish Medical and Research Center, Denver. Dr. Martin is professor of medicine and head of the pulmonary division at the same facility.
For a list of references, please call John Crawford at (610) 278-1400, ext. 1499, or visit www.Respiratory-care-sleep-medicine.advanceweb.com.