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When to suspect allergic bronchopulmonary aspergillosis

The Journal of Respiratory DiseasesThe Journal of Respiratory Diseases Vol 6 No 3
Volume 6
Issue 3

Abstract: Inhalation of Aspergillus is responsible for a variety of lung infections and diseases; Aspergillus fumigatus is the most common causative agent. Allergic bronchopulmonary aspergillosis (ABPA), caused by sensitivity to A fumigatus, is diagnosed primarily in persons with asthma or cystic fibrosis. Differentiating ABPA from other Aspergillus-related lung infections and diseases is often challenging. A patient's symptoms, underlying risk factors, and any prior pulmonary disease contribute to the diagnosis. Findings include pulmonary infiltrates, total serum IgE levels greater than 1000 IU/mL, IgE and IgA anti-A fumigatus antibodies, peripheral blood and pulmonary eosinophilia, and central bronchiectasis. Untreated ABPA often results in chronic bronchiectasis, pulmonary fibrosis, and dependence on corticosteroids; an accurate diagnosis of ABPA is critical to avoiding irreparable disease. (J Respir Dis. 2006;27(3):123-134)

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic hypersensitivity lung disease caused by Aspergillus fumigatus. Patients with asthma and cystic fibrosis (CF) are at increased risk for ABPA.

If ABPA is not appropriately treated, it can lead to bronchiec- tasis, pulmonary fibrosis, and a dependence on corticosteroids. Therefore, it is important to recognize ABPA as promptly as possible.

In this article, I will briefly review the diseases that can be caused by A fumigatus. I will then review the diagnosis and treatment of ABPA.



Exposure to A fumigatus can cause a variety of lung diseases, including invasive aspergillosis, mycetoma, and hypersensitivity pneumonitis (Table 1).1-3

Invasive aspergillosis

Host defense responses to Aspergillus involve both innate and adaptive immunity. Patients with congenital neutrophil defects, such as chronic granulomatous disease and leukocyte adhesion deficiency, are susceptible to the development of invasive pneumonitis caused by exposure to A fumigatus.

Similarly, infants who have congenital T-cell immunodeficiencies, such as severe combined immunodeficiency, are susceptible to invasive A fumigatus infections. A number of secreted molecules, such as surfactant protein A2 and long chain pentraxin 3, also demonstrate antimicrobial activity against A fumigatus.

Symptoms of A fumigatus pneumonitis vary depending on the underlying host factors, but they should not be confused with those of ABPA. Patients with A fumiga- tus pneumonitis typically have fever, dyspnea, and nonproductive cough. Chest radiographs often reveal a micronodular, or ground-glass, appearance.

Lung biopsy frequently demonstrates granulomatous inflammatory response with staining that is positive for A fumigatus hyphae. Interestingly, in patients with chronic granulomatous disease, small percentages of eosinophils are often present, indicating that these cells may play a role in host defense against Aspergillus.


Patients with mycetoma often have underlying lung disease--typically cavitary lung disease and/or bronchiectasis. When Aspergillus spores are inhaled, they form a hyphae mass--in essence, a fungus ball--in the abnormal lung structure. Patients with such masses are largely asymptomatic and have extremely elevated levels of IgG anti-Aspergillus antibodies.

Hypersensitivity pneumonitis

This TH1-mediated hypersensitivity lung disease is caused by sensitivity to a variety of avian and fungal antigens.2-4 The Aspergillus species that most commonly cause hypersensitivity pneumonitis are A fumigatus and Aspergillusclavatus from germinating barley (malt-worker's lung disease). The clinical presentation and histologic findings depend on whether the hypersensitivity pneumonitis is in an acute, subacute, or chronic stage.

With an acute antigen exposure, patients are typically febrile, dyspneic, and hypoxic, and they have a nonproductive cough. The chest radiograph shows interstitial infiltrates. Pulmonary function studies reveal a restrictive pattern with decreased carbon monoxide-diffusing capacity in all stages of hypersensitivity pneumonitis. In subacute and chronic antigen exposures, which typically involve lower antigen doses, patients are often afebrile, but they do have nonproductive cough, dyspnea, and hypoxia. Chest CT can detect micronodularity, which, if untreated, can progress to honeycombing.

Lung biopsies and bronchoalveolar lavage (BAL) analyses reveal a predominance of lymphomononuclear infiltrate and granulomatous formation. The lymphocytes are predominantly CD8+ T cells and natural killer cells. Although IgG antibodies to the precipitating antigen are present, there is no evidence of immune complex deposition. Single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF) receptor molecules and HLA-DR restriction in pigeon breeder's disease have been identified as genetic risk factors.


Sensitivity to A fumigatus can occur in atopic patients with asthma or CF; like other allergens, A fumigatus can cause bronchospasm on exposure. Many patients with asthma or CF (particularly the latter) are allergic to other fungi, such as Alternaria and Cladosporium. Numerous epidemiologic studies have reported that sensitivity to Alternaria in the United States and to Cladosporium in Europe is associated with increased bronchial hyperresponsiveness and severity of asthma in children and adults.3-15

The major fungi that cause allergic reactions are in the phylum Ascomycota (Alternaria,Aspergillus,Cladosporium, and Penicillium) and in the subphylum Basidiomycota (Malassezia,Coprinus, and Psilocybe).16,17 Individual fungi and molds produce 40 or more differ-ent antigens (and A fumigatus has 22 identified recombinant allergens)that can stimulate IgE production.14 Many of these antigens cross-react among different fungi.

IgE reactivity to fungal antigens has been reported in patients with fungal-sensitive asthma or sinusitis.18-20 The presence of IgE, IgG, and IgA antibodies to A fumigatus is a criterion for the diagnosis of ABPA. In contrast, in patients with fungal-sensitive asthma and rhinitis, IgG reactivity is typically absent. However, Vailes and associates19 reported that patients with Alternaria sensitivity produce both IgE and IgG antibodies to Alternariaalternata.

We have observed the same results with A fumigatus antigens in patients with asthma and CF who do not have ABPA.2Patients with ABPA produce extremely elevated levels of IgE and IgG anti-A fumigatus antibodies; patients without ABPA produce lower levels of IgE and IgG anti-Aspergillus antibodies. The differences in IgG and IgE antibodies in patients with asthma and ABPA versus those with asthma and fungal sensitivity may result from a much greater amount of antigen in the bronchial airway in patients with ABPA.

In addition, fungal antigens have biologic activity that directly affects the respiratory epithelia and immune reactivity. In particular, proteases of Aspergillus, Penicillium,Cladosporium,Alternaria, Basidiomycetes, and Botrytis appear within 24 hours of culture and have a direct effect on bronchial epithelium.21,22 Fungal proteases disrupt bronchial integrity, permitting epithelial shedding, which allows for antigen exposure to subepithelial cells.

Fungal proteases also stimulate the bronchial epithelium to produce TNF, interleukin (IL)-6, and IL-8. A fumigatus is clearly the most potent, but other fungi also stimulate cytokine synthesis and disrupt bronchial epithelium.

House dust mites and fungal proteases act on a family of protease-activated receptors (PAR), which are transmembrane G protein-coupled receptors that are stimulated by serine receptors.23 In particular, PAR-2 expression on respiratory epithelium is increased in patients with asthma. PAR-2 activity has been associated with increased bronchial hyperreactivity, eosinophilic infiltration, and IgE production.

Sinobronchial allergic mycosis

Venarske and deShazo24 referred to the coexistence of allergic fungal sinusitis (AFS) and allergic bronchopulmonary mycosis as "sinobronchial allergic mycosis" (SAM) syndrome. Patients with SAM syndrome demonstrate chronic sinusitis, asthma, elevated total serum IgE levels, elevated fungal-specific IgE levels, eosinophilia, and central bronchiectasis.

In patients with SAM syndrome, mucoid material from sinuses and BAL fluid demonstrates allergic mucin that contains a dense accumulation of eosinophils and Charcot-Leyden crystals. Serum IgE levels are distinctly elevated, at greater than 5000 IU/mL. After surgical and corticosteroid treatment, the IgE level decreases, although it remains elevated through a process similar to that seen with ABPA. A variety of fungi that can cause AFS have been identified in patients with SAM syndrome. Interestingly, a heterozygous mutation in the CF transmembrane conductance regulator gene, similar to that seen in patients who have asthma and ABPA, was identified by Miller and associates.25


This TH2 cell-mediated hypersensitivity lung disease is caused by bronchial colonization with A fumigatus. Sensitization to A fumigatus is common in patients with asthma or CF, yet only a small percentage have ABPA; it affects about 1% to 2% of patients with asthma and 7% to 9% of those with CF.1,26

ABPA is characterized by wheezing; pulmonary infiltrates; eosinophilia; increased total serum IgE levels; and increased IgE, IgG, and IgA anti-A fumigatus antibodies (Table 2). Sequelae of ABPA include bronchiectasis and pulmonary fibrosis, which progressively compromise respiratory function, thereby increasing morbidity and mortality.

We propose that patients with ABPA have genetic risk factors for the development of ABPA. Chauhan and colleagues27-29 found that patients with ABPA have increased frequency of HLA-DR2 and HLA-DR5. My colleagues and I proposed that another genetic risk factor for ABPA is increased sensitivity of IL-4-mediated activities secondary to SNPs of the IL-4 binding region of the IL-4R.30-33 Thus, in patients with ABPA, increased sensitivity to IL-4 in conjunction with HLA-DR2/DR5 restriction to Aspergillus antigens results in increased B-cell IgE responses, a monocyte/dendritic cell phenotype that polarizes Aspergillus-specific TH2 responses, increased Aspergillus-specific TH2 responses, and increased epithelial responses.

Differentiating between Aspergillus sensitization and the development of ABPA can be difficult, especially in patients with CF. The incidence of atopy in patients with CF is approximately 20%, and sensitization to mold is common in these patients.

In addition, the incidence of colonization with A fumigatus and the development of sensitization to Aspergillus proteins increase with age. Numerous studies indicate that 60% to 70% of patients with CF have sensitization to Aspergillus proteins.

Reactive airway disease with wheezing is common in patients with CF, and obstructive airway disease is part of the pathogenesis of CF lung disease. In patients with CF who experience bronchopulmonary exacerbations associated with Pseudomonasaeruginosa and Staphylococcusaureus, pulmonary infiltrates develop; with repeated infections, central bronchiectasis also occurs. Thus, it can be very difficult to distinguish a CF flare from an ABPA flare.

To further complicate the diagnosis, ABPA occurs in stages: acute primary episode, remission, exacerbations, corticosteroid-dependent asthma, and pulmonary fibrosis/bronchiectasis (Table 3). We propose that the distinction between patients with asthma or CF who have A fumigatus sensitivity and those with ABPA is quantitative, not qualitative--that is, the difference is attributable to genetic risk factors, which may aid in the diagnosis.


In the pathogenesis of ABPA, A fumigatus spores 3 to 5 µm in size are inhaled and germinate into hyphae deep within the bronchi.34,35 This suggests the potential for the respiratory epithelium and bronchoalveolar lymphoid tissue (BALT) mucosal immune system to be exposed to high concentrations of A fumigatus allergens. Greenberger and associates36 demonstrated that IgE and IgA anti-Aspergillus antibodies were primarily synthesized in the BALT, whereas IgG anti- Aspergillus antibodies were produced in the peripheral lymphoid tissue.

An analysis of cells obtained from BAL fluid in patients with ABPA reveals an admixture of alveolar macrophages, eosinophils, and lymphocytes similar to that found in patients with asthma. Eosinophilic infiltration predominates in both BAL fluid and lung tissue, as is evident in lung biopsy.34 In addition, eosinophils are activated and release mediators, including major basic protein and eosinophil cationic protein. The TH2 cytokine IL-5, essential for the activation of eosinophils, is crucial in the development of ABPA.

An important pathogenic feature of Aspergillus and other fungi is their ability to interact with epithelial cells on the mucosal surface. Proteases from Aspergillus and such fungi as Alternaria and Cladosporium have been shown to cause epithelial cell detachment and increased leakage.21,37-42

In addition to damaging the integrity of the normal bronchial epithelial cell layer, protease-containing culture infiltrates of A fumigatus and other fungi induce bronchial cell lines to produce proinflammatory chemokines and cytokines, including monocyte chemoattractant protein (MCP)-1, IL-8, and IL-6.21 MCP-1 has been implicated in the direct stimulation of the development of TH2 cells.43 These observations suggest that proteolytic enzymes released by Aspergillus, which grow on and among epithelial cells, are responsible for the induction of chemoattractant cytokines by epithelial cells and the corresponding inflammation. In addition, the results of studies suggest that asthmatic bronchial epithelia respond differently to allergen proteases and to IL-4/IL-13 stimulation.

In patients with asthma, remodeling is characterized by changes involving epithelial cell hyperplasia and metaplasia, collagen deposition, thickening of the lamina reticularis, smooth muscle hyperplasia, and proliferation of airway blood vessels and nerves.24,44-46 Holgate's group46 examined airway remodeling in asthma by studying the relationship between the epithelial mesenchymal trophic unit (EMTU) and allergic inflammation. They proposed that injury to the bronchial epithelium caused by inflammation reactivates the EMTU, resulting in the remodeling of airways, as seen with fibrosis. In asthma, damage to the bronchial epithelium and to the TH2 cytokines causes disturbances of the EMTU.

My colleagues and I found that the T-cell responses of primary isolated T cells and T-cell clones stimulated with crude Aspergillus extract or purified Aspergillus allergens demonstrate a TH2 phenotype.47-50 We showed that the frequency of Aspergillus-specific IL-4+ CD3+ T cells is increased in persons with ABPA compared with Aspergillus-sensitive persons without ABPA. IL-5 secretion is significantly increased in persons with ABPA compared with those without ABPA. IL-10 synthesis is increased by Asp f2/f3/f4 stimulation both in patients with and in those without ABPA.31,32

In another study, Brouard and colleagues51 reported the association of the -1082GG genotype of the IL-10 promoter and its colonization with A fumigatus and the development of ABPA. This genotype results in increased serum IL-10 levels, which may skew Aspergillus-specific TH2 responses.

We have described an increased sensitivity to IL-4 stimulation in ABPA, which results in elevated expression of CD23+CD86+ B cells. This leads to a positive feedback cycle that increases CD4+ TH2 cell responses and IgE synthesis. We have also observed increased expression of CD23+CD86+ B cells during flares of ABPA.30-33

We hypothesized that IL-4Ra SNPs were responsible for this gain of function of IL-4 stimulation.52,53 In 92% of patients with ABPA, we observed IL-4Ra SNPs, 79% of which were extracellular IL-4- binding SNPs.

HLA-DR restriction has been shown to be a risk factor for ABPA. Chauhan and colleagues27-29 observed that patients with asthma and CF who expressed HLA-DR2 and/or DR5 but lacked HLA-DQ2 were at increased risk for ABPA after exposure to A fumigatus. Within HLA-DR2 and HLA-DR5--in particular the restricted genotypes--HLA-DRB1*1501 and 1503 provide high relative risk.


The symptoms and signs of ABPA include increased coughing, episodes of wheezing, malaise, fever, and expectoration of brown plugs. ABPA can present acutely with symptoms and signs associated with transient pulmonary infiltrates and eosinophilia or with mucoid impaction. It may also present as an exacerbation of a chronic disease characterized by proximal bronchiectasis.1-3

In chronic ABPA, the acute episodes are superimposed on a background of chronic cough and sputum production. It is thought that the chronic form develops after the acute process and that it can be prevented by effective therapy.

ABPA may have its onset during childhood or may present in adolescents and adults. In adults, ABPA usually affects those with asthma who are younger than 40 years.

ABPA rarely affects children with asthma; it has only been reported in 3 children younger than 2 years.1,3 ABPA is more likely to occur in children with CF. These patients' symptoms may appear to be simply a worsening of their pulmonary status or an acute pulmonary exacerbation of CF. Children and adults with CF frequently do not have severe CF pulmonary disease at the onset of ABPA. However, the development of ABPA seems to exacerbate their pulmonary disease. Thus, it is vital to detect ABPA in patients with CF, and it is now recommended that this population be screened for ABPA annually.

The classic diagnostic features of acute flares or exacerbations of ABPA are:

• Worsening of asthma.

• Pulmonary infiltrates.

• Total serum IgE levels greater than 1000 IU/mL.

• IgE anti-A fumigatus antibodies.

• IgG anti-A fumigatus antibodies.

• Peripheral blood and pulmonary eosinophilia.

• Central bronchiectasis.

The severity of underlying asthma is variable. The symptoms may be somewhat subtle, with dys- pnea and increased coughing and wheezing.

During exacerbations of ABPA, patients may have bronchiectasis, with production of sputum containing golden brown plugs. During flares of ABPA, symptoms worsen, and pulmonary function studies reveal decreased forced expiratory volume in 1 second (FEV1) and forced expiratory flow at 25% to 75% of forced vital capacity.

Pulmonary infiltrates classically occur in the upper lobes, but they can appear in the lower lobes, often in conjunction with upper lobe involvement. Chest radiographs may demonstrate areas of consolidation, especially in the posterior segments of the upper lobes (Table 4).

Histologic examination of the infiltrates shows an allergic eosinophilic inflammatory reaction, and bronchiectasis occursin the area of the infiltrates. Tram-line shadows--2 parallel lines that extend distally from the hilum--representing bronchial wall edema may also be seen. These changes are reversible with corticosteroid treatment. However, parallel-line shadows and ring shadows, which represent bronchiectasis, are permanent.

High-resolution CT of the chest is very sensitive for detecting central bronchiectasis. Greenberger1 has proposed that central bronchiectasis ABPA be noted as ABPA-CB and that the absence of bronchiectasis be noted as seropositive ABPA (ABPA-S).

Minor criteria are the presence of golden brown sputum plugs and identification of Aspergillus hyphae and eosinophils in sputum and/or BAL fluid specimens (Figure). We have found that cytologic and microbiologic examination of sputum and/or BAL fluid aid in distinguishing between an ABPA flare and a CF bacterial flare. In ABPA, eosin-ophils are the predominant find-ing on cytologic examination and Aspergillus is identified; in a CF pulmonary flare, P aeruginosa and neutrophils are found.

During acute and exacerbation stages of ABPA, extremely elevated total serum IgE concentrations and elevated levels of IgE anti-Aspergillus antibodies are characteristic.54-63 The exact level of total serum IgE that is diagnostic of an ABPA flare is controversial. Some groups require an IgE greater than 1000 IU/mL for a diagnosis of ABPA, whereas other groups specify an IgE level greater than 1000 ng/mL (2.4 IU = 1 ng).

Recently, a Cystic Fibrosis Foundation Consensus report of ABPA outlined that an IgE level greater than 1000 IU/mL was diagnostic of ABPA if the other criteria were present and that an IgE level greater than 500 IU/mL but less than 1000 IU/mL was the "minimal" criterion for a diagnosis of ABPA.26 If the IgE level is 200 to 500 IU/mL and ABPA is suspected, it is recommended that measurement of the IgE level be repeated 1 to 3 months later. Furthermore, there are numerous examples of ABPA diagnosed when the IgE level is less than 500 IU/mL.64

During remission, the total serum IgE level decreases, but typically it remains elevated--it generally does not return to baseline. When serum IgE is measured serially, sharp elevations of IgE levels, including new radiographic infiltrates, are frequently associated with flares of ABPA. The elevated total IgE levels are accompanied by elevated anti-Aspergillus-specific IgE levels (in response to crude extracts of Aspergillus); this helps identify ABPA in patients with asthma and CF.

Patients with ABPA produce IgE antibodies to a greater number of Aspergillus antigens than do patients without ABPA. This was first determined by Western blot analyses. Using purified antigens, investigators have reported that patients with ABPA synthesize IgE antibodies to Asp f1, f2, f3, and f4; however, patients with asthma and CF who are Aspergillus-sensitive but do not have ABPA synthesize IgE antibodies only to Asp f1 and f3.61,62

My colleagues and I have found that in patients with CF, IgE antibody titers to Aspergillus allergens were significantly increased--especially to Asp f2, f3, f4, f6, and f16--after the development of ABPA.60 Patients with ABPA have a more positive reactivity to Asp f3 and Asp f4 than patients with Aspergillus sensitivity, which helps distinguish those with ABPA. We also observed that IgE reactivity to Asp f3 and Asp f4 in patients with ABPA remained elevated even during periods of remission.

Serial evaluation of IgE reactivity to purified Aspergillus allergens may be a better tool for assessing disease activity than evaluation of IgE reactivity to an Aspergillus crude extract.60 This was demonstrated in 9 patients who were serially evaluated. Although the IgE reactivity to a crude Aspergillus extract increased during flares, this increase was not as dramatic as the significant increases to Asp f1, f2, f3, f4, and f6.

IgG anti-Aspergillus antibodies are also present in patients with ABPA.57,60 Traditionally, this was determined by measuring precipitating antibodies to Aspergillus using the Ouchterlony technique. Anti- A fumigatus precipitins are highly prevalent during acute flares and exacerbations of ABPA; during remission, these precipitins decrease and may become undetectable.

Similarly, IgG anti-A fumigatus antibodies measured by enzyme-linked immunosorbent assay quantitatively increase during flares of ABPA and decrease during remissions. These antibodies are elevated, but to a lesser degree, in patients with CF who do not have ABPA. Levels of IgA anti-A fumigatus antibodies are similar to those of IgG anti-A fumigatus antibodies.


The primary goals of treatment are to detect and treat exacerbations of ABPA and to prevent bronchiectasis and fibrosis. Corticosteroids are the mainstay of pharmacologic treatment.

For acute ABPA and its exacerbations, the Northwestern group36 recommends 25 to 40 mg (0.5 mg/kg) of prednisone daily for 2 weeks, followed by alternate-day dosing, with weaning over 2 months. Serial IgE levels, pulmonary function, and symptoms are monitored, and the prednisone dose is gradually tapered. In children with CF and ABPA, we typically use a prednisone dose of 1 mg/kg/d for 2 weeks, then switch to alternate-day dosing, tapering over 2 to 6 months. For the management of corticosteroid-dependent ABPA, long-term alternate-day dosing of prednisone (usually at low doses), along with inhaled corticosteroids, is required.

Antifungal agents, such as itraconazole, have been used as adjunctive therapy. When used in conjunction with corticosteroids, antifungal agents have been demonstrated to be beneficial. Itraconazole has been used during the duration of corticosteroid treatment, then discontinued.1,26

Serial monitoring of the patient for exacerbations of ABPA is necessary to prevent further lung destruction. After an exacerbation, total IgE levels are measured every 4 to 6 weeks. As the pulmonary infiltrates clear and pulmonary function returns to baseline, IgE levels may be measured every 6 months. Symptoms and pulmonary findings (including the results of pulmonary function tests) do not detect all exacerbations. Thus, serial laboratory evaluations are important. A sharp rise in total IgE level and a decrease in FEV1 of greater than 15% may indicate an exacerbation.

Immunotherapy with Aspergillus as well as with other molds has not been recommended because of the uncertainties that are associated with exacerbation of pulmonary disease. However, immunotherapy with purified Aspergillus antigens, altered purified antigens, or peptides that can safely be administered has been a long-term goal of many investigators.

A better understanding of the immunopathogenesis of ABPA and asthma may lead to novel therapies aimed at immunomodulation. In particular, omalizumab has been shown to be effective in moderate to severe atopic asthma. Indeed, the ABPA Committee of the American Academy of Allergy, Asthma and Immunology has proposed a trial of omalizumab for patients with ABPA to determine whether exacerbations can be decreased.

In a phase 1 trial, anti-CD23 monoclonal antibody treatment lessened symptoms, and it improved pulmonary function in patients with asthma. Because CD23+CD86+ B cells are increased in persons with ABPA, inhibiting this molecule may be key. Although anti-IL-5 therapy has not been demonstrated to be effective in asthma, it may be effective in ABPA, in which Aspergillus-stimulated secretion of IL-5 is markedly increased and eosinophilic inflammatory reaction is pronounced.


For children with ABPA, the prognosis is good if the disease is detected early and treatment is started promptly. It is important that treatment be started before permanent lung damage from bronchiectasis and fibrosis occurs. In such patients, there should be no disease progression, although relapses can occur many years later. Long-term follow-up is recommended for these patients.

Relapses seem to be more frequent in children with CF than in those with asthma, and careful surveillance is necessary to ensure resolution of the disease. It is difficult to wean some patients with CF off corticosteroids without an increase in symptoms such as dyspnea and wheezing. It is unclear whether this increase is caused by the underlying CF lung disease or by exacerbations of ABPA caused by withdrawal of corticosteroids.

In general, symptoms are not a reliable guide to therapy. It is important, therefore, to reevaluate the patient's chest radiograph and the serum IgE level at regular inter- vals until a long-term remission is established.



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