Population prevalence of aspergillus sensitization and allergic bronchopulmonary aspergillosis in COPD subjects in North India.

BACKGROUND: Sensitization to Aspergillus fumigatus (AS) has been recently described in chronic obstructive pulmonary disease (COPD) patients. However, there is no data on the community prevalence of AS in COPD. OBJECTIVES: To assess the prevalence of AS among COPD subjects. The secondary objectives were to (1) assess the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in COPD and (2) compare the lung function in COPD subjects with and without AS. METHODS: We conducted a cross-sectional study in rural (29 villages) and urban (20 wards) communities in North India. We identified individuals with respiratory symptoms (IRS) through a house-to-house survey using a modified IUATLD questionnaire. We then diagnosed COPD through specialist assessment and spirometry using the GOLD criteria. We assayed A.fumigatus-specific IgE in COPD subjects. In those with A. fumigatus-specific IgE ≥0.35 kUA/L (AS), ABPA was diagnosed with raised serum total IgE and raised A.fumigatus-specific IgG or blood eosinophil count. RESULTS: We found 1315 (8.2%) IRS among 16,071 participants >40 years and diagnosed COPD in 355 (2.2%) subjects. 291 (82.0%) were men and 259 (73.0%) resided in rural areas. The prevalence of AS and ABPA was 17.7% (95% CI, 13.9-21.8) and 6.6% (95% CI, 4.4-8.8). We found a lower percentage predicted FEV1 in COPD subjects with AS than those without (p =.042). CONCLUSIONS: We found an 18% community prevalence of AS in COPD subjects in a specific area in North India. Studies from different geographical areas are required to confirm our findings. The impact of AS and ABPA on COPD requires further research.

Allergic bronchopulmonary aspergillosis in India.

Allergic bronchopulmonary aspergillosis (ABPA) is a lung disorder caused by immune-mediated reactions mounted against Aspergillus fumigatus. The disorder most commonly complicates the course of patients with asthma and cystic fibrosis. From its first description in 1952, significant advances have been made in understanding the pathogenesis and the diagnosis and treatment of ABPA. In the last two decades, most research on ABPA has been published from India. The prevalence and clinical presentation may differ in India from that reported elsewhere. Herein, we review the epidemiology, clinical and radiological characteristics, and distinctive features of ABPA in the Indian subcontinent. To support the review, we surveyed pulmonologists nationwide to understand the challenges in diagnosing and managing ABPA. The survey has yielded valuable insights into the practices associated with the diagnosis and management of ABPA in India.

Clinical characteristics of allergic bronchopulmonary aspergillosis in patients with and without bronchiectasis.

OBJECTIVE: Allergic bronchopulmonary aspergillosis (ABPA) is classified radiologically as serologic ABPA (ABPA-S) or ABPA with central bronchiectasis (ABPA-CB). This retrospective case series study aimed to describe and compare the clinical characteristics of both forms of ABPA. METHODS: Patients with ABPA treated in the hospital between February 2011 and June 2019 were enrolled and were divided into ABPA-S and ABPA-CB groups based on whether their cases were complicated with central bronchiectasis. Demographic data, symptoms, laboratory values, comorbidities, and image findings were collected. ABPA-S patients were followed up retrospectively through medical records. RESULTS: Ninety-three (93) patients were enrolled, including 74 ABPA-CB patients and 19 ABPA-S patients. The most common predisposing condition was asthma (36.6%), with a median course of 30 years (IQR 13-42.5) prior to ABPA diagnosis. Patients of 54.8% had been misdiagnosed, with ABPA-S more likely than ABPA-CB to have been misdiagnosed as asthma (p < 0.01). Obstructive ventilation dysfunction and mixed ventilation dysfunction were found in 21 patients (22.6%) and 16 patients (17.2%), respectively. Compared with ABPA-S, ABPA-CB had a higher median blood eosinophil count (880 vs. 700 cells/µl), serum IgE (2957 vs. 2616 IU/ml), and Aspergillus fumigatus specific-IgE (20.6 vs. 7.31 kUA/L), although these findings were not statistically significant. Three ABPA-S patients developed bronchiectasis during follow-up and experienced relapses more than twice. CONCLUSIONS: Our findings suggested that the clinical characteristics between ABPA-CB and ABPA-S were mostly similar. ABPA-S had a relatively lower immunological activity level than ABPA-CB but was still immunologically active and could develop bronchiectasis.

Epidemiology and outcomes of allergic bronchopulmonary aspergillosis in the elderly.

BACKGROUND: The prevalence and outcomes of allergic bronchopulmonary aspergillosis (ABPA) in the elderly remain unknown. METHODS: We reviewed our database to identify the proportion of subjects diagnosed with ABPA at ≥60 years of age (ABPA-elderly). We compared the clinical features, treatment and outcomes of ABPA-elderly versus the non-elderly (ABPA diagnosed at <60 years of age). RESULTS: Between 2007 and 2019, we encountered 810 ABPA subjects with a mean age of 34.9 years (49.4% women). Of these, 43 (5.3%) were aged ≥60 years (ABPA-elderly). There was a trend towards lower median (interquartile range [IQR]) serum total IgE (4900 [2659-10000] vs. 7156 [23360-11963] IU/mL; P = .06) and Aspergillus fumigatus-specific IgE (12.3 [4.8-29.6] vs. 22.4 [7.7-41.5] kUA/L; P = .06) in the elderly than the non-elderly. Eosinophil counts were similar in the two groups. The median [IQR] number of segments involved by bronchiectasis (5 [2-9] vs. 7 [4-11]) was significantly lower in the ABPA-elderly (P = .001). The proportion of subjects experiencing ABPA exacerbations was significantly (P = .047) lower in the elderly (25.6%) vs. the non-elderly (40.8%). There was also a tendency towards a lower mean number of exacerbations in the elderly (155 vs. 208 exacerbation per 1000 person-years) than the non-elderly (P = .09). There was also a trend towards longer mean time to first exacerbation in the ABPA-elderly than the non-elderly (1612 vs. 1159 days). CONCLUSION: ABPA was uncommon in the elderly. The bronchiectasis is less extensive with a trend towards lower immunological severity and fewer exacerbations in the elderly than the non-elderly subjects with ABPA.

Estimated burden of serious fungal infections in Togo.

BACKGROUND: Over the years, the focus of infectious diseases in many African countries has been mainly on viral, bacterial and parasitic infections. Serious fungal infections (SFIs) with comparable morbidity rate in these countries remain neglected. OBJECTIVES: To estimate the burden of SFI in Togo and to stimulate efforts for improved attention. METHODS: Literature was thoroughly searched for epidemiological data on SFI in Togo. Incidence and/or prevalence of SFI was estimated using socio-demographics, health system's information, risk-groups data and SFI rates obtained from national and international studies. RESULTS: About 5.29% of the 7,265,286 Togolese population is estimated to suffer from SFI annually. Among HIV patients, 1,342, 1,650 and 330 may develop cryptococcal meningitis, Pneumocystis pneumonia and disseminated histoplasmosis respectively per year. Oral and oesophageal candidiasis may annually affect 19,800 and 7,535 persons, respectively, living with HIV. Estimated incidence of invasive aspergillosis (IA) was 283 cases. Prevalence of chronic pulmonary aspergillosis (CPA) was estimated at 191 cases. The annual incidence of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) was 4,577 and 6,042 cases, respectively. Tinea capitis and recurrent Candida vaginitis presumably affect 232,271 children and 108,979 women respectively. Candidaemia incidence is estimated at 5 cases per 100, 000 inhabitants and fungal keratitis may affect 981 persons annually. CONCLUSIONS: SFIs in Togo are probably more significant than expected. These findings underscore the need to increase awareness among healthcare professionals, enhance diagnostic and therapeutic capacities and intensify epidemiological studies for effective management of fungal infections in Togo.

Invasive Pulmonary Aspergillosis in Chronic Obstructive Pulmonary Disease Exacerbations.

Nowadays, reports in the literature support that patients with severe chronic obstructive pulmonary disease (COPD) are at higher risk to develop invasive pulmonary aspergillosis (IPA). However, the interpretation of Aspergillus-positive cultures from the airways in critically ill COPD is still a challenge. Indeed, as the patient could be merely colonized, tissue samples are required to ascertain IPA diagnosis but they are rarely obtained before death. Consequently, diagnosis is often only suspected on the basis of a combination of three elements: clinical characteristics, radiological images (mostly thoracic CT scan), and microbiological, and occasionally serological, results. To facilitate the analysis of these data, several algorithms have been developed, and the best effectiveness has been demonstrated by the Clinical algorithm. This is of importance as IPA prognosis in these patients remains presently very poor and using such an algorithm could promote prompter diagnosis, early initiation of treatment, and subsequently improved outcome.While the most classical presentation of IPA in critically ill COPD patients features a combination of obstructive respiratory failure, antibiotic-resistant pneumonia, recent or chronic corticosteroid therapy, and positive Aspergillus cultures from the lower respiratory tract, the present article will also address less typical presentations and discuss the most appropriate treatments which could alter prognosis.

Allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is an inflammatory disease caused by immunologic reactions initiated against Aspergillus fumigatus colonizing the airways of patients with asthma and cystic fibrosis. The common manifestations include treatment-resistant asthma, transient and fleeting pulmonary opacities and bronchiectasis. It is believed that globally there are about five million cases of ABPA, with India alone accounting for about 1.4 million cases. The occurrence of ABPA among asthmatic patients in special clinics may be as high as 13 per cent. Thus, a high degree of suspicion for ABPA should be entertained while treating a patient with bronchial asthma, particularly in specialized clinics. Early diagnosis and appropriate treatment can delay (or even prevent) the onset of bronchiectasis, which suggests that all patients of bronchial asthma should be screened for ABPA, especially in chest clinics. The current review summarizes the recent advances in the pathogenesis, diagnosis and management of ABPA.

Prevalence and Risk Factors of Allergic Bronchopulmonary Aspergillosis and Aspergillus Sensitization in Children with Poorly Controlled Asthma.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) may be a risk factor for poorly controlled asthma in children. The studies regarding prevalence and risk factors of ABPA in children with poorly controlled asthma are limited in number. OBJECTIVES: To determine prevalence and risk factors of ABPA and aspergillus sensitization (AS) in children with poorly controlled asthma. METHODS: In this prospective cross-sectional study from a tertiary care center in India, we enrolled asthmatic children 5-15 years of age with poorly controlled asthma. We did the following investigations: spirometry, skin prick test, serum total immunoglobulin E (IgE), aspergillus-specific IgE and immunoglobulin G, serum precipitin for Aspergillus, absolute eosinophil count, chest X-ray and high-resolution computed tomography of the chest. ABPA and AS were diagnosed as per the recently proposed criteria. RESULTS: We enrolled 106 children [boys 72 (67.9%); mean age of 10.2 ± 2.6 years] with poorly controlled asthma. The prevalence of ABPA and AS were 11.3% (95% CI, 5.2-17.5%) and 61.3% (95% CI, 52.0-70.7%), respectively. The presence of brownish sputum was significantly more in ABPA compared with non-ABPA patients (33.3 vs. 4.2%, p = 0.002). The age, gender, allergic rhinitis and gastroesophageal reflux were not significantly different in ABPA compared with non-ABPA patients. CONCLUSION: The prevalence of ABPA and AS was 11.3 and 61.3%, respectively in children with poorly controlled asthma. We could not find any risk factors for ABPA except that the presence of brownish sputum was more in children with ABPA. Spirometry parameters were not significantly different in ABPA compared with non-ABPA patients.

Prevalence of allergic bronchopulmonary aspergillosis in cystic fibrosis patients using two different diagnostic criteria.

Summary: Objective.There are different diagnostic criteria for the diagnosis of Allergic bronchopulmonary aspergillosis (ABPA) in CF patients. In this present study we evaluated the prevalence of ABPA in Iranian CF patients by two more usual diagnostic criteria as ISHAM working criteria (A) and CF Foundation Consensus Conference criteria (B). Methods.Eighty-six CF patients were included in the study. All CF patients underwent for Aspergillus skin prick test (AST), Aspergillus-specific IgE (sIgEAf) and Aspergillus-specific IgG (sIgGAf), total IgE. The ABPA prevalence was estimated by two diagnostic criteria, (A) and (B) and compared. Results. The frequency of positive AST, total IgE, sIgEAf and sIgGAf were 47 (54.6%), 9 (10.5%), 42 (48.8%) and 67 (77.9%), respectively. The obtained rate of ABPA prevalence (10.5%) was identical in two diagnostic criteria A and B (kappa value of 1.000). Conclusions.The applied diagnostic criteria had no significant effect on the reported rate of ABPA prevalence.

Prevalence of sensitization to Aspergillus flavus in patients with allergic bronchopulmonary aspergillosis.

Aspergillus fumigatus is the most common Aspergillus species worldwide; however, A. flavus has also been shown to be prevalent in North India. Herein, we investigate the prevalence of sensitization to A. flavus in subjects with allergic bronchopulmonary aspergillosis (ABPA). We also evaluate the occurrence of allergic bronchopulmonary mycosis (ABPM) due to A. flavus. Treatment-naive subjects with ABPA underwent sputum culture; and, skin testing, fungal-specific immunoglobulin E (IgE) and serum precipitation tests for A. fumigatus and A. flavus. Sensitization to A. flavus was diagnosed if any immunological test for A. flavus was positive in subjects with ABPA. ABPM was labelled as probable if sputum cultures grew A. flavus and A. flavus-specific IgE was greater than A. fumigatus-specific IgE; and, possible if only A. flavus-specific IgE was greater than A. fumigatus-specific IgE. Fifty-three subjects with a mean (SD) age of 34.2 (12.8) years were included. Sensitization to A. flavus was seen in 51 (96.2%) subjects, with overlap occurring in 49 (92.5%), 21 (39.6%), and 12 (22.6%) instances on fungal-specific IgE, skin prick test and precipitins, respectively. Sputum culture was positive in 18 (33.9%; A. flavus [n = 12], A. fumigatus [n = 6]) subjects. ABPM due to A. flavus was diagnosed in 16 (30.2%) subjects (10 probable, 6 possible). They were more likely to have high-attenuation mucus and a trend towards higher occurrence of sinusitis, compared to ABPA. We found a high occurrence of sensitization to A. flavus in subjects with ABPA. Subjects with A. flavus-related ABPM had a higher likelihood of high-attenuation mucus and probability of sinusitis. More studies are required to confirm this observation.

Vitamin D levels in asthmatic patients with and without allergic bronchopulmonary aspergillosis.

Vitamin D deficiency is believed to be a pathogenetic factor in patients with allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis. Whether vitamin D deficiency is also prevalent in ABPA complicating asthma, remains unknown. Herein, we evaluated vitamin D levels in asthmatic patients with and without ABPA. In a prospective study, plasma vitamin D (25[OH]D) levels were measured in consecutive subjects with asthma (n = 75), ABPA (n = 158) and healthy volunteers (n = 50). Vitamin D levels <20 ng/mL were considered as vitamin D deficiency. There was no difference in mean (95% CI) vitamin D levels between healthy controls (15.3 [12.7-17.9]), asthmatics (19.2 [16.3-22.1]) and subjects with ABPA (18.9 [16.9-20.8]) (P = .22). Vitamin D deficiency was encountered in 70%, 64% and 65% of the healthy controls, asthmatics and ABPA subjects, respectively, and was not different between the groups (P = .79). There was no difference in the asthma control, pulmonary function, immunological findings and the severity of bronchiectasis, in patients with ABPA, with and without vitamin D deficiency. Vitamin D deficiency is equally prevalent in asthmatic patients with or without ABPA in the Indian subcontinent, and does not appear to play a major role in the pathogenesis of ABPA complicating asthma.

Allergic bronchopulmonary aspergillosis in Japan: A nationwide survey.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an allergic pulmonary disease characterized by a hypersensitivity reaction to Aspergillus species colonizing the airways. The clinical characteristics of ABPA may differ depending on genetic and environmental background. We performed a nationwide survey to determine the clinical characteristics of ABPA in Japan. METHODS: In 2013, a questionnaire on physician-diagnosed ABPA/allergic bronchopulmonary mycosis was sent to 903 medical centers specializing in respiratory or allergic diseases. Cases fulfilling the following criteria were categorized as possible ABPA-central bronchiectasis (ABPA-CB): 1) presence of specific serum immunoglobulin E (IgE) antibodies or a positive skin reaction to Aspergillus, and 2) bronchiectasis or mucoid impaction in the central bronchi. RESULTS: Of 499 physician-diagnosed cases reported by 132 clinical centers, 358 cases met the criteria for possible ABPA-CB. Median age of ABPA-CB onset was 57 (interquartile range, 44-68) years; later-onset disease, developing ≥50 years of age, accounted for 66% of the cases and was associated with female sex, delayed onset of asthma, and lower levels of serum IgE. A third of the patients (120 patients, 34%) exhibited low levels of serum total IgE (<1000 IU/mL). Aspergillus species were isolated from sputum in 126/213 cases (59%), and Schizophyllum commune was identified in 12 (6%) patients. During the course of the treatment, ABPA recurred in 169 (48%) cases. CONCLUSIONS: This nationwide survey identified several unique clinical characteristics of ABPA in Japan, such as late-onset, relatively lower serum IgE levels, and frequent recurrences/flares.

Azole-Resistant Aspergillosis: Epidemiology, Molecular Mechanisms, and Treatment.

Aspergillus fumigatus remains the most common species in all pulmonary syndromes, followed by Aspergillus flavus which is a common cause of allergic rhinosinusitis, postoperative aspergillosis and fungal keratitis. The manifestations of Aspergillus infections include invasive aspergillosis, chronic pulmonary aspergillosis and bronchitis. Allergic manifestations of inhaled Aspergillus include allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Triazoles are the mainstay of therapy against Aspergillus infections for treatment and prophylaxis. Lately, increased azole resistance in A. fumigatus has become a significant challenge in effective management of aspergillosis. Earlier studies have brought to light the contribution of non-cyp51 mutations along with alterations in cyp51A gene resulting in azole-resistant phenotypes of A. fumigatus. This review highlights the magnitude of azole-resistant aspergillosis and resistance mechanisms implicated in the development of azole-resistant A. fumigatus and address the therapeutic options available.

Co-morbidities in severe asthma: Clinical impact and management.

Patients with severe asthma represent a minority of the total asthma population, but carry a majority of the morbidity and healthcare costs. Achieving better asthma control in this group of patients is therefore of key importance. Systematic assessment of patients with possible severe asthma to identify treatment barriers and triggers of asthma symptoms, including co-morbidities, improves asthma control and reduces healthcare costs and is recommended by international guidelines on management of severe asthma. This review provides the clinician with an overview of the prevalence and clinical impact of the most common co-morbidities in severe asthma, including chronic rhinosinusitis, nasal polyposis, allergic rhinitis, dysfunctional breathing, vocal cord dysfunction, anxiety and depression, obesity, obstructive sleep apnoea syndrome (OSAS), gastroesophageal reflux disease (GERD), bronchiectasis, allergic bronchopulmonary aspergillosis (ABPA) and eosinophilic granulomatous with polyangiitis (EGPA). Furthermore, the review offers a summary of recommended diagnostic and management approaches for each co-morbidity. Finally, the review links co-morbid conditions to specific phenotypes of severe asthma, in order to guide the clinician on which co-morbidities to look for in specific patients.

Correlation of aspergillus skin hypersensitivity with the duration and severity of asthma.

Asthma is a significant health problem worldwide and Allergic Bronchopulmonary aspergillosis (ABPA) complicates the course of 1-2% of patients of asthma. Aspergillus skin hypersensitivity (AH) is the first step for diagnosis of ABPA. This study was conducted to know the correlation of AH with severity and duration of asthma. Patients, age >15 years, of asthma attending this hospital from January 2015 to December 2015 were included. Asthma was diagnosed clinically and confirmed with spirometry. Of 282 patients 206 patients were AH positive. The AST-positivity in patients having severe asthma (96.8%) was higher than that in patients having mild (36.8%) and moderate asthma (80.4%). The median (IQR) duration of asthma of AH positive patients was 5.0 yrs. This study emphasized the need of ABPA screening by intradermal skin test especially in patients having severe asthma and/or those having asthma for longer duration in order for early diagnosis of ABPA.

[Allergic bronchopulmonary aspergillosis in patients with asthma: Results of a prospective study]. / Allergicheskii bronkholegochnyi aspergillez u bol'nykh bronkhial'noi astmoi: rezul'taty prospektivnogo issledovaniia.

AIM: To estimate the frequency of fungal sensitization and the incidence of allergic bronchopulmonary aspergillosis (ABPA) in asthmatic patients. SUBJECTS AND METHODS: A total of 140 asthmatic patients were examined. They underwent allergologic (skin tests for fungal allergens, estimation of total and fungal allergen-specific IgE levels) and mycological (microscopy and inoculation of respiratory biosubstrates) examinations. Chest computed tomography, when indicated, was done. A group of patients with ABPA and that of patients with severe asthma and fungal sensitization were identified. RESULTS: The frequency of fungal sensitization in asthmatic patients was 36%; the main allergenic fungi were Aspergillus and Alternaria. The incidence of ABPA was as high as 4% in the patients with asthma and 11% in those with severe asthma and fungal sensitization. CONCLUSION: The given current diagnostic criteria will assist practitioners to identify ABPA, to prevent its progression, and to initiate specific anti-inflammatory and antifungal therapy in due time.

Aspergillus fumigatus components distinguish IgE but not IgG4 profiles between fungal sensitization and allergic broncho-pulmonary aspergillosis.

Aspergillus fumigatus is the causative agent of allergic broncho-pulmonary aspergillosis. Prompt and accurate diagnosis may be difficult to achieve with current clinical and laboratory scores, which do not include immune responses to recombinant A. fumigatus allergens. We measured specific immunoglobulin E and G4 directed to recombinant A. fumigatus allergens in 55 cystic fibrosis patients without allergic broncho-pulmonary aspergillosis but sensitized to A. fumigatus and in nine patients with allergic broncho-pulmonary aspergillosis (two with cystic fibrosis and seven with asthma). IgG4 responses to recombinant A. fumigatus allergens were detected in all patients, but neither prevalence nor levels were different between the two patient groups. On the other hand, both prevalence and levels of IgE responses to Asp f 3, Asp f 4, and Asp f 6 helped distinguish allergic broncho-pulmonary aspergillosis from A. fumigatus sensitization with good negative and positive predictive values.

Allergic bronchopulmonary aspergillosis is associated with pet ownership in cystic fibrosis.

BACKGROUND: Late diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is associated with significant lung function decline and morbidity in cystic fibrosis (CF). The association of ABPA and domestic pet ownership in patients with CF has not been elucidated yet. Our objective was to determine the association of ABPA with pet ownership in patients with CF. METHODS: Clinical and microbiological data from certified local patient registry were analyzed for 109 patients with CF aged 1-64 years: 55 pet owner and 54 non-pet owners. The primary outcome of the retrospective observational study was the occurrence of ABPA in pet owners and non-pet owners with CF. The free statistical software R was utilized to investigate logistic regression models for association factors. RESULTS: Of the 109 patients included in the study, 61 (56%) were female. The mean age of the total group was 25.4 ± 13.2 years. Adjusted analysis revealed that ABPA (OR 5.0227, 95% CI: 1.182-21.340, p = 0.029) was associated with pet ownership in patients with CF. Furthermore, ABPA in pet owners with CF was associated with an increased number of exacerbations (OR 6.446, 95% CI: 1.057-39.328, p = 0.043). Other outcomes did not significantly differ. CONCLUSION: Owning a pet was associated with ABPA in patients with CF. Future prospective multicenter longitudinal studies are needed to investigate chronological causality between pet ownership, ABPA development, and pulmonary exacerbations and to determine whether these estimates are generalizable for ABPA susceptible patients beyond CF (asthma, bronchiectasis).

Elevated total serum immunoglobulin E (>1000 IU/mL): implications?

Atopic eczema, allergic broncho-pulmonary aspergillosis, helminthic infections and rare primary immunodeficiencies are known to elevate total serum immunoglobulin E (IgE) above 1000 IU/mL. However, of 352 patients with IgE >1000 IU/mL seen in our hospital over a 5-year period, less than 50% had these conditions. Markedly elevated IgE levels in the rest of the patients were associated with asthma, allergic rhinitis and food allergy, instances where the test is of limited diagnostic utility.