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Indication - Aspergillosis
Aspergillus IgG antibody
Facility level:
2. Laboratory
Assay formats
RDT; Immunoassay
Status history
First added in 2020
Purpose type
Aid to diagnosis
Purpose
To aid in the diagnosis of chronic pulmonary aspergillosis
Specimen types
Serum, Plasma
Codes
ICD11 code: 1F20.Z

Summary of evidence evaluation

Diagnosing CPA requires evidence of infection, and there is evidence that measuring IgG response related to aspergillosis infection provides this in a high proportion of cases. No evidence was provided to support the suitability of IgG measures for monitoring disease progression and treatment success. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3

Summary of SAGE IVD deliberations

There are no systematic reviews on the clinical utility or impact of Aspergillus antibody diagnosis. But the IgG antibody test is already in use and is the subject of several studies. The Aspergillus IgG assay result also forms part of the Global Action Fund for Fungal Infections’ definition of CPA and as such is critical for a CPA diagnosis. All ICT, plate ELISA, and auto ELISA for Aspergillus-specific IgG have sufficient sensitivity and specificity for a differential diagnosis between CPA and other chronic pulmonary disease (including TB). The data submitted show it to be a simple, robust and easy-to-use test that is particularly adaptable to LMIC contexts, where there are no realistic diagnostic alternatives.

SAGE IVD recommendation

SAGE IVD recommended including the Aspergillus IgG antibody test category in the third EDL: • as a disease-specific IVD for clinical laboratories (EDL 3, Section II.b, Aspergillosis); • using an RDT or immunoassay format; • to aid in the diagnosis of chronic pulmonary aspergillosis; The group highlighted the need for more information on RDTs and other tests that are currently in the pipeline, for which existing data are scarce.

Details of submission from 2020

Background

Disease condition and impact on patients Chronic pulmonary aspergillosis (CPA) is a slowly destructive lung infection, with marked systemic (weight loss, fatigue) and pulmonary features (productive cough, haemoptysis, breathlessness) almost indistinguishable from TB. Chest imaging may reveal nodules, cavities or fungal balls. CPA often presents as “smear-negative” or “GeneXpert-negative” TB (1). It usually occurs after a pulmonary insult or chronic problem including TB, sarcoidosis, non-tuberculous mycobacterial infection, pneumothorax, emphysema, COPD, asthma and RA. Occasionally (5–10% of cases), it is observed in people with no history of lung disease and is often mistaken for TB. Some subtle immune defects, including low CD4 cells (not HIV related), low NK cells, gamma interferon or interleukin-12 production defects, and some poorly defined genetic defects also predispose to CPA. It is also found in HIV-infected people with slightly different radiological manifestations. Does the test meet a medical need? The test is important in the differential diagnosis of chronic pulmonary infections, especially in patients with underlying lung disease. Aspergillus antibody serology and chest radiograph and/or computed tomography (CT) scanning with accurate interpretation is critical to establishing the correct diagnosis. CPA progression rates vary, but worsening symptoms and lung destruction or fibrosis occur over many months or years. The key diagnostic features are cavitary lung lesions on radiology, sometimes containing a fungal ball (aspergilloma), and Aspergillus IgG antibodies. How the test is used The diagnosis of CPA requires presence of symptoms for more than 3 months, consistent radiographic features, and microbiological or immunological evidence of Aspergillus infection. The last is achieved by performing an Aspergillus IgG test on serum.

Public health relevance

Prevalence There are an estimated 3 million CPA cases worldwide (2). While CPA is regarded as a rare disease in HICs, its burden in LMICs with high incidences of TB is considerable. One estimate for India (3) put the 5-year prevalence at 290 147 cases of complicated pulmonary TB, or 24 per 100 000 population; an estimate for Pakistan (4) put it at 72 438 cases, or 39 per 100 000 population, including all underlying diseases. A prospective study in Uganda in both HIV-infected and uninfected patients found an annual rate of CPA development of 6.5% in those with a residual cavity at the end of TB treatment, which is typically found in 22–35% of cases (5). Socioeconomic impact The economic impact of aspergillosis has been measured in US hospitals (6) but not in LMICs, where most of the CPA burden can be expected. In US hospitals it has been estimated that costs can be saved through prevention, improved diagnosis and management. CPA is associated with severe morbidity and mortality; but outcomes can be improved with long-term antifungal therapy or surgery.

WHO or other clinical guidelines relevant to the test

ESCMID, ERS and ECMM published clinical guidelines in 2018 (7). These recommend using Aspergillus IgG antibody testing to diagnose or exclude CPA, in combination with other diagnostic criteria, that is in non-immunocompromised patients with cavitary or nodular pulmonary infiltrate (level of evidence: II; grade of recommendation: A).

Evidence for diagnostic accuracy

The sensitivity and specificity of quantitative Aspergillus IgG tests in diagnosing CPA in various primary studies ranged from 71% to 98% and 81% to 100%, respectively. The variation was chiefly due to different cut-off values. Receiver operating characteristic (ROC) curve analyses of commercial assays identified optimal cut-offs that were different from manufacturer-recommended cut-offs, but optimal cut-offs have been proposed in one study (8). The commercial tests available also have variable reproducibility and precision in these primary studies. The tests have a coefficient of variation ranging from 3.4% to 43.7% (9), and acceptable precision levels have not been defined. The tests are designed to detect Aspergillus fumigatus antibody, and may have lower sensitivities for detecting CPA caused by non-fumigatus species.

Evidence for clinical usefulness and impact

Guidelines recommend using Aspergillus IgG to diagnose CPA in non-immunocompromised patients. Mycological cultures may be used in immunocompromised patients, and a comparison of the utility of culture with aspergillus IgG is unavailable. It is, however, generally accepted that cultures can remain negative in patients with CPA. According to one primary study, Aspergillus IgG tests were superior to GM in diagnosing CPA (10). Aspergillus IgG levels also decrease in patients with CPA on effective antifungal treatment, and the test’s use has been proposed to monitor antifungal effectiveness. But this use has not been validated in reviews or recommended in guidelines.

Evidence for economic impact and/or cost–effectiveness

No data or sensitivity analyses were available.

Ethical issues, equity and human rights issues

Diagnosis of CPA with the Aspergillus IgG antibody test is targeted at several vulnerable populations, including those with past or present TB or underlying pulmonary disease.
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