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Essential in vitro diagnostics for advanced HIV and serious fungal diseases: international experts’ consensus recommendations

  • Felix Bongomin
  • Nelesh P. Govender
  • Arunaloke Chakrabarti
  • Florence Robert-Gangneux
  • David R. Boulware
  • Afia Zafar
  • Rita O. Oladele
  • Malcolm D. Richardson
  • Jean-Pierre Gangneux
  • Ana Alastruey-Izquierdo
  • Joel Bazira
  • Tom H. Boyles
  • Jahit Sarcarlal
  • Mathieu Nacher
  • Taminori Obayashi
  • William Worodria
  • Alessandro C. Pasqualotto
  • David B. Meya
  • Ben Cheng
  • Charlotte Sriruttan
  • Conrad Muzoora
  • Andrew Kambugu
  • Juan Luis Rodriguez Tudela
  • Alexander Jordan
  • Tom M. Chiller
  • David W. DenningEmail author
Editorial

Keywords

HIV Tuberculosis Cryptococcosis Histoplasmosis Aspergillosis Pneumocystis Itraconazole Voriconazole Flucytosine 

Perspective

An accurate, timely diagnosis is the cornerstone of good medical practice. For opportunistic fungal infections in AIDS and other invasive mycoses, this is dependent on the availability of and accessibility to the relevant diagnostic tests. A call for a model List of Essential In Vitro Diagnostics (EDL)—“listed tests that should be reasonably available for people who need them, whether in the form of point-of-care tests in physicians’ offices and pharmacies or as high-complexity tests in reference laboratories”—has been published [1]. In addition to better medical practice, other potential benefits of an EDL include clarification of priorities for policy makers, setting common goals for laboratory testing, improved healthcare delivery and overall better patient outcomes [1]. In the context of extensive antimicrobial resistance (AMR), a reduction in empiricism with more accurate diagnosis will play a key role in AMR control [2].

Globally, 37 million people are living with HIV [3], over a third of whom present or return to care after treatment interruption with advanced HIV disease defined as a CD4 cell count < 200 cells/mm3 or a World Health Organization (WHO) clinical stage 3 or 4 event [4, 5]. The commonest causes of death in advanced AIDS are tuberculosis (TB), cryptococcosis, Pneumocystis pneumonia, bacterial pneumonia or sepsis, disseminated histoplasmosis (some regions), and cerebral toxoplasmosis [5]. There is a very close link between advanced HIV disease and serious fungal infections and TB [5, 6], and the greatest burden of these diseases is seen in low- and middle-income countries (LMICs). Annually, about 1 million people die of AIDS-related illnesses [3] and beyond HIV in total over 1.5 million people die from serious fungal infections [7]. This is comparable with the 1.7 million TB-related deaths in total [8]. Simple, fast, accurate and stable diagnostic tests are essential to improvement in targeted treatment and hence reducing deaths and suffering related to these diseases [9, 10]. Modelling by the Global Action Fund for Fungal Infections (GAFFI) suggests that making the key diagnostic tests for serious fungal diseases available for only 60% of patients in need, with treatments, could save over a million lives in the next 5 years [6], on top of the likely survival benefits of the ambitious 90-90-90 target, The 90-90-90 target is that by 2020, 90% of all people living with HIV will know their HIV status, 90% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy (ART), and 90% of all people receiving ART will have viral suppression.

Led by GAFFI, which is focussed on ensuring universal access to diagnostics for serious fungal infections by 2025 [11], a workshop on essential diagnostics for serious fungal diseases, TB and other opportunistic infections in advanced HIV disease was convened in Kampala, Uganda, between 10th and 12th April 2018. The meeting was timed to precede and help inform the WHO’s Strategic Advisory Group of Experts on In Vitro Diagnostics (SAGE-IVD) meeting from which the new WHO EDL emanated [12]. The overall aim of the workshop was to gather experts and review evidence on available diagnostics for HIV/AIDS-associated opportunistic infections and serious fungal diseases for inclusion in the WHO EDL, the first version of which has now been published [12]. The specific objectives of the meeting were, firstly, to review the evidence base for key tests to produce a consensus for recommendation at different strata of health care facility level (Tier) for inclusion in the WHO EDL. Secondly, the meeting aimed to provide the specific arguments and diagnostic performance criteria for the EDL applications to the WHO and thirdly to publish a summary report on the forum, highlighting strengths, weaknesses (gaps), opportunities and challenges with the commercially available diagnostic test portfolios.

Ninety-five participants including experienced clinicians, senior laboratory staff and public health practitioners contributed to the meeting. Participants were drawn from 27 countries, mainly LMICs, including Brazil, Cameroon, Egypt, Ethiopia, France, French Guiana, India, Ireland, Japan, Kenya, Malawi, Mozambique, Nigeria, Pakistan, Portugal, Senegal, Slovenia, South Africa, South Sudan, Spain, Swaziland, Tanzania, Uganda, Ukraine, the UK, the USA and Zambia. Contributors included representatives from WHO, UNITAID, Medecins Sans Frontieres, African Society for Laboratory Medicine, Clinton Health Access Initiative, Medical Access, WHO Collaborating Centers for Reference and Research on Fungi of Medical Importance/Antimicrobial Resistance (India/South Africa/USA), ministries of health, national reference laboratories, US Centers for Disease Control and Prevention, research institutes and both diagnostic and pharmaceutical companies with an interest in HIV/AIDS and/or fungal diseases.

The meeting included workshops on pre-selected key non-culture diagnostics, e.g. TB urinary antigen (LAM), cryptococcal antigen (CrAg), Histoplasma antigen, Aspergillus IgG, Pneumocystis PCR and Toxoplasma IgG/IgM and one on antifungal therapeutic monitoring. Shorter summaries of the clinical value of another 6 diagnostics, mainly, culture-based methods and other biomarker assays were also presented in the context of LMICs. The main question for each diagnostic method was—“is it essential?”. Each presentation by an expert in the topic area reviewed the available evidence on diagnostic performance of each test, their ease of use and cost-effectiveness. The strength of recommendation was derived from the diagnostic performance, clinical value and suitability of the selected tests for LMICS (Table 1). Panel discussions then lead to a consensus recommendation for each diagnostic test (Table 2). For more broadly based tests such as direct microscopy, blood culture, and fungal culture, the meeting concluded that such tests were essential, although these were not reviewed in a systematic manner.
Table 1

Categorisation of recommendation for non-culture based tests

Recommendation

Diagnostic performance

Clinical value

Suitability for LMICs

Very strong

Excellent (> 95% sensitivity/specificity)

Immediately life-saving

Yes

Strong

Excellent or good (> 90% sensitivity and > 90% specificity)

A critical diagnosis which changes treatment

Yes

Moderate

Excellent, good or quite good (> 80% sensitivity and > 80% specificity)

Allows specific therapy to be started or stopped, reducing diagnostic uncertainty

Partial

Low

Inadequate (sensitivity < 80% and specificity < 80%)

Allows specific therapy to be started or stopped, reducing diagnostic uncertainty

Not suitable

None

Test complex, variable performance, difficult to interpret or lack of specificity

Lack of survival benefit or clinical utility or more studies required in LMICs

Not suitable

Table 2

Consensus recommendation by experts on the essentiality of the different diagnostic modalities in low- and middle-income countries

Diagnostic assay

Recommendation

Setting

Comments

Cryptococcal antigen lateral flow assay

Very strong*

LMICs, AIDS-related cryptococcal meningitis

Four commercial assays#, simple, fast (0–15 min), performance not equal between assays.

Older CrAg latex agglutination is inferior to the FDA-approved CrAg LFA

Histoplasma antigen

Very strong

Areas of high incidence/prevalence, disseminated histoplasmosis in AIDS, otherwise as reference test

Urine or serum (1 ELISA)—significant improvement in diagnostic sensitivity, major regional variations in prevalence

Toxoplasma IgG

Strong

MICs with high toxoplasma prevalence

5 good commercial assays, including one LFA and 3 ELISAs and 1 agglutination assay (laboratory based), LFA (20 min) could be bedside (detection of both IgG and IgM on whole blood). Allow stopping high-dose cotrimoxazole treatment if negative (reduce unnecessary toxicity and resistance development) and avoid misdiagnosis with TB or cryptococcosis. Could also prevent congenital toxoplasmosis in pregnant women. More data required on LMIC performance in AIDS and operational value

Moderate

LICs

Aspergillus IgG

Strong

TB services in LMICs

7 commercial assays, automated assays (high quality/reference laboratory), ELISA moderate complexity

Cryptococcal antigen quantification/titres

Strong

LMICs

4 tests commercially available—laboratory test, alternative to LFA

LFA titres are not equivalent between manufacturers

Pneumocystis pneumonia PCR

Moderate

MICs only and not recommended in LICs

~ 8 commercial assays, superior to microscopy—laboratory with regular electricity, moderate complexity, appropriate for MICs and reference/research labs in LICs. Issue regarding result interpretation (colonization or PCP?)

Antifungal drug monitoring

Strong

MICs only and not recommended in LICs

Bioassay in LMICs. For the life-saving, essential medicines itraconazole, voriconazole and flucytosine, to ensure adequate levels in the blood, often a problem in neonates and patients with renal dysfunction (flucytosine), long-term therapy for aspergillosis (itraconazole), or in children, following dose changes, after a shift from intravenous to oral treatment or following a change in the patient’s clinical condition (voriconazole)

TB LAM antigen

Very strong*

LMICs

1 assay commercially available—simple (20 min), probably best used at the bedside or community; turnaround time of < 2 h

Direct microscopy/histopathology

Strong*

All laboratories of LMICs

Low cost, good turnaround time, variable sensitivity

1,3 Beta-d-glucan

None

Test complexity high, more studies required for opportunistic infections in advanced HIV and children with PCP, not able to identify the fungus

Blood culture

Strong*

All laboratories of LMICs

Bacterial, mycobacterial and fungal sepsis, allows optimal therapy, susceptibility testing and infection control, cost a major issue

Bacterial culture

Strong*

All laboratories of LMICs

Bacterial and mycobacterial infection

Fungal culture

Strong*

All laboratories of LMICs

Invasive fungal infections, scope of in vitro susceptibility testing, identify the agent helping in antifungal choice

Galactomannan

None

Test complex, more studies required in HIV and LMICs. Usually represents aspergillosis, but not able to identify the fungus

Lateral flow assay now available

LMICs low- and middle-income countries, MICs middle-income countries, LICs low-income countries, ELISA enzyme-linked immunosorbent assays, LFA lateral flow assays, PCR polymerase chain reaction, TB tuberculosis, LAM lipoarabinomannan, PCP Pneumocystis pneumonia

*Included on the 2018 WHO List of Essential In Vitro Diagnostic. #1 FDA approved and 2 CE marked

This workshop represents the first time that a consensus meeting to define essential diagnostics for advanced HIV and serious fungal diseases has been held. If implemented and made available in each country, these diagnostic tests will directly improve patient care and public health. TB LAM and CrAg tests both in the context of advanced HIV disease and blood culture for the diagnosis of bacterial and fungal bloodstream infections have been listed as general IVDs for health care facilities with clinical laboratories (Tier II) and direct microscopy for primary health care (Tier I) [12].

With the current knowledge that the WHO EDL will be expanded and be updated annually, several tests endorsed at the meeting will be the subject of future applications for inclusion on the EDL for LMICs. The highest priority tests for inclusion are Histoplasma antigen detection and therapeutic drug monitoring of itraconazole and voriconazole. More data are needed from LMICs on both Aspergillus IgG and toxoplasma serology performance and interpretation. Pneumocystis PCR is routine in Europe and has replaced microscopy, and the meeting endorsed its incorporation into the EDL for MICs but not LICs because of the need for frozen shipping, laboratory complexity, and reliable electricity. A simpler test would negate these difficulties. We also advocate for CrAg LFA to be added on the Tier I list to enable screening. Optimal usage of these tests will require CD4 counts (which have been included on the EDL), notably TB LAM (best performance in those with < 100 CD4 cells), and CrAg and Histoplasma antigen (best performance in those with < 200 CD4 counts).

Beyond advanced HIV disease, serious fungal infections, severe bacterial sepsis, TB and toxoplasmosis also occur in patients with cancers or who are on cancer treatment, transplant recipients, those critically ill and many other patients, so availability of diagnostics will be of universal benefit to humankind.

Notes

Acknowledgements

Representatives from WHO attended the meeting and provided input on WHO recommendations for advanced HIV disease but were not part of the group that produced consensus recommendations for inclusion of diagnostic tests in the EDL. These consensus recommendations do not represent the views of WHO or CDC.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Felix Bongomin
    • 1
    • 2
  • Nelesh P. Govender
    • 3
    • 4
  • Arunaloke Chakrabarti
    • 5
  • Florence Robert-Gangneux
    • 6
  • David R. Boulware
    • 7
  • Afia Zafar
    • 8
  • Rita O. Oladele
    • 9
  • Malcolm D. Richardson
    • 10
    • 11
  • Jean-Pierre Gangneux
    • 6
  • Ana Alastruey-Izquierdo
    • 12
  • Joel Bazira
    • 13
  • Tom H. Boyles
    • 4
  • Jahit Sarcarlal
    • 14
  • Mathieu Nacher
    • 15
  • Taminori Obayashi
    • 16
  • William Worodria
    • 17
  • Alessandro C. Pasqualotto
    • 18
  • David B. Meya
    • 17
    • 19
  • Ben Cheng
    • 20
  • Charlotte Sriruttan
    • 3
  • Conrad Muzoora
    • 13
  • Andrew Kambugu
    • 17
    • 19
  • Juan Luis Rodriguez Tudela
    • 1
  • Alexander Jordan
    • 21
  • Tom M. Chiller
    • 21
  • David W. Denning
    • 1
    • 10
    Email author
  1. 1.Global Action Fund for Fungal InfectionsGenevaSwitzerland
  2. 2.Department of Medical Microbiology and Immunology Gulu UniversityGuluUganda
  3. 3.National Institute for Communicable Diseases (Centers for Healthcare-Associated Infections, Antimicrobial Resistance and Mycoses)JohannesburgSouth Africa
  4. 4.University of the WitwatersrandJohannesburgSouth Africa
  5. 5.Postgraduate Institute of Medical Education and ResearchChandigarhIndia
  6. 6.Université Rennes et Centre Hospitalier Universitaire de RennesRennesFrance
  7. 7.University of MinnesotaMinneapolisUSA
  8. 8.Aga Khan UniversityKarachiPakistan
  9. 9.University of LagosLagosNigeria
  10. 10.The University of ManchesterManchesterUK
  11. 11.Mycology Reference CentreManchesterUK
  12. 12.Mycology Reference Laboratory, National Centre for MicrobiologyInstituto de Salud Carlos IIIMadridSpain
  13. 13.Mbarara University of Science and TechnologyMbararaUganda
  14. 14.Department of Microbiology, Faculty of Medicine University Eduardo MondlaneMaputoMozambique
  15. 15.The University of French GuianaCayenneFrench Guiana
  16. 16.Higashi Saitama General HospitalSaitamaJapan
  17. 17.College of Health SciencesMakerere UniversityKampalaUganda
  18. 18.Universidade Federal de Ciências da Saúde de Porto AlegrePorto AlegreBrazil
  19. 19.Infectious Disease InstituteMakerere UniversityKampalaUganda
  20. 20.Global Health Impact GroupAtlantaUSA
  21. 21.Centers for Disease Control and PreventionAtlantaUSA

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