Cryptococcal Disease in the Era of “Test and Treat”: Is There Cause for Concern?

Cryptococcal Disease in the Era of “Test and Treat”: Is There Cause for Concern? Open Forum Infectious Diseases BRIEF REPORT Case 1 Cryptococcal Disease in the Era of A 45-year-old, newly diagnosed HIV-seropositive, ART-naïve “Test and Treat”: Is There Cause for man presented to an urban HIV clinic with 5 months of recur- Concern? rent fevers and 4 days of bloody diarrhea. He appeared mark- edly wasted, but otherwise had an unremarkable physical 1,2 1,2 1,2,3 2 Mahsa Abassi, Joshua Rhein, David B. Meya, and David R. Boulware examination. He was started on ciprofloxacin and metronida- 1 2 Infectious Diseases Institute, Kampala, Uganda; University of Minnesota, Minneapolis, Minnesota; School of Medicine, College of Health Sciences, Makerere University, Kampala, zole for presumptive infectious colitis and given a 1-week fol- Uganda low-up date. Upon return to clinic, his laboratory test results were reviewed and found to be notable for a CD4 count of 20 Treatment of cryptococcosis requires deferred initiation of anti- cells/μL. He underwent ART counseling and was immediately retroviral therapy (ART). Early ART initiation may be detri- initiated on tenofovir, lamivudine, and efavirenz (TDF/3TC/ mental in the context of cryptococcal infection by increasing the EFV). Given his low CD4 count, a serum cryptococcal anti- risk of immune reconstitution inflammatory syndrome (IRIS). gen (CrAg) was requested to be run from the central labo- We present 3 cases where early ART initiation in the presence of ratory. Ten days later, he returned to the clinic complaining unrecognized cryptococcal disease had fatal outcomes. of evening fevers, cough, anorexia, and malaise. The serum Keywords. cryptococcal immune reconstitution syndrome; HIV; test and treat. CrAg results were reviewed and were positive, with a titer of 1:80. Clinical evaluation and symptom assessment found him to be asymptomatic for cryptococcal meningitis, and he was prescribed fluconazole 800  mg/d for asymptomatic crypto- In an effort to scale up responses to the HIV epidemic, the Joint coccal antigenemia. Four days later (2 weeks from ART initi- United Nations Programme on HIV/AIDS [1] set an ambitious ation), he returned to the clinic in a wheelchair, unconscious. 90-90-90 treatment target aiming for 90% of all HIV-infected His caretaker stated that he deteriorated at home, having persons knowing their status, 90% of HIV-infected persons experienced several seizures, worsening anorexia, and gen- receiving antiretroviral therapy (ART), and 90% of individu- eralized weakness. While in clinic triage, he experienced a als on ART achieving viral suppression [2]. The World Health tonic-clonic seizure, leaving him unresponsive, hypotensive, Organization, citing evidence that earlier ART results in better and hypoxic, with a Glasgow Coma Scale score of 6 out of long-term outcomes and reduced HIV transmission, updated 15. Despite resuscitation efforts, he died before he could be HIV guidelines to recommend ART initiation in all persons transferred to a hospital. regardless of CD4 counts [3]. e m Th ove toward HIV testing followed by immediate ART Case 2 initiation (“test and treat”) has become a recommended tool A 35-year-old man was newly diagnosed HIV-seropositive at to help reach the 90-90-90 treatment target. In addition, early a rural HIV clinic 3 weeks prior to hospital admission. His ART initiation aer m ft any opportunistic infections results in baseline CD4 was noted to be 7 cells/μL. At the time of HIV fewer deaths and less AIDS progression vs delayed ART initia- diagnosis, he had been experiencing persistent headaches. tion [4]. However, cryptococcosis provides a notable exception, However, CrAg testing was not performed, and he was ini- where early ART initiation could lead to worse outcomes com- tiated on TDF/3TC/EFV 9  days prior to hospital admission. pared with delayed ART initiation [5]. We present 3 cases from At hospital presentation, examination was notable for visual Uganda where “test and treat” in the setting of undiagnosed and hearing impairment, but he was awake, alert, and ori- cryptococcal disease had detrimental outcomes. ented. Laboratory test results were positive for both serum and cerebrospinal fluid (CSF) CrAg. His intracranial pressure was Received 2 October 2017; editorial decision 13 December 2017; accepted 24 December 2017. markedly elevated, with an opening pressure of 50  cmH O, Correspondence: M. Abassi, DO, Infectious Diseases Institute, P.O. Box 22148, Mulago CSF WBC  <5 cells/μL, and CSF culture of 630 000 colony Hospital Complex, Kampala, Uganda (abass004@umn.edu). forming units/mL of Cryptococcus. He was started on ampho- Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases tericin B (50 mg IV daily) and fluconazole (800 mg/d) for the Society of America. This is an Open Access article distributed under the terms of the Creative treatment of cryptococcal meningitis. He required 3 subse- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any quent lumbar punctures on consecutive days for persistently medium, provided the original work is not altered or transformed in any way, and that the work elevated intracranial pressure. He deteriorated on the fifth day is properly cited. For commercial re-use, please contact journals.permissions@oup.com of hospitalization and died. DOI: 10.1093/ofid/ofx274 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Case 3 routine laboratory testing practices, rather than using the A 35-year-old man newly diagnosed HIV-seropositive with CrAg lateral flow assay (LFA) as a point-of-care test. Effective a baseline CD4 of 28 cells/μL presented to the hospital with CrAg screening programs largely depend on concurrent CD4 4 weeks of a dry cough, 2 weeks of headaches, and 1  day of testing and reflex laboratory-based CrAg screening. As CrAg vomiting. One month prior to hospital admission, he was screening is often dependent on CD4 count testing, there can found to be HIV-seropositive at a local clinic and initiated be a delay from HIV diagnosis to detection of cryptococcal on TDF/3TC/EFV. Two weeks prior to hospital admission, antigenemia in an at-risk person. Cases 2 and 3 highlight the he was initiated on empiric antituberculosis therapy based lack of CrAg screening in HIV clinics, both rural and urban, on clinical symptoms and an abnormal chest radiograph. He either because of a lack of CrAg LFA kits or training and had no known history of cryptococcal disease, and no prior awareness among health care workers. Case 3 also highlights CrAg testing was performed. At hospital admission, he was the challenges faced in persons with cryptococcal disease who alert, awake, oriented, and clinically stable. Laboratory test have been misdiagnosed as having tuberculosis, leading to results were positive for both serum and cerebrospinal fluid missed opportunities and delays in CrAg screening and treat- (CSF) CrAg. CSF white cells were <5 cells/μL, CSF opening ment. In all 3 cases, ART initiation prior to CrAg screening pressure was 20 cmH O, and CSF cultures grew Cryptococcus and preemptive fluconazole therapy likely contributed to rapid with a low fungal burden (10 colony-forming units/mL). He clinical deterioration and death. More streamlined approaches was started on amphotericin B (50 mg IV daily) and flucona- to cryptococcosis diagnosis are clearly needed with the para- zole (800 mg/d) for the treatment of cryptococcal meningitis digm shift to “test and treat.” according to national guidelines. Four days following admis- Cryptococcal infection must be considered in any newly sion, he became confused, unresponsive, and developed res- diagnosed HIV-seropositive persons with a headache, particu- piratory failure. Vancomycin and piperacillin-tazobactam larly when the CD4 count is low. Cases 2 and 3 suggest a missed were administered for possible sepsis, and dexamethasone was opportunity for early diagnosis of cryptococcal meningitis at administered for potential unmasking immune reconstitu- the time of ART initiation. ART initiation in the context of tion inflammatory syndrome (IRIS). Despite these measures, early signs of cryptococcal meningitis may lead to the devel- he continued to deteriorate and died 13  days after hospital opment of overt meningitis, rapid clinical deterioration, and admission. death, as these cases demonstrate. When symptoms sugges- tive of cryptococcal meningitis are present at the time of HIV DISCUSSION diagnosis, a lumbar puncture should be performed to rule out Cryptococcosis deaths are estimated to account for approxi- cryptococcal meningitis prior to ART initiation. Where lum- mately 15% of AIDS-related mortality [6]. Estimates place the bar punctures are not possible, persons with CrAg antigenemia global prevalence of cryptococcal antigenemia at 6.0% among in the presence of symptoms should be emergently referred HIV-infected persons with CD4  <100 cells/μL, resulting in to centers for further evaluation, and ART should be delayed. 278 000 (95% confidence interval, 195 500–340 600) people Clinicians, in their commitment to comply with the new guide-       with cryptococcal infection annually; the majority of these lines for “test and treat,” should not lose sight of potentially cases occur in Sub-Saharan Africa [6]. In order to prevent serious complications associated with opportunistic infections new cases of cryptococcal meningitis, the 2017 World Health and ART initiation, such as IRIS or unmasking disease, which Organization (WHO) guidelines, including current Ugandan can be fatal [9]. National guidelines [7], recommend CrAg screening of all HIV- Unmasking cryptococcal-related immune reconstitution seropositive adolescents and adults with CD4  <100 cell/μL, inflammatory syndrome can lead to severe and rapid clin- followed by preemptive therapy with fluconazole for asymp- ical deterioration following the restoration of immune func- tomatic cryptococcal antigenemia [8]. The WHO recommends tion after ART initiation (Box 1 )  [10]. Since the widespread consideration of delaying ART initiation for 2 weeks after start- rollout of ART, the “90-90-90” goals set forth by UNAIDS, ing antifungal therapy in persons with asymptomatic crypto- and the recommendation by the WHO to “test and treat,” coccal antigenemia, albeit with a low level of evidence. Current an increasing percentage of people are receiving ART at the WHO guidelines for management of cryptococcosis are under time of cryptococcal meningitis diagnosis. In 2017, a major- review. ity of persons with cryptococcosis are now receiving ART at In Uganda, inadequate infrastructure, resources, and train- the time of meningitis diagnosis [11, 12]. Persons receiving ing have led to critical gaps in cryptococcal antigen screening. ART at cryptococcal diagnosis have higher mean CD4 counts The cases presented here depict missed or delayed oppor - and lower CSF fungal burden, yet similar acute mortality to tunities for early CrAg screening and treatment. In case 1, ART-naïve persons [13]. However, we have observed that Cryptococcus was considered only after a CD4  <100 cell/μL individuals who initiate ART within 14  days of developing was noted, and further CrAg testing was delayed by following cryptococcal meningitis are at higher risk of death than those 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 shown to be effective in preventing mortality from cryptococcal Box 1. Abbreviated Case Definition of Unmasking Cryptococcal meningitis [17]. It is unclear if the improved mortality in this Immune Reconstitution Inflammatory Syndrome study was the result of preventing new infections, preventing the evolution of meningitis in cases of unrecognized crypto- • U nrecognized cryptococcal disease at the initi- coccal antigenemia, or the reduced risk of developing IRIS by ation, reintroduction, or switch of antiretroviral treating other possible opportunistic infections and improv- therapy ing immune function. It is possible that some combination of • E xaggerated or heightened inflammatory empiric or prophylactic uco fl nazole together with serum CrAg response: testing could be effective in preventing cryptococcal disease and ○ Markedly elevated cerebrospinal fluid leuko- minimizing mortality using a “test and treat” strategy. cyte count (>50 cells/μL) e co Th ntribution of health systems in failing to curtail the high ○ Elevated opening pressure refractory to incidence of cryptococcal deaths in Africa, despite widespread therapy ART roll out, may require new tailored approaches, both human ○ Painful or suppurating lymphadenopathy and financial, to improve outcomes in persons with cryptococcal ○ Rapidly expanding central nervous system disease. Measures should be taken to disseminate and implement lesions, cryptococcoma(s) guidelines for cryptococcal antigen screening, equip health care ○ Unusual focal site (ie, not within the central facilities with point-of-care diagnostic test kits, and ensure an nervous system, lung, skin, or lymph nodes) adequate supply of antifungals. Failure to enhance screening for ○ Granulomatous inflammation on histology cryptococcal antigenemia or cryptococcal meningitis while scal- • Pneumonitis ing up ART availability and distribution will undoubtedly lead to • C linical deterioration occurring early after anti- increasing fatalities of unmasking IRIS in an already vulnerable retroviral therapy initiation, within 3 months and severely immunocompromised population. Acknowledgments We thank Dr Noela Clara Owarwo and Dr. Martin Balaba at the Infectious receiving ART for >14  days [14]. ART-experienced persons Diseases Institute in Kampala, Uganda, for contributing a case for our man- with cryptococcal meningitis are not all the same, as the uscript. We would also like to thank the entire ASTRO-CM team for the timing of ART is crucial, and those with unmasking IRIS vs tireless and wonderful work that they do. We appreciate the institutional support provided by Prof. Paul Bohjanen and Dr Andrew Kambugu. virologic failure may differ vastly immunologically. While Financial support. This work was supported by the Fogarty dexamethasone was administered in case 3, it is unclear International Center (K01TW010268 and R25TW009345), the National whether this is an effective management strategy for the treat- Institute of Neurological Disorders and Stroke (R01NS086312), the National Institute of Allergy and Infectious Diseases (T32AI055433) of the ment of unmasking IRIS. While current evidence appears to National Institute of Health, and DELTAS Africa Initiative grant No. DEL- support a short course of corticosteroids in cases of severe 15-011 to THRiVE-2 (D.M.). paradoxical cryptococcal meningitis IRIS [15], there are lim- Potential conifl cts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of ited data to support corticosteroid use for unmasking IRIS. In Potential Conflicts of Interest. Conflicts that the editors consider relevant to a recent trial that included ART-experienced participants in the content of the manuscript have been disclosed. Southeast Asia and Sub-Saharan Africa, universal adjunctive dexamethasone did not provide benefit when added to stand- References ard antifungal therapy and was associated with more adverse 1. UNAIDS. Prevention Gap Report. UNAIDS; 2016. 2. Joint United Nations Programme on HIV/AIDS. Global AIDS Update 2016. events [9]. Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS; 2016. Immune reconstitution in the presence of cryptococcal dis- 3. World Health Organization. Guideline on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. WHO; 2015. ease should be a concern in centers where baseline CD4 testing 4. Zolopa AR, Andersen J, Komarow L, et  al. Early antiretroviral therapy reduces is unavailable and where routine CrAg screening has a delayed AIDS progression/death in individuals with acute opportunistic infections: a turnaround time or has not yet been implemented. In the absence multicenter randomized strategy Trial. PLoS ONE 2009; 4:e5575. doi:10.1371/ journal.pone.0005575 of a more streamlined approach to diagnosis, however, further 5. Boulware DR, Meya DB, Muzoora C, et al; COAT Trial Team. Timing of antiretroviral consideration may be given to the role of empiric fluconazole therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370:2487–98. 6. Rajasingham R, Smith RM, Park BJ, et  al. Global burden of disease of HIV- therapy pending results of CD4 and CrAg testing in cases where associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; ART is initiated immediately aer HIV di ft agnosis. Earlier stud- 17:873–81. 7. Ministry of Health. Consolidated Guidelines for Prevention and Treatment of ies have demonstrated that daily prophylaxis with fluconazole HIV in Uganda. Ministry of Health; 2016. is effective in reducing the risk of invasive cryptococcosis [16]. 8. World Health Organization. Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy. Geneva, Switzerland: WHO; 2017. Most recently, an enhanced prophylaxis regimen consisting 9. Beardsley J, Wolbers M, Kibengo FM, et al; CryptoDex Investigators. Adjunctive of fluconazole, trimethoprim–sulfamethoxazole, isoniazid– dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016; pyridoxine, azithromycin, and a single dose of albendazole was 374:542–54. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 10. Haddow LJ, Colebunders R, Meintjes G, et al; International Network for the Study Retroviruses and Opportunistic Infections; February 23–26, 2015; Seattle, WA. of HIV-associated IRIS (INSHI). Cryptococcal immune reconstitution inflamma- Abstract Number 836. tory syndrome in HIV-1-infected individuals: proposed clinical case definitions. 15. Perfect JR, Dismukes WE, Dromer F, et  al. Clinical practice guidelines for the Lancet Infect Dis 2010; 10:791–802. doi:10.1016/S1473-3099(10)70170-5 management of cryptococcal disease: 2010 update by the Infectious Diseases 11. Williamson PR. The relentless march of cryptococcal meningitis. Lancet Infect Society of America. Clin Infect Dis 2010; 50:291–322. Dis 2017; 17:790–1. 16. Powderly WG, Finkelstein D, Feinberg J, et  al. A randomized trial com- 12. Rhein J, Morawski BM, Hullsiek KH, et al; ASTRO-CM Study Team. Efficacy of paring fluconazole with clotrimazole troches for the prevention of fun- adjunctive sertraline for the treatment of HIV-associated cryptococcal meningi- gal infections in patients with advanced human immunodeficiency tis: an open-label dose-ranging study. Lancet Infect Dis 2016; 16:809–18. virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995; 13. Longley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflam- 332:700–5. matory syndrome. Curr Opin Infect Dis 2013; 26:26–34. 17. Hakim J, Musiime V, Szubert AJ, et al; REALITY Trial Team. Enhanced proph- 14. Rhein J, Hullsiek KH, Bahr NC, et al. Detrimental outcomes of unmasking crypto- ylaxis plus antiretroviral therapy for advanced HIV infection in Africa. N Engl J coccal meningitis with recent ART initiation. Paper presented at: Conference on Med 2017; 377:233–45. 4 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Cryptococcal Disease in the Era of “Test and Treat”: Is There Cause for Concern?

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Abstract

Open Forum Infectious Diseases BRIEF REPORT Case 1 Cryptococcal Disease in the Era of A 45-year-old, newly diagnosed HIV-seropositive, ART-naïve “Test and Treat”: Is There Cause for man presented to an urban HIV clinic with 5 months of recur- Concern? rent fevers and 4 days of bloody diarrhea. He appeared mark- edly wasted, but otherwise had an unremarkable physical 1,2 1,2 1,2,3 2 Mahsa Abassi, Joshua Rhein, David B. Meya, and David R. Boulware examination. He was started on ciprofloxacin and metronida- 1 2 Infectious Diseases Institute, Kampala, Uganda; University of Minnesota, Minneapolis, Minnesota; School of Medicine, College of Health Sciences, Makerere University, Kampala, zole for presumptive infectious colitis and given a 1-week fol- Uganda low-up date. Upon return to clinic, his laboratory test results were reviewed and found to be notable for a CD4 count of 20 Treatment of cryptococcosis requires deferred initiation of anti- cells/μL. He underwent ART counseling and was immediately retroviral therapy (ART). Early ART initiation may be detri- initiated on tenofovir, lamivudine, and efavirenz (TDF/3TC/ mental in the context of cryptococcal infection by increasing the EFV). Given his low CD4 count, a serum cryptococcal anti- risk of immune reconstitution inflammatory syndrome (IRIS). gen (CrAg) was requested to be run from the central labo- We present 3 cases where early ART initiation in the presence of ratory. Ten days later, he returned to the clinic complaining unrecognized cryptococcal disease had fatal outcomes. of evening fevers, cough, anorexia, and malaise. The serum Keywords. cryptococcal immune reconstitution syndrome; HIV; test and treat. CrAg results were reviewed and were positive, with a titer of 1:80. Clinical evaluation and symptom assessment found him to be asymptomatic for cryptococcal meningitis, and he was prescribed fluconazole 800  mg/d for asymptomatic crypto- In an effort to scale up responses to the HIV epidemic, the Joint coccal antigenemia. Four days later (2 weeks from ART initi- United Nations Programme on HIV/AIDS [1] set an ambitious ation), he returned to the clinic in a wheelchair, unconscious. 90-90-90 treatment target aiming for 90% of all HIV-infected His caretaker stated that he deteriorated at home, having persons knowing their status, 90% of HIV-infected persons experienced several seizures, worsening anorexia, and gen- receiving antiretroviral therapy (ART), and 90% of individu- eralized weakness. While in clinic triage, he experienced a als on ART achieving viral suppression [2]. The World Health tonic-clonic seizure, leaving him unresponsive, hypotensive, Organization, citing evidence that earlier ART results in better and hypoxic, with a Glasgow Coma Scale score of 6 out of long-term outcomes and reduced HIV transmission, updated 15. Despite resuscitation efforts, he died before he could be HIV guidelines to recommend ART initiation in all persons transferred to a hospital. regardless of CD4 counts [3]. e m Th ove toward HIV testing followed by immediate ART Case 2 initiation (“test and treat”) has become a recommended tool A 35-year-old man was newly diagnosed HIV-seropositive at to help reach the 90-90-90 treatment target. In addition, early a rural HIV clinic 3 weeks prior to hospital admission. His ART initiation aer m ft any opportunistic infections results in baseline CD4 was noted to be 7 cells/μL. At the time of HIV fewer deaths and less AIDS progression vs delayed ART initia- diagnosis, he had been experiencing persistent headaches. tion [4]. However, cryptococcosis provides a notable exception, However, CrAg testing was not performed, and he was ini- where early ART initiation could lead to worse outcomes com- tiated on TDF/3TC/EFV 9  days prior to hospital admission. pared with delayed ART initiation [5]. We present 3 cases from At hospital presentation, examination was notable for visual Uganda where “test and treat” in the setting of undiagnosed and hearing impairment, but he was awake, alert, and ori- cryptococcal disease had detrimental outcomes. ented. Laboratory test results were positive for both serum and cerebrospinal fluid (CSF) CrAg. His intracranial pressure was Received 2 October 2017; editorial decision 13 December 2017; accepted 24 December 2017. markedly elevated, with an opening pressure of 50  cmH O, Correspondence: M. Abassi, DO, Infectious Diseases Institute, P.O. Box 22148, Mulago CSF WBC  <5 cells/μL, and CSF culture of 630 000 colony Hospital Complex, Kampala, Uganda (abass004@umn.edu). forming units/mL of Cryptococcus. He was started on ampho- Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases tericin B (50 mg IV daily) and fluconazole (800 mg/d) for the Society of America. This is an Open Access article distributed under the terms of the Creative treatment of cryptococcal meningitis. He required 3 subse- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any quent lumbar punctures on consecutive days for persistently medium, provided the original work is not altered or transformed in any way, and that the work elevated intracranial pressure. He deteriorated on the fifth day is properly cited. For commercial re-use, please contact journals.permissions@oup.com of hospitalization and died. DOI: 10.1093/ofid/ofx274 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Case 3 routine laboratory testing practices, rather than using the A 35-year-old man newly diagnosed HIV-seropositive with CrAg lateral flow assay (LFA) as a point-of-care test. Effective a baseline CD4 of 28 cells/μL presented to the hospital with CrAg screening programs largely depend on concurrent CD4 4 weeks of a dry cough, 2 weeks of headaches, and 1  day of testing and reflex laboratory-based CrAg screening. As CrAg vomiting. One month prior to hospital admission, he was screening is often dependent on CD4 count testing, there can found to be HIV-seropositive at a local clinic and initiated be a delay from HIV diagnosis to detection of cryptococcal on TDF/3TC/EFV. Two weeks prior to hospital admission, antigenemia in an at-risk person. Cases 2 and 3 highlight the he was initiated on empiric antituberculosis therapy based lack of CrAg screening in HIV clinics, both rural and urban, on clinical symptoms and an abnormal chest radiograph. He either because of a lack of CrAg LFA kits or training and had no known history of cryptococcal disease, and no prior awareness among health care workers. Case 3 also highlights CrAg testing was performed. At hospital admission, he was the challenges faced in persons with cryptococcal disease who alert, awake, oriented, and clinically stable. Laboratory test have been misdiagnosed as having tuberculosis, leading to results were positive for both serum and cerebrospinal fluid missed opportunities and delays in CrAg screening and treat- (CSF) CrAg. CSF white cells were <5 cells/μL, CSF opening ment. In all 3 cases, ART initiation prior to CrAg screening pressure was 20 cmH O, and CSF cultures grew Cryptococcus and preemptive fluconazole therapy likely contributed to rapid with a low fungal burden (10 colony-forming units/mL). He clinical deterioration and death. More streamlined approaches was started on amphotericin B (50 mg IV daily) and flucona- to cryptococcosis diagnosis are clearly needed with the para- zole (800 mg/d) for the treatment of cryptococcal meningitis digm shift to “test and treat.” according to national guidelines. Four days following admis- Cryptococcal infection must be considered in any newly sion, he became confused, unresponsive, and developed res- diagnosed HIV-seropositive persons with a headache, particu- piratory failure. Vancomycin and piperacillin-tazobactam larly when the CD4 count is low. Cases 2 and 3 suggest a missed were administered for possible sepsis, and dexamethasone was opportunity for early diagnosis of cryptococcal meningitis at administered for potential unmasking immune reconstitu- the time of ART initiation. ART initiation in the context of tion inflammatory syndrome (IRIS). Despite these measures, early signs of cryptococcal meningitis may lead to the devel- he continued to deteriorate and died 13  days after hospital opment of overt meningitis, rapid clinical deterioration, and admission. death, as these cases demonstrate. When symptoms sugges- tive of cryptococcal meningitis are present at the time of HIV DISCUSSION diagnosis, a lumbar puncture should be performed to rule out Cryptococcosis deaths are estimated to account for approxi- cryptococcal meningitis prior to ART initiation. Where lum- mately 15% of AIDS-related mortality [6]. Estimates place the bar punctures are not possible, persons with CrAg antigenemia global prevalence of cryptococcal antigenemia at 6.0% among in the presence of symptoms should be emergently referred HIV-infected persons with CD4  <100 cells/μL, resulting in to centers for further evaluation, and ART should be delayed. 278 000 (95% confidence interval, 195 500–340 600) people Clinicians, in their commitment to comply with the new guide-       with cryptococcal infection annually; the majority of these lines for “test and treat,” should not lose sight of potentially cases occur in Sub-Saharan Africa [6]. In order to prevent serious complications associated with opportunistic infections new cases of cryptococcal meningitis, the 2017 World Health and ART initiation, such as IRIS or unmasking disease, which Organization (WHO) guidelines, including current Ugandan can be fatal [9]. National guidelines [7], recommend CrAg screening of all HIV- Unmasking cryptococcal-related immune reconstitution seropositive adolescents and adults with CD4  <100 cell/μL, inflammatory syndrome can lead to severe and rapid clin- followed by preemptive therapy with fluconazole for asymp- ical deterioration following the restoration of immune func- tomatic cryptococcal antigenemia [8]. The WHO recommends tion after ART initiation (Box 1 )  [10]. Since the widespread consideration of delaying ART initiation for 2 weeks after start- rollout of ART, the “90-90-90” goals set forth by UNAIDS, ing antifungal therapy in persons with asymptomatic crypto- and the recommendation by the WHO to “test and treat,” coccal antigenemia, albeit with a low level of evidence. Current an increasing percentage of people are receiving ART at the WHO guidelines for management of cryptococcosis are under time of cryptococcal meningitis diagnosis. In 2017, a major- review. ity of persons with cryptococcosis are now receiving ART at In Uganda, inadequate infrastructure, resources, and train- the time of meningitis diagnosis [11, 12]. Persons receiving ing have led to critical gaps in cryptococcal antigen screening. ART at cryptococcal diagnosis have higher mean CD4 counts The cases presented here depict missed or delayed oppor - and lower CSF fungal burden, yet similar acute mortality to tunities for early CrAg screening and treatment. In case 1, ART-naïve persons [13]. However, we have observed that Cryptococcus was considered only after a CD4  <100 cell/μL individuals who initiate ART within 14  days of developing was noted, and further CrAg testing was delayed by following cryptococcal meningitis are at higher risk of death than those 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 shown to be effective in preventing mortality from cryptococcal Box 1. Abbreviated Case Definition of Unmasking Cryptococcal meningitis [17]. It is unclear if the improved mortality in this Immune Reconstitution Inflammatory Syndrome study was the result of preventing new infections, preventing the evolution of meningitis in cases of unrecognized crypto- • U nrecognized cryptococcal disease at the initi- coccal antigenemia, or the reduced risk of developing IRIS by ation, reintroduction, or switch of antiretroviral treating other possible opportunistic infections and improv- therapy ing immune function. It is possible that some combination of • E xaggerated or heightened inflammatory empiric or prophylactic uco fl nazole together with serum CrAg response: testing could be effective in preventing cryptococcal disease and ○ Markedly elevated cerebrospinal fluid leuko- minimizing mortality using a “test and treat” strategy. cyte count (>50 cells/μL) e co Th ntribution of health systems in failing to curtail the high ○ Elevated opening pressure refractory to incidence of cryptococcal deaths in Africa, despite widespread therapy ART roll out, may require new tailored approaches, both human ○ Painful or suppurating lymphadenopathy and financial, to improve outcomes in persons with cryptococcal ○ Rapidly expanding central nervous system disease. Measures should be taken to disseminate and implement lesions, cryptococcoma(s) guidelines for cryptococcal antigen screening, equip health care ○ Unusual focal site (ie, not within the central facilities with point-of-care diagnostic test kits, and ensure an nervous system, lung, skin, or lymph nodes) adequate supply of antifungals. Failure to enhance screening for ○ Granulomatous inflammation on histology cryptococcal antigenemia or cryptococcal meningitis while scal- • Pneumonitis ing up ART availability and distribution will undoubtedly lead to • C linical deterioration occurring early after anti- increasing fatalities of unmasking IRIS in an already vulnerable retroviral therapy initiation, within 3 months and severely immunocompromised population. Acknowledgments We thank Dr Noela Clara Owarwo and Dr. Martin Balaba at the Infectious receiving ART for >14  days [14]. ART-experienced persons Diseases Institute in Kampala, Uganda, for contributing a case for our man- with cryptococcal meningitis are not all the same, as the uscript. We would also like to thank the entire ASTRO-CM team for the timing of ART is crucial, and those with unmasking IRIS vs tireless and wonderful work that they do. We appreciate the institutional support provided by Prof. Paul Bohjanen and Dr Andrew Kambugu. virologic failure may differ vastly immunologically. While Financial support. This work was supported by the Fogarty dexamethasone was administered in case 3, it is unclear International Center (K01TW010268 and R25TW009345), the National whether this is an effective management strategy for the treat- Institute of Neurological Disorders and Stroke (R01NS086312), the National Institute of Allergy and Infectious Diseases (T32AI055433) of the ment of unmasking IRIS. While current evidence appears to National Institute of Health, and DELTAS Africa Initiative grant No. DEL- support a short course of corticosteroids in cases of severe 15-011 to THRiVE-2 (D.M.). paradoxical cryptococcal meningitis IRIS [15], there are lim- Potential conifl cts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of ited data to support corticosteroid use for unmasking IRIS. In Potential Conflicts of Interest. Conflicts that the editors consider relevant to a recent trial that included ART-experienced participants in the content of the manuscript have been disclosed. Southeast Asia and Sub-Saharan Africa, universal adjunctive dexamethasone did not provide benefit when added to stand- References ard antifungal therapy and was associated with more adverse 1. UNAIDS. Prevention Gap Report. UNAIDS; 2016. 2. Joint United Nations Programme on HIV/AIDS. Global AIDS Update 2016. events [9]. Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS; 2016. Immune reconstitution in the presence of cryptococcal dis- 3. World Health Organization. Guideline on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. WHO; 2015. ease should be a concern in centers where baseline CD4 testing 4. Zolopa AR, Andersen J, Komarow L, et  al. Early antiretroviral therapy reduces is unavailable and where routine CrAg screening has a delayed AIDS progression/death in individuals with acute opportunistic infections: a turnaround time or has not yet been implemented. In the absence multicenter randomized strategy Trial. PLoS ONE 2009; 4:e5575. doi:10.1371/ journal.pone.0005575 of a more streamlined approach to diagnosis, however, further 5. Boulware DR, Meya DB, Muzoora C, et al; COAT Trial Team. Timing of antiretroviral consideration may be given to the role of empiric fluconazole therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370:2487–98. 6. Rajasingham R, Smith RM, Park BJ, et  al. Global burden of disease of HIV- therapy pending results of CD4 and CrAg testing in cases where associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; ART is initiated immediately aer HIV di ft agnosis. Earlier stud- 17:873–81. 7. Ministry of Health. Consolidated Guidelines for Prevention and Treatment of ies have demonstrated that daily prophylaxis with fluconazole HIV in Uganda. Ministry of Health; 2016. is effective in reducing the risk of invasive cryptococcosis [16]. 8. World Health Organization. Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy. Geneva, Switzerland: WHO; 2017. Most recently, an enhanced prophylaxis regimen consisting 9. Beardsley J, Wolbers M, Kibengo FM, et al; CryptoDex Investigators. Adjunctive of fluconazole, trimethoprim–sulfamethoxazole, isoniazid– dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016; pyridoxine, azithromycin, and a single dose of albendazole was 374:542–54. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018 10. Haddow LJ, Colebunders R, Meintjes G, et al; International Network for the Study Retroviruses and Opportunistic Infections; February 23–26, 2015; Seattle, WA. of HIV-associated IRIS (INSHI). Cryptococcal immune reconstitution inflamma- Abstract Number 836. tory syndrome in HIV-1-infected individuals: proposed clinical case definitions. 15. Perfect JR, Dismukes WE, Dromer F, et  al. Clinical practice guidelines for the Lancet Infect Dis 2010; 10:791–802. doi:10.1016/S1473-3099(10)70170-5 management of cryptococcal disease: 2010 update by the Infectious Diseases 11. Williamson PR. The relentless march of cryptococcal meningitis. Lancet Infect Society of America. Clin Infect Dis 2010; 50:291–322. Dis 2017; 17:790–1. 16. Powderly WG, Finkelstein D, Feinberg J, et  al. A randomized trial com- 12. Rhein J, Morawski BM, Hullsiek KH, et al; ASTRO-CM Study Team. Efficacy of paring fluconazole with clotrimazole troches for the prevention of fun- adjunctive sertraline for the treatment of HIV-associated cryptococcal meningi- gal infections in patients with advanced human immunodeficiency tis: an open-label dose-ranging study. Lancet Infect Dis 2016; 16:809–18. virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995; 13. Longley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflam- 332:700–5. matory syndrome. Curr Opin Infect Dis 2013; 26:26–34. 17. Hakim J, Musiime V, Szubert AJ, et al; REALITY Trial Team. Enhanced proph- 14. Rhein J, Hullsiek KH, Bahr NC, et al. Detrimental outcomes of unmasking crypto- ylaxis plus antiretroviral therapy for advanced HIV infection in Africa. N Engl J coccal meningitis with recent ART initiation. Paper presented at: Conference on Med 2017; 377:233–45. 4 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx274/4774678 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Open Forum Infectious DiseasesOxford University Press

Published: Jan 1, 2018

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