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Article ; Online: Monocyte to Lymphocyte ratio is highly specific in diagnosing latent tuberculosis and declines significantly following tuberculosis preventive therapy: A cross-sectional and nested prospective observational study.

Mayito, Jonathan / Meya, David B / Miriam, Akia / Dhikusooka, Flavia / Rhein, Joshua / Sekaggya-Wiltshire, Christine

2023 Volume 18, Issue 11, Page(s) e0291834

Abstract: Background: Interferon-gamma release assay and tuberculin skin test use is limited by costly sundries and cross-reactivity with non-tuberculous mycobacteria and Bacille Calmette-Guérin (BCG) vaccination respectively. We investigated the Monocyte to ... ...

Abstract	Background: Interferon-gamma release assay and tuberculin skin test use is limited by costly sundries and cross-reactivity with non-tuberculous mycobacteria and Bacille Calmette-Guérin (BCG) vaccination respectively. We investigated the Monocyte to Lymphocyte ratio (MLR) as a biomarker to overcome these limitations and for use in monitoring response to tuberculosis preventive therapy (TPT). Methods: We conducted a cross-sectional and nested prospective observational study among asymptomatic adults living with Human Immuno-deficiency Virus (HIV) in Kampala, Uganda. Complete blood count (CBC) and QuantiFERON-TB® Gold-plus were measured at baseline and CBC repeated at three months. Multivariable logistic regression was performed to identify factors associated with a high MLR and decline in MLR. Results: We recruited 110 adults living with HIV and on antiretroviral therapy, of which 82.5% (85/110) had suppressed viral loads, 71.8% (79/110) were female, and 73.6% (81/110) had a BCG scar. The derived MLR diagnostic cut-off was 0.35, based on which the MLR sensitivity, specificity, positive predictive value, and negative predictive value were 12.8%, 91.6%, 45.5%, and 65.7% respectively. The average MLR declined from 0.212 (95% CI: 0.190-0.235) at baseline to 0.182 (95% CI: 0.166-0.198) after three months of TPT. A viral load of >50 copies/ml (aOR, 5.67 [1.12-28.60]) was associated with a high MLR while that of <50 copies/ml (aOR, 0.07 [0.007-0.832]) was associated with a decline in MLR. Conclusion: MLR was highly specific in diagnosing latent TB and declined significantly following three months of TPT. Implications of a high MLR and decline in MLR after TPT need further evaluation in a larger cohort.
MeSH term(s)	Adult ; Humans ; Female ; Male ; Latent Tuberculosis/diagnosis ; Monocytes ; Cross-Sectional Studies ; BCG Vaccine ; Uganda/epidemiology ; Tuberculin Test ; Interferon-gamma Release Tests ; Lymphocytes ; HIV Infections
Chemical Substances	BCG Vaccine
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0291834
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: NK cell subsets and dysfunction during viral infection: a new avenue for therapeutics?

Bjorgen, Jacob C / Dick, Jenna K / Cromarty, Ross / Hart, Geoffrey T / Rhein, Joshua

Frontiers in immunology

2023 Volume 14, Page(s) 1267774

Abstract: In the setting of viral challenge, natural killer (NK) cells play an important role as an early immune responder against infection. During this response, significant changes in the NK cell population occur, particularly in terms of their frequency, ... ...

Abstract	In the setting of viral challenge, natural killer (NK) cells play an important role as an early immune responder against infection. During this response, significant changes in the NK cell population occur, particularly in terms of their frequency, location, and subtype prevalence. In this review, changes in the NK cell repertoire associated with several pathogenic viral infections are summarized, with a particular focus placed on changes that contribute to NK cell dysregulation in these settings. This dysregulation, in turn, can contribute to host pathology either by causing NK cells to be hyperresponsive or hyporesponsive. Hyperresponsive NK cells mediate significant host cell death and contribute to generating a hyperinflammatory environment. Hyporesponsive NK cell populations shift toward exhaustion and often fail to limit viral pathogenesis, possibly enabling viral persistence. Several emerging therapeutic approaches aimed at addressing NK cell dysregulation have arisen in the last three decades in the setting of cancer and may prove to hold promise in treating viral diseases. However, the application of such therapeutics to treat viral infections remains critically underexplored. This review briefly explores several therapeutic approaches, including the administration of TGF-β inhibitors, immune checkpoint inhibitors, adoptive NK cell therapies, CAR NK cells, and NK cell engagers among other therapeutics.
MeSH term(s)	Humans ; Killer Cells, Natural ; Virus Diseases/therapy ; Immunotherapy, Adoptive
Language	English
Publishing date	2023-10-19
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1267774
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Article: "False negative" CSF cryptococcal antigen with clinical meningitis: Case reports and review of literature.

Rutakingirwa, Morris K / Kiiza, Tadeo K / Rhein, Joshua

Medical mycology case reports

2020 Volume 29, Page(s) 29–31

Abstract: There is an increasing recognition of patients presenting with cryptococcal meningitis despite having a negative CSF cryptococcal antigen (CrAg). In this report, we describe three cases of patients with advanced immunosuppression who presented to ... ...

Abstract	There is an increasing recognition of patients presenting with cryptococcal meningitis despite having a negative CSF cryptococcal antigen (CrAg). In this report, we describe three cases of patients with advanced immunosuppression who presented to hospital with "false negative" CSF cryptococcal antigen, two of whom had a positive fungal culture. We describe the challenge of CSF-CrAg negative cryptococcal meningitis and explore ways to overcome this challenge using newer diagnostic techniques.
Language	English
Publishing date	2020-06-11
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2670415-8
ISSN	2211-7539
ISSN	2211-7539
DOI	10.1016/j.mmcr.2020.06.003
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Article: “False negative” CSF cryptococcal antigen with clinical meningitis: Case reports and review of literature

Rutakingirwa, Morris K / Kiiza, Tadeo K / Rhein, Joshua

Medical mycology case reports. 2020 Sept., v. 29

2020

Abstract	There is an increasing recognition of patients presenting with cryptococcal meningitis despite having a negative CSF cryptococcal antigen (CrAg). In this report, we describe three cases of patients with advanced immunosuppression who presented to hospital with “false negative” CSF cryptococcal antigen, two of whom had a positive fungal culture. We describe the challenge of CSF-CrAg negative cryptococcal meningitis and explore ways to overcome this challenge using newer diagnostic techniques.
Keywords	antigens ; case studies ; diagnostic techniques ; fungal culture ; hospitals ; immunosuppression ; literature ; meningitis ; mycology ; patients
Language	English
Dates of publication	2020-09
Size	p. 29-31.
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-light
ISSN	2211-7539
DOI	10.1016/j.mmcr.2020.06.003
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Article: The Impact of Chronic Pulmonary Aspergillosis Co-infection on the Health-Related Quality of Life of Patients with Pulmonary Tuberculosis in Uganda.

Namusobya, Martha / Bongomin, Felix / Mukisa, John / Batte, Charles / Olwit, William Kane / Rhein, Joshua / Sekaggya-Wiltshire, Christine / Prasad, Shailendra

Research square

2023

Abstract: Background Both pulmonary tuberculosis (PTB) and chronic pulmonary aspergillosis (CPA) significantly affect health-related quality of life (HR-QoL). We aimed to determine the impact of CPA co-infection on the HR-QoL of Ugandans with PTB. Methods We ... ...

Abstract	Background Both pulmonary tuberculosis (PTB) and chronic pulmonary aspergillosis (CPA) significantly affect health-related quality of life (HR-QoL). We aimed to determine the impact of CPA co-infection on the HR-QoL of Ugandans with PTB. Methods We conducted a prospective study among participants with PTB with persistent pulmonary symptoms after 2 months of anti-TB treatment at Mulago Hospital, Kampala, Uganda between July 2020 and June 2021. HR-QoL was assessed using St. George Respiratory Questionnaire (SGRQ) at enrollment and at the end of PTB treatment (4 months apart). SGRQ scores range from 0 to 100, with higher score representing a poorer HR-QoL. Results Of the 162 participants enrolled, 32 (19.8%) had CPA + PTB and 130 (80.2%) had PTB only. The baseline characteristics of the two groups were comparable. Regarding overall health, a higher proportion of the PTB only group rated their HR-QoL as "very good" compared to those who had both TB and CPA (68 (54.0%)
Language	English
Publishing date	2023-01-13
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2389854/v1
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Article ; Online: The Impact of Chronic Pulmonary Aspergillosis Co-infection on the Health-Related Quality of Life of Patients with Pulmonary Tuberculosis in Uganda.

Namusobya, Martha / Bongomin, Felix / Mukisa, John / Batte, Charles / Olwit, William Kane / Rhein, Joshua / Sekaggya-Wiltshire, Christine / Prasad, Shailendra

Mycopathologia

2023 Volume 188, Issue 5, Page(s) 713–720

Abstract: Background: Both pulmonary tuberculosis (PTB) and chronic pulmonary aspergillosis (CPA) significantly affect health-related quality of life (HR-QoL). We aimed to determine the impact of CPA co-infection on the HR-QoL of Ugandans with PTB.: Methods: ... ...

Abstract	Background: Both pulmonary tuberculosis (PTB) and chronic pulmonary aspergillosis (CPA) significantly affect health-related quality of life (HR-QoL). We aimed to determine the impact of CPA co-infection on the HR-QoL of Ugandans with PTB. Methods: We conducted a prospective study as part of a larger study among participants with PTB with persistent pulmonary symptoms after 2 months of anti-TB treatment at Mulago Hospital, Kampala, Uganda between July 2020 and June 2021. HR-QoL was assessed using St. George Respiratory Questionnaire (SGRQ) at enrollment and at the end of PTB treatment (4 months apart). SGRQ scores range from 0 to 100, with higher score representing a poorer HR-QoL. Results: Of the 162 participants enrolled in the larger study, 32 (19.8%) had PTB + CPA and 130 (80.2%) had PTB. The baseline characteristics of the two groups were comparable. Regarding overall health, a higher proportion of the PTB group rated their HR-QoL as "very good" compared to those who had PTB + CPA (68 [54.0%] versus 8 [25.8%]). At enrollment, both groups had comparable median SGRQ scores. However, at follow up, the PTB group had statistically significantly better SGRQ scores (interquartile range); symptoms (0 [0-12.4] versus 14.4 [0-42.9], p < 0.001), activity ((0 [0-17.1] versus 12.2 [0-35.5], p = .03), impact (0 [0-4.0] versus 3.1 [0-22.5], p = 0.004), and total scores ((0 [0-8.5] versus 7.6[(0-27.4], p = 0.005). Conclusion: CPA co-infection impairs HR-QoL of people with PTB. Active screening and management of CPA in patients with PTB is recommended to improve HR-QoL of these individuals.
Language	English
Publishing date	2023-05-17
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391081-7
ISSN	1573-0832 ; 0369-299X ; 0301-486X ; 0027-5530
ISSN (online)	1573-0832
ISSN	0369-299X ; 0301-486X ; 0027-5530
DOI	10.1007/s11046-023-00741-1
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Article ; Online: Culture-negative cryptococcal meningitis.

Ssebambulidde, Kenneth / Skipper, Caleb / Rhein, Joshua

The Lancet. Infectious diseases

2019 Volume 19, Issue 9, Page(s) 929–930

MeSH term(s)	Adult ; Botswana ; Cohort Studies ; Cryptococcus ; Humans ; Meningitis ; Meningitis, Cryptococcal
Language	English
Publishing date	2019-09-03
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(19)30442-6
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Article ; Online: Utility of the monocyte to lymphocyte ratio in diagnosing latent tuberculosis among HIV-infected individuals with a negative tuberculosis symptom screen.

Mayito, Jonathan / Meya, David B / Rhein, Joshua / Sekaggya-Wiltshire, Christine

PloS one

2020 Volume 15, Issue 11, Page(s) e0241786

Abstract: Background: Latent Tuberculosis Infection (LTBI) remains a major driver of the TB epidemic, and individuals with Human Immuno-deficiency Virus (HIV) are particularly at a heightened risk of developing LTBI. However, LTBI screening among HIV-infected ... ...

Abstract	Background: Latent Tuberculosis Infection (LTBI) remains a major driver of the TB epidemic, and individuals with Human Immuno-deficiency Virus (HIV) are particularly at a heightened risk of developing LTBI. However, LTBI screening among HIV-infected individuals in resource limited setting is largely based on a negative symptom screen, which has low specificity. Methods: In a cross sectional diagnostic study, 115 HIV infected participants with a negative symptom screen will be consented and enrolled. They will be requested to donate 5 ml of blood for complete blood count (CBC) and interferon gamma release assay (IGRA) testing. In a nested prospective study, the 115 participants will be initiated on Tuberculosis Preventive Therapy and the CBC testing repeated after 3 months. In the analysis of study finding, the monocyte to lymphocyte ratio (MLR) will be derived from the dividend of the absolute monocyte and lymphocyte counts. The optimal MLR positivity cut-off for elevated or normal MLR will be the highest value of Youden's index, J (sensitivity + specificity-1). The MLR will be cross tabulated with the IGRA status to determine the sensitivity, specificity, negative and positive predictive values of the MLR. The area under the receiver operating characteristic (ROC) curve will be determined to give the overall diagnostic accuracy of MLR. The baseline and 3 month CBC will be used to determine the change in MLR, and a random effect logistic regression will be used to determine factors associated with the change in the MLR. Discussion: If positive results are realized from this study, the MLR could become an inexpensive alternative biomarker with potential to improve the specificity of the negative symptom screen in identifying individuals that should be targeted for TB preventive therapy.
MeSH term(s)	Adult ; Cross-Sectional Studies ; Female ; HIV Infections/immunology ; Humans ; Interferon-gamma Release Tests ; Latent Tuberculosis/metabolism ; Lymphocytes/cytology ; Male ; Middle Aged ; Monocytes/cytology ; Prospective Studies ; ROC Curve ; Tuberculosis/immunology
Language	English
Publishing date	2020-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0241786
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Article: High Burden of Cryptococcal Meningitis Among Antiretroviral Therapy-Experienced Human Immunodeficiency Virus-Infected Patients in Northern Uganda in the Era of "Test and Treat": Implications for Cryptococcal Screening Programs.

Okwir, Mark / Link, Abigail / Rhein, Joshua / Obbo, John Stephen / Okello, James / Nabongo, Betty / Alal, Jimmy / Meya, David / Bohjanen, Paul R

Open forum infectious diseases

2022 Volume 9, Issue 2, Page(s) ofac004

Abstract: Background: The impact of the "test and treat" program for human immunodeficiency virus (HIV) treatment in rural areas of Uganda on cryptococcal antigen (CrAg) screening or cryptococcal meningitis (CM) is poorly understood.: Methods: We ... ...

Abstract	Background: The impact of the "test and treat" program for human immunodeficiency virus (HIV) treatment in rural areas of Uganda on cryptococcal antigen (CrAg) screening or cryptococcal meningitis (CM) is poorly understood. Methods: We retrospectively evaluated clinical factors in 212 HIV-infected patients diagnosed with CM from February of 2017 to November of 2019 at Lira Regional Referral Hospital in northern Uganda. Results: Among 212 patients diagnosed with CM, 58.5% were male. Median age was 35 years; CD4 count and HIV viral load (VL) were 86 cells/μL and 9463 copies/mL, respectively. Only 10% of patients had a previous history of CM. We found that 190 of 209 (90.9%) patients were ART experienced and 19 (9.1%) were ART naive. Overall, 90 of 212 (42.5%) patients died while hospitalized (median time to death, 14 days). Increased risk of death was associated with altered mental status (hazard ratio [HR], 6.6 [95% confidence interval {CI}, 2.411-18.219]; Conclusions: Current guidelines recommend CrAg screening based on low CD4 counts for ART-naive patients and VL or clinical failure for ART-experienced patients. Using current guidelines for CrAg screening, some ART-experienced patients miss CrAg screening in resource-limited settings, when CD4 or VL tests are unavailable. We found that the majority of HIV-infected patients with CM were ART experienced (90.9%) at presentation. The high burden of CM in ART-experienced patients supports a need for improved CrAg screening of ART-exposed patients.
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofac004
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Article ; Online: Safety and virologic impact of haploidentical NK cells plus IL-2 or N-803 in HIV infection.

Miller, Jeffrey S / Rhein, Joshua / Davis, Zachary B / Cooley, Sarah / McKenna, David / Anderson, Jodi / Escandón, Kevin / Wieking, Garritt / Reichel, Jarrett / Thorkelson, Ann / Jorstad, Siri / Safrit, Jeffrey T / Soon-Shiong, Patrick / Beilman, Gregory J / Chipman, Jeffrey G / Schacker, Timothy W

The Journal of infectious diseases

2024

Abstract: Background: NK cells are dysfunctional in chronic HIV infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by IL-2 or IL-15, could decrease virus-producing cells in the lymphatic tissues.: Methods: We ...

Abstract	Background: NK cells are dysfunctional in chronic HIV infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by IL-2 or IL-15, could decrease virus-producing cells in the lymphatic tissues. Methods: We conducted a phase 1 pilot study in 6 persons living with HIV (PLHIV), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). Results: The approach was well tolerated with no unexpected adverse events. We did not pre-treat recipients with cyclophosphamide or fludarabine to "make immunologic space", reasoning that PLHIV on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (like what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA+ cells in lymph nodes. Conclusion: There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy.
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad578
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