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Felix Bongomin,1,2 Senai Goitom Sereke,3 Jerom Okot,2 Ronald Katsigazi,1 Tadeo Kiiza Kandole,4 Anthony Oriekot,5 Ronald Olum,1 Angella Atukunda,6 Joseph Baruch Baluku,5 Frederick Nakwagala6 1Department of Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda; 2Department of Medical Microbiology and Immunology, Faculty of Medicine, Gulu University, Gulu, Uganda; 3Department of Radiology and Radiotherapy, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda; 4Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda; 5Division of Pulmonology, Kiruddu National Referral Hospital, Kampala, Uganda; 6Department of Medicine, Mulago National Referral Hospital, Kampala, UgandaCorrespondence: Felix BongominDepartment of Medical Microbiology and Immunology, Faculty of Medicine, Gulu University, Gulu, UgandaTel +256-784-523-395Email drbongomin@gmail.comBackground: Several viral, bacterial and fungal co-infections have been associated with increased morbidity and mortality among patients with COVID-19. We report a fatal case of severe COVID-19 pneumonia in a patient with a recent diagnosis of advanced HIV disease complicated by cryptococcal meningitis, disseminated tuberculosis and acute ischemic stroke.Case Presentation: A 37-year-old Ugandan woman was diagnosed with HIV infection 8 days prior to her referral to our center. She was antiretroviral naïve. Her chief complaints were worsening cough, difficulty in breathing, fever and altered mental status for 3 days with a background of a 1-month history of coughing with associated drenching night sweats and weight loss. The reverse transcriptase–polymerase chain reaction for SARS-CoV-2 of her nasopharyngeal swab sample was positive. Chest radiograph demonstrated military pattern involvement of both lungs. The serum and cerebrospinal fluid cryptococcal antigen tests were positive. Urine lipoarabinomannan and sputum GeneXpert were positive for Mycobacterium tuberculosis. Computed tomography of the brain showed a large acute ischemic infarct in the territory of the right middle cerebral artery. Regardless of the initiation of treatment, that is, fluconazole 1200 mg once daily, enoxaparin 60 mg, intravenous (IV) dexamethasone 6 mg once daily, oral fluconazole 1200 mg once daily, IV piperacillin/tazobactam 4.5 g three times daily and oxygen therapy, the patient passed on within 36 hours of admission.Conclusion: Co-infections worsen COVID-19 outcomes.Keywords: COVID-19, HIV, cryptococcal meningitis, stroke, tuberculosis, co-infection

Background: Mortality associated with HIV-associated cryptococcal meningitis remains high even in the context of clinical trials (24-45% at 10 weeks); mortality at 12-months is up to 78% in resource limited settings. Co-prevalent tuberculosis (TB) is common and preventable, and likely contributes to poor patient outcomes. Innovative strategies to increase TB preventative therapy (TPT) provision and uptake within this high-risk group are needed., Protocol: The IMPROVE trial (Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease) is a nested open label, two arm, randomised controlled strategy trial to evaluate the safety (adverse events) and feasibility (adherence and tolerability) of two ultra-short course TPT strategies, in the context of recent diagnosis and treatment for cryptococcal meningitis. We will enrol 205 adults with HIV-associated cryptococcal meningitis from three hospitals in Uganda. Participants will be randomised to either inpatient initiation (early) or outpatient initiation (standard, week 6) of 1HP (one month of isoniazid and rifapentine). Participant follow-up is to include TB screening, 1HP pill counts and tolerability reviews on alternate weeks until week-18. The trial primary endpoint is TB-disease free 1HP treatment completion at 18-weeks, secondary endpoints: 1HP treatment completion, 1HP discontinuation, grade ≥3 adverse events and serious adverse events, drug-induced liver injury, incident active TB, 18-week survival; rifapentine, fluconazole and dolutegravir concentrations will be measured with intensive sampling in a pharmacokinetic sub-study of 15 eligible participants., Discussion: The IMPROVE trial will provide preliminary safety and feasibility data to inform 1HP TPT strategies for adults with advanced HIV disease and cryptococcal meningitis. The potential impact of demonstrating that inpatient initiation of 1HP TPT is safe and feasible amongst this high-risk subpopulation with advanced HIV disease, would be to expand the range of clinical encounters in which clinicians can feasibly provide 1HP, and therefore increase the reach of TPT as a preventative intervention., Isrctn Registration: ISRCTN18437550 (05/11/2021)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Ellis J et al.)

Background: Quantitative culture is the most common method to determine the fungal burden and sterility of cerebrospinal fluid (CSF) among persons with cryptococcal meningitis. A major drawback of cultures is a long turnaround-time. Recent evidence demonstrates that live and dead Cryptococcus yeasts can be distinguished using trypan blue staining. We hypothesized that trypan blue staining combined with haemocytometer counting may provide a rapid estimation of quantitative culture count and detection of CSF sterility. To test this, we evaluated 194 CSF specimens from 96 HIV-infected participants with cryptococcal meningitis in Kampala, Uganda. Cryptococcal meningitis was diagnosed by CSF cryptococcal antigen (CRAG). We stained CSF with trypan blue and quantified yeasts using a haemocytometer. We compared the haemocytometer readings versus quantitative Cryptococcus CSF cultures., Results: Haemocytometer counting with trypan blue staining had a sensitivity of 98% (64/65), while CSF cultures had a sensitivity of 95% (62/65) with reference to CSF CRAG for diagnostic CSF specimens. For samples that were positive in both tests, the haemocytometer had higher readings compared to culture. For diagnostic specimens, the median of log 10 transformed counts were 5.59 (n = 64, IQR = 5.09 to 6.05) for haemocytometer and 4.98 (n = 62, IQR = 3.75 to 5.79) for culture; while the overall median counts were 5.35 (n = 189, IQR = 4.78-5.84) for haemocytometer and 3.99 (n = 151, IQR = 2.59-5.14) for cultures. The percentage agreement with culture sterility was 2.4% (1/42). Counts among non-sterile follow-up specimens had a median of 5.38 (n = 86, IQR = 4.74 to 6.03) for haemocytometer and 2.89 (n = 89, IQR = 2.11 to 4.38) for culture. At diagnosis, CSF quantitative cultures correlated with haemocytometer counts (R 2  = 0.59, P < 0.001). At 7-14 days, quantitative cultures did not correlate with haemocytometer counts (R 2  = 0.43, P = 0.4)., Conclusion: Despite a positive correlation, the haemocytometer counts with trypan blue staining did not predict the outcome of quantitative cultures in patients receiving antifungal therapy.