Subphenotypes of self-reported symptoms and outcomes in long COVID: a prospective cohort study with latent class analysis.

OBJECTIVE: To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC). DESIGN: Prospective, observational cohort study of subjects with PASC. SETTING: Academic tertiary centre from five clinical referral sources. PARTICIPANTS: Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19. EXPOSURES: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR. OUTCOMES MEASURES: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load. RESULTS: We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6-11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1-6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. CONCLUSIONS: We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease.

Background: Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30-50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives: This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results: While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion: While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.

A Chest Pain Conundrum: Dapsone-Induced Methemoglobinemia in a Heart Transplant Patient.

We present the case of a 39-year-old male with a past medical history of orthotopic heart transplantation who presented with chest pain and dyspnea on exertion. He was diagnosed with dapsone-induced methemoglobinemia toward the end of his hospital course, and his condition clinically improved with the discontinuation of the offending agent. This case highlights the importance of medication review and history-taking. Clinicians should be mindful of dapsone-induced methemoglobinemia, especially when encountering patients with dyspnea and a history of dapsone intake.

Sepsis in Immunocompromised Host and a Hematologic Complication.

CASE PRESENTATION: A 43-year-old Puerto Rican man with a kidney transplant presented to the ED with 2 weeks of flu-like symptoms, nausea, and vomiting. He had plasma exchange therapy 2 months before for acute transplant rejection and has been tolerating a heightened immunosuppressive regimen. CT scans characterized opacities as possibly early tree-in-bud opacities (Fig 1A). Patient remained stable throughout hospital stay with an unremarkable workup and was discharged with doxycycline for nonspecific pneumonia.

Inter-rater reliability and prognostic value of baseline Radiographic Assessment of Lung Edema (RALE) scores in observational cohort studies of inpatients with COVID-19.

OBJECTIVES: To reliably quantify the radiographic severity of COVID-19 pneumonia with the Radiographic Assessment of Lung Edema (RALE) score on clinical chest X-rays among inpatients and examine the prognostic value of baseline RALE scores on COVID-19 clinical outcomes. SETTING: Hospitalised patients with COVID-19 in dedicated wards and intensive care units from two different hospital systems. PARTICIPANTS: 425 patients with COVID-19 in a discovery data set and 415 patients in a validation data set. PRIMARY AND SECONDARY OUTCOMES: We measured inter-rater reliability for RALE score annotations by different reviewers and examined for associations of consensus RALE scores with the level of respiratory support, demographics, physiologic variables, applied therapies, plasma host-response biomarkers, SARS-CoV-2 RNA load and clinical outcomes. RESULTS: Inter-rater agreement for RALE scores improved from fair to excellent following reviewer training and feedback (intraclass correlation coefficient of 0.85 vs 0.93, respectively). In the discovery cohort, the required level of respiratory support at the time of CXR acquisition (supplemental oxygen or non-invasive ventilation (n=178); invasive-mechanical ventilation (n=234), extracorporeal membrane oxygenation (n=13)) was significantly associated with RALE scores (median (IQR): 20.0 (14.1-26.7), 26.0 (20.5-34.0) and 44.5 (34.5-48.0), respectively, p<0.0001). Among invasively ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, soluble receptor of advanced glycation end-products and soluble tumour necrosis factor receptor 1 (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted HR 1.04 (1.02-1.07), p=0.002). We replicated the significant associations of RALE scores with baseline disease severity and mortality in the independent validation data set. CONCLUSIONS: With a reproducible method to measure radiographic severity in COVID-19, we found significant associations with clinical and physiologic severity, host inflammation and clinical outcomes. The incorporation of radiographic severity assessments in clinical decision-making may provide important guidance for prognostication and treatment allocation in COVID-19.

Cryptococcus neoformans Presenting as a Lung Mass in an Immunocompromised Patient.

BACKGROUND Pulmonary cryptococcosis is an uncommon infection mainly affecting immunocompromised individuals. Presentation of cryptococcal disease ranges from asymptomatic pulmonary colonization to severe pneumonia. It can progress to acute respiratory failure and life-threatening meningoencephalitis. CASE REPORT A 55-year-old woman with a history of a kidney transplant, on immunosuppressive therapy, presented to the hospital with persistent low-grade fever, headache, weight loss, and fatigue for 2 weeks. On arrival, she was tachycardic, normotensive, and saturating 99% on room air. Her chest X-ray showed right middle lung opacity measuring 1.9×2.8 cm. She was admitted and started on broad-spectrum antibiotics for suspected pneumonia. Her chest computed tomography (CT) scan showed a 3.0×1.7 cm hypo-dense opacity at the right upper lobe. Overnight, she developed a severe headache and neck stiffness. Her serum cryptococcal antigen and cerebrospinal fluid culture results were positive. The patient was started on intravenous liposomal amphotericin B plus flucytosine. A CT-guided lung biopsy was performed to rule out malignancy. Cultures came back positive for Cryptococcus neoformans. She completed a 2-week course of amphotericin and flucytosine and was switched to oral fluconazole to complete an 8-week course. CONCLUSIONS Prompt diagnosis and effective management of the cryptococcal disease can decrease morbidity and mortality. Diagnosis requires CT-guided lung biopsy, with culture growing mucoid colonies of Cryptococcus neoformans. Antifungal therapy with intravenous liposomal amphotericin B plus flucytosine is the mainstay of treatment. Clinicians should be aware of the various presentations of pulmonary cryptococcosis, especially in immunocompromised patients.

Milk-Alkali Syndrome: How Electronic Medical Record Open Notes Helped to Rule Out Cancer.

BACKGROUND Milk-alkali syndrome is caused by excessive consumption of calcium and absorbable alkali and typically presents as a triad of hypercalcemia, acute renal failure, and metabolic alkalosis. In the era of histamine receptor blockers and proton pump inhibitors, the incidence of milk-alkali syndrome has decreased. However, the disease has not been eliminated, due to existing calcium-containing therapies. Here, we present a case of severe milk-alkali syndrome with a challenging initial diagnosis. CASE REPORT We present the case of a 64-year-old man who came to the hospital with encephalopathy. Serologic evaluation revealed acute renal failure, severe hypercalcemia, and metabolic alkalosis. He underwent volume resuscitation, with the initiation of calcitonin. Despite our efforts, the patient developed anuria and proceeded to intermittent hemodialysis. His workup was unrevealing, including an appropriately suppressed parathyroid hormone level, low vitamin D, and normal serum protein electrophoresis and angiotensin converting enzyme levels. Considering his persistent encephalopathy, the team was unable to obtain information from the patient regarding his calcium intake. However, at home, the patient's significant other read his progress notes in the electronic medical record and reported that he consumed at least 1 bottle of calcium carbonate (Tums) every week. Once the encephalopathy resolved, the patient confirmed this information. CONCLUSIONS The search for malignancy in the setting of hypercalcemia was ceased because of the family's at-home electronic medical record use and reporting of Tums overuse. Milk-alkali syndrome, although a rarity, should not be forgotten as a cause of hypercalcemia.

Radiographic Assessment of Lung Edema (RALE) Scores are Highly Reproducible and Prognostic of Clinical Outcomes for Inpatients with COVID-19.

INTRODUCTION: Chest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs). METHODS: We performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens. RESULTS: We found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, p<0.0001). Among invasively-ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, sRAGE and TNFR1 levels (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted hazard ratio 1.04[1.02-1.07], p=0.002). We validated significant associations of RALE scores with baseline severity and mortality in an independent dataset of 415 COVID-19 inpatients. CONCLUSION: Reproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.