SARS-CoV-2 not Detected in the Nasopharyngeal Sample but in Bronchoalveolar Lavage Fluid.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection typically relies on reverse transcription-polymerase chain reaction (RT-PCR) technology. However, there is a certain rate of missed detection of SARS-CoV-2 in nasopharyngeal samples, particularly among immunosuppressed individuals. METHODS: In this case, SARS-CoV-2 was detected in nasopharyngeal swabs and bronchoalveolar lavage fluid (BALF) using RT-PCR. Pulmonary imaging was performed using computed tomography (CT). Patient clinical data were retrieved from the Laboratory Information System (LIS). RESULTS: SARS-CoV-2 was negative in two nasopharyngeal tests of the patient, but was finally detected in BALF, confirming that the lung lesions were infected by SARS-CoV-2. CONCLUSIONS: In the post-epidemic era, it is necessary to use BALF to identify SARS-CoV-2 infection in cases where other factors have been ruled out in immunosuppressed individuals with pulmonary infections, especially when the nasopharyngeal test yields a negative result.

Pulmonary Nocardiosis in Renal Transplant Recipients From Pakistan: Risk Factors, Clinical Presentation, and Mortality.

OBJECTIVES: Nocardia is an opportunistic infection among renal transplant recipients with an incidence of <1% but high mortality. Data from Pakistan are scarce. Our aim was to find the risk factors, clinical and radiographic findings, antimicrobial sensitivity, and outcomes of Nocardia infection among renal transplant recipients in Pakistan. MATERIALS AND METHODS: All adult renal transplant recipients diagnosed with nocardiosis between 2013 and 2020 were included. The cases were matched 1:2 with controls based on sex, age (±1 year), and transplant date (±1 year). Risk factors, clinical features, antibiotic sensitivities and outcomes were analyzed. RESULTS: A total of 48 patients developed nocardiosis. Around 25% of patients presented with disseminated disease. Median time from transplant to disease development was 2.68 years. High-dose methylprednisolone and presence of cytomegalovirus infection within 90 days of disease development were independent risk factors for Nocardia infection. The mortality rate was 20%. Central nervous system disease and cytomegalovirus infection within 90 days were significantly associated with mortality. The most susceptible drugs were co-trimoxazole and linezolid. Imipenem susceptibility was only 20%. CONCLUSIONS: High-dose methylprednisolone and cytomegalovirus infection were independent risk factors for Nocardia infection. Central nervous system disease was associated with mortality. Nocardia species were highly resistant to ceftriaxone and imipenem in our patient population.

[Lactobacillemia: A Rare Entity in Immunocompromised Patients. Description of a Clinical Case and Literature Review].

Bacteremia caused by Lactobacillus is rare, data on its clinical significance are based only on case reports and a limited number of studies, often difficult to interpret. Lactobacillus species is a commensal colonizer of the mouth, gastrointestinal and genitourinary tract. Its significance as a pathogen is overlooked frequently. The diagnosis of these infections requires a mutual relationship between the physician and the microbiologist to rule out contamination risk. Most patients with Lactobacillus bacteremia are immunosuppressed or patients at increased risk of symptomatic bacteremia with comorbidities, treated with broad-spectrum antibiotics and have indwelling venous catheters. Risk factors related to Lactobacillus bacteremia include impaired host defenses and severe underlying diseases, as well as prior surgery and prolonged antibiotic therapy ineffective for lactobacilli. We describe an unusual case of a woman, on chronic hemodialysis treatment, with a sepsis due to Lactobacillus casei and review the literature.

Transfusion-related acute lung injury (TRALI) following intravenous immunoglobulin infusion in a rituximab immunosuppressed patient with long-shedding SARS-CoV-2.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported. CASE PRESENTATION: A 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI. CONCLUSION: IVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected.

Haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis in a patient with leprosy.

Multidrug therapy has significantly reduced the global burden of Hansen's disease; however, complications from long-term treatment persist. A male resident of southern Kentucky, in his 30s and of Micronesian descent, presented with worsening abdominal pain associated with anorexia, fatigue, functional decline and occasional haemoptysis. He was compliant with multidrug therapy for leprosy. Laboratory investigations revealed pancytopenia. He was initially treated under a sepsis protocol and later switched to high-dose steroids due to a suspected immune reaction from missed corticosteroid doses. Despite aggressive treatment for refractory pancytopenia, the patient's condition deteriorated, and he passed away from cardiac arrest. Posthumous bone marrow biopsy revealed haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis with bone marrow infiltration. This case highlights the importance of proactive fungal screening in immunocompromised leprosy patients, particularly in endemic regions, as early detection and timely intervention can prevent severe complications.

A second-generation recombinant BCG strain combines protection against murine tuberculosis with an enhanced safety profile in immunocompromised hosts.

Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). While BCG protects against TB in children, its protection against pulmonary TB in adults is suboptimal, and the development of a better TB vaccine is a global health priority. Previously, we reported two recombinant BCG strains effective against murine TB with low virulence and lung pathology in immunocompromised mice and guinea pigs. We have recently combined these two recombinant BCG strains into one novel vaccine candidate (BCGΔBCG1419c::ESAT6-PE25SS) and evaluated its immunogenicity, efficacy and safety profile in mice. This new vaccine candidate is non-inferior to BCG in protection against TB, presents reduced pro-inflammatory immune responses and displays an enhanced safety profile.

Hepatitis E virus immunosuppressed animal models.

Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.

Prolonged COVID-19 Pneumonitis and Severe Lung Injury in a Patient with a History of Diffuse Large B-cell Lymphoma after CAR-T Therapy: Highlighting the Role of Corticosteroids.

INTRODUCTION: COVID-19 can have severe consequences for immunocompromised individuals, including those with hematological malignancies. Prolonged infections causing pneumonia and lung injury are rare in patients with diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR-T). CASE PRESENTATION: A 43-year-old male with a history of DLBCL, in remission for 2 years after CAR-T therapy, developed a persistent COVID infection, as confirmed via positive polymerase chain reaction. This slowly progressed to symptomatic hypoxemic pneumonitis and biopsy-proven diffuse alveolar damage, which responded to corticosteroid treatment. DISCUSSION: COVID-19 poses increased risks to patients with a history of hematologic malignancies and can lead to severe respiratory distress and mortality. Studies have shown prolonged pneumonitis may require corticosteroids for improvement. However, data on appropriate regimen for managing prolonged COVID-19 pneumonitis are lacking. CONCLUSIONS: This case highlights challenges of the treatment of COVID-19 infections in immunocompromised individuals with hematological malignancies. Corticosteroid treatment shows benefits, but dosing and duration should be based on individual patient response. Extended monitoring, individualized treatment plans, and research are crucial for optimizing outcomes in this vulnerable population.

Mycobacterium abscessus Cutaneous Infection in the Immunosuppressed: A Case Report on an Atypical Pathogen.

Mycobacterium abscessus complex (MAbc) is a rapidly growing nontuberculous mycobacterium that represents an increasingly prevalent cause of skin infections. This report describes an atypical presentation of MAbc to heighten physician awareness of the pathogen. A 69-year-old woman with immunocompromised status presented with a 4-month history of a solitary, nonhealing ulcer on her right lower extremity after an insect bite. After no improvement following oral amoxicillin/clavulanate and topical mupirocin for the initial diagnosis of cellulitis, biopsy and culture of the lesion revealed MAbc. Microscopic examination revealed reactive cutaneous inflammation without evidence of malignancy. Acid-fast bacteria (AFB) stain was negative, and no granulomas were noted histologically. Clarithromycin and doxycycline were initiated while awaiting susceptibility testing results. Final culture showed MAbc sensitive to amikacin, cefoxitin, and clarithromycin. Unfortunately, before antibiotic therapy could be modified, the patient died. The presentation of a solitary lower-extremity ulcer is rare compared with current literature. This case occurred after a suspected insect bite rather than instrumentation. In addition, this case demonstrated negative AFB stain and absence of granulomas on histologic analysis. The patient's death did not allow for evaluation of treatment efficacy. Existing literature characterizing MAbc is sparse. Most cases present as multiple papules, nodules, and abscesses with positive AFB staining and granulomas; it is possible for deviations to exist depending on host immune status. Considering the highly drug-resistant nature of M abscessus, prompt diagnosis and treatment are crucial. For this to occur, clinicians must maintain high clinical suspicion for M abscessus infection in any chronic, nonhealing wound failing to respond to initial treatment.

RSV in transplant and immunocompromised patients.

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in infants, older adults, and patients with weakened immune systems. Disease severity differs by underlying immunologic pathologies, with worse outcomes associated with progression from upper to lower respiratory disease. In this review we address the impact of RSV in immunocompromised populations, and discuss the limited available treatments and the potential impact of newer RSV prevention strategies on immunocompromised adults and children.

Vaccination and Therapeutics.

In the wake of the novel Coronavirus, it has become imperative to develop vaccines that can alert our immune system to the virus, hence reducing the severity of disease if exposed to it. Different types of vaccines have been studied in this respect, such as nucleic acid vaccines (mRNA and DNA vaccines), vector-based vaccines, whole-virus vaccines (inactivated virus and live-attenuated vaccine), as well as protein subunits vaccines. The results have demonstrated that these vaccines are efficient against both the original strain and emerging variants. Furthermore, they also proved their safety with no grave adverse events. Despite this, hesitancy toward taking these vaccines is still present among certain groups in society due to various factors. Special emphasis has been placed on studies concerning pregnant women, children, elderly people, and immunocompromised individuals where efficacy and safety were proven.

What do we know About the Usefulness of 18F-FDG PET-CT for the Management of Invasive Fungal Infection? An International Survey.

BACKGROUND: Recent data support 18F-FDG PET-CT for the management of infections in immunocompromised patients, including invasive fungal infection (IFI). However, its role is not well established in clinical practice. We performed an international survey to evaluate the knowledge of physicians about the usefulness of 18F-FDG PET-CT in IFI, in order to define areas of uncertainty. METHODS: An online survey was distributed to infectious diseases working groups in December 2023-January 2024. It included questions regarding access to 18F-FDG PET-CT, knowledge on its usefulness for IFI and experience of the respondents. A descriptive analysis was performed. RESULTS: 180 respondents answered; 60.5% were Infectious Diseases specialists mainly from Spain (52.8%) and Italy (23.3%). 84.4% had access to 18F-FDG PET-CT at their own center. 85.6% considered that 18F-FDG PET-CT could be better than conventional tests for IFI. In the context of IFI risk, 81.1% would consider performing 18F-FDG PET-CT to study fever without a source and around 50% to evaluate silent lesions and 50% to assess response, including distinguishing residual from active lesions. Based on the results of the follow-up 18F-FDG PET-CT, 56.7% would adjust antifungal therapy duration. 60% would consider a change in the diagnostic or therapeutic strategy in case of increased uptake or new lesions. Uncovering occult lesions (52%) and diagnosing/excluding endocarditis (52.7%) were the situations in which 18F-FDG PET-CT was considered to have the most added value. There was a great variability in responses about timing, duration of uptake, the threshold for discontinuing treatment or the influence of immune status. CONCLUSION: Although the majority considered that 18F-FDG PET-CT may be useful for IFI, many areas of uncertainty remain. There is a need for protocolized research to improve IFI management.

Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections.

We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n = 15). All patients received remdesivir and some also received nirmatrelvir-ritonavir (n = 3) or therapeutic monoclonal antibodies (n = 4). Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient sequentially treated with nirmatrelvir-ritonavir and remdesivir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.

Case reports of persistent SARS-CoV-2 infection outline within-host viral evolution in immunocompromised patients.

BACKGROUND: SARS-CoV-2 is responsible for the ongoing global pandemic, and the continuous emergence of novel variants threatens fragile populations, such as immunocompromised patients. This subgroup of patients seems to be seriously affected by intrahost viral changes, as the pathogens, which are keen to cause replication inefficiency, affect the impaired immune system, preventing efficient clearance of the virus. Therefore, these patients may represent an optimal reservoir for the development of new circulating SARS-CoV-2 variants. The following study aimed to investigate genomic changes in SARS-CoV-2-positive immunocompromised patients over time. METHODS: SARS-CoV-2-positive nasopharyngeal swabs were collected at different time points for each patient (patient A and patient B), extracted and then analyzed through next-generation sequencing (NGS). The resulting sequences were examined to determine mutation frequencies, describing viral evolution over time. CASE PRESENTATION: Patient A was a 53-year-old patient with onco-hematological disease with prolonged infection lasting for 51 days from May 28th to July 18th, 2022. Three confirmed SARS-CoV-2-positive samples were collected on May 28th, June 15th and July 4th. Patient B was 75 years old and had onco-hematological disease with prolonged infection lasting for 146 days. Two confirmed positive SARS-CoV-2 samples were collected at the following time points: May 21st and August 18th. CONCLUSION: Heat map construction provided evidence of gain and/or loss of mutations over time for both patients, suggesting within-host genomic evolution of the virus. In addition, mutation polymorphisms and changes in the SARS-CoV-2 lineage were observed in Patient B. Sequence analysis revealed high mutational pattern variability, reflecting the high complexity of viral replication dynamics in fragile patients.

Disseminated MDR-TB missed in a patient treated with TNF inhibitor.

A previously healthy man developed pulmonary symptoms 2 weeks after starting treatment with a tumour necrosis factor (TNF) inhibitor. A negative interferon-gamma release assay (IGRA) test was obtained prior to TNF inhibitor exposure, without consideration of the fact that the patient was already immunosuppressed and had a previous positive IGRA test 17 months earlier. The patient was treated for pneumonia twice but did not achieve remission. His physical health progressively deteriorated over the following months. Malignancy was suspected but not found. Eight months after the onset of symptoms, Mycobacterium tuberculosis was found in samples from mediastinal lymph nodes, and the patient was diagnosed with multidrug-resistant tuberculosis (MDR-TB).This case illustrates the diagnostic challenge of TB, the need to raise awareness of the increased risk of TB in patients treated with TNF inhibitors and the need to increase knowledge regarding the effect of immunosuppressive agents on IGRA tests.

Epidemiology, pathogenesis, clinical characteristics, and treatment of mucormycosis: a review.

AIM: This review aims to summarize the epidemiology, etiology, pathogenesis, clinical manifestations, and current diagnostic and therapeutic approaches for mucormycosis. The goal is to improve understanding of mucormycosis and promote early diagnosis and treatment to reduce mortality. METHODS: A comprehensive literature review was conducted, focusing on recent studies and data on mucormycosis. The review includes an analysis of the disease's epidemiology, etiology, and pathogenesis, as well as current diagnostic techniques and therapeutic strategies. RESULTS: Mucormycosis is increasingly prevalent due to the growing immunocompromised population, the COVID-19 pandemic, and advances in detection methods. The pathogenesis is closely associated with the host immune status, serum-free iron levels, and the virulence of Mucorales. However, the absence of typical clinical manifestations complicates diagnosis, leading to missed or delayed diagnoses and higher mortality. CONCLUSION: An enhanced understanding of the epidemiology, pathogenesis, and clinical presentation of mucormycosis, along with the adoption of improved diagnostic and therapeutic approaches, is essential for reducing mortality rates associated with this opportunistic fungal infection. Early diagnosis and prompt treatment are critical to improving patient outcomes.

The incidence of mucormycosis has increased following the COVID-19 pandemic.The presence of the halo sign and reverse halo sign may indicate the onset of pulmonary mucormycosis.Early implementation of molecular diagnostic methods, such as mNGS and qPCR, may improve the early diagnosis rate of mucormycosis.Isavuconazole and posaconazole can also be considered as first-line treatments for the initial management of mucormycosis.

Application of metagenomic next-generation sequencing and targeted metagenomic next-generation sequencing in diagnosing pulmonary infections in immunocompetent and immunocompromised patients.

Background: Metagenomic next-generation sequencing (mNGS) technology has been widely used to diagnose various infections. Based on the most common pathogen profiles, targeted mNGS (tNGS) using multiplex PCR has been developed to detect pathogens with predesigned primers in the panel, significantly improving sensitivity and reducing economic burden on patients. However, there are few studies on summarizing pathogen profiles of pulmonary infections in immunocompetent and immunocompromised patients in Jilin Province of China on large scale. Methods: From January 2021 to December 2023, bronchoalveolar lavage fluid (BALF) or sputum samples from 546 immunocompetent and immunocompromised patients with suspected community-acquired pneumonia were collected. Pathogen profiles in those patients on whom mNGS was performed were summarized. Additionally, we also evaluated the performance of tNGS in diagnosing pulmonary infections. Results: Combined with results of mNGS and culture, we found that the most common bacterial pathogens were Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii in both immunocompromised and immunocompetent patients with high detection rates of Staphylococcus aureus and Enterococcus faecium, respectively. For fungal pathogens, Pneumocystis jirovecii was commonly detected in patients, while fungal infections in immunocompetent patients were mainly caused by Candida albicans. Most of viral infections in patients were caused by Human betaherpesvirus 5 and Human gammaherpesvirus 4. It is worth noting that, compared with immunocompetent patients (34.9%, 76/218), more mixed infections were found in immunocompromised patients (37.8%, 14/37). Additionally, taking final comprehensive clinical diagnoses as reference standard, total coincidence rate of BALF tNGS (81.4%, 48/59) was much higher than that of BALF mNGS (40.0%, 112/280). Conclusions: Our findings supplemented and classified the pathogen profiles of pulmonary infections in immunocompetent and immunocompromised patients in Jilin Province of China. Most importantly, our findings can accelerate the development and design of tNGS specifically used for regional pulmonary infections.