Immunodeficient Patients Research Articles

An educational program for trainees in serving underserved primary immunodeficiency patients

Despite increasing awareness of barriers to healthcare, disparity of care in primary immune deficiency is a reality. Many of the clinical imperatives are larger in scope: political advocacy for newborn screening programs, establishing more centers of excellence in hematopoietic stem cell transplantation in impoverished areas, and combating systemic injustice. However, achieving these objectives depends on training a new generation of committed clinical immunologists.

Tixagevimab-Cilgavimab Rollout on Common Variable Immunodeficient Patients: Early Lessons from an Academic Allergy and Immunology Clinic

Tixagevimab-cilgavimab is a combination of two monoclonal antibodies against SARS-CoV-2. In December 2021, the FDA issued emergency use authorization for intramuscular injection of tixagevimab-cilgavimab for prophylaxis against SARS-CoV-2 in immunocompromised patients. Shortly thereafter, our clinic distributed tixagevimab-cilgavimab to patients with Common Variable Immunodeficiency (CVID). To our knowledge, no prior study has looked at effects of this monoclonal antibody combination on CVID patients.

Disseminated nontuberculous mycobacterial infection in a patient with idiopathic CD4 lymphocytopenia and IFN-γ neutralizing antibodies: a case report

BackgroundDisseminated nontuberculous mycobacterial (NTM) infection usually occurs in immunodeficient patients, such as those with human immunodeficiency virus infection and idiopathic CD4 lymphopenia. However, disseminated NTM diseases have also been reported in immunocompetent patients. Autoantibodies to interferon-gamma (IFN-γ) are known to be involved in disseminated NTM disease, although anti-IFN-γ antibodies are mainly seen in immunocompetent patients rather than those with immunodeficiency. Here, we report a rare case of disseminated NTM patient with idiopathic CD4 lymphopenia and anti-IFN-γ antibodies.Case presentationA 64-year-old Asian male presented with fever, back pain, anorexia and weight loss. Physical examination revealed subcutaneous masses in the forehead, sternoclavicular joint, and right inguinal region. Computed tomography showed multiple osteosclerotic changes with soft structures and osteolytic changes. Both blood and sputum cultures were positive for Mycobacterium intracellulare, confirming the presence of disseminated NTM infection. Histopathological evaluation of the subcutaneous mass in the right inguinal region showed numerous granulomas consisting of epithelioid cells with Langhans-type giant cells. He was diagnosed with idiopathic CD4 lymphocytopenia. Interestingly, he also had anti-IFN-γ autoantibodies with suppression of IFN-γ-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation. Two-drug combination therapy with clarithromycin and ethambutol was started for the NTM infection, which resulted in a favorable disease course.ConclusionsIn patients with disseminated NTM infection, idiopathic CD4 lymphocytopenia and anti-IFN-γ autoantibody-positive immunodeficiency can be coexisted. It is necessary to clarify the pathogenesis and clinical course of CD4 lymphocytopenic conditions and IFN-γ neutralizing antibody-positive in the disseminated NTM disease.

Past, current, and potential treatments for cryptosporidiosis in humans and farm animals: A comprehensive review.

The intracellular protozoan parasite of the genus Cryptosporidium is among the leading causes of waterborne diarrheal disease outbreaks throughout the world. The parasite is transmitted by ingestion of infective oocysts that are highly stable in the environment and resistant to almost all conventional disinfection methods and water treatments. Control of the parasite infection is exceedingly difficult due to the excretion of large numbers of oocysts in the feces of infected individuals that contaminate the environment and serve as a source of infection for susceptible hosts including humans and animals. Drug development against the parasite is challenging owing to its limited genetic tractability, absence of conventional drug targets, unique intracellular location within the host, and the paucity of robust cell culture platforms for continuous parasite propagation. Despite the high prevalence of the parasite, the only US Food and Drug Administration (FDA)-approved treatment of Cryptosporidium infections is nitazoxanide, which has shown moderate efficacy in immunocompetent patients. More importantly, no effective therapeutic drugs are available for treating severe, potentially life-threatening cryptosporidiosis in immunodeficient patients, young children, and neonatal livestock. Thus, safe, inexpensive, and efficacious drugs are urgently required to reduce the ever-increasing global cryptosporidiosis burden especially in low-resource countries. Several compounds have been tested for both in vitro and in vivo efficacy against the disease. However, to date, only a few experimental compounds have been subjected to clinical trials in natural hosts, and among those none have proven efficacious. This review provides an overview of the past and present anti-Cryptosporidium pharmacotherapy in humans and agricultural animals. Herein, we also highlight the progress made in the field over the last few years and discuss the different strategies employed for discovery and development of effective prospective treatments for cryptosporidiosis.

Clinical and Genetic Characteristics of BCG Disease in Chinese Children: a Retrospective Study.

Summarize the characteristics of a large cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and patients without identified genetic etiology. We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID), and gene negative group. A total of 134 patients were reviewed, and most of them had PID. A total of 111 (82.8%) patients had 18 different types of pathogenic gene mutations, most of whom (91.0%) were classified with CGD, MSMD, and SCID. CYBB was the most common gene mutation (52/111). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P < 0.001), age at diagnosis (P = 0.013), frequency of recurrent fever (P = 0.007), and vaccination-homolateral axillary lymph node enlargement (P = 0.039) and infection severity (P = 0.006) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (48.3%). The course of anti-tuberculosis treatment and the survival time between patients with PID and without identified genetic etiology were similar. Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Patients without identified genetic etiology had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered.

Synergistic Anticandidal Activities of Greenly Synthesized ZnO Nanomaterials with Commercial Antifungal Agents against Candidal Infections.

The high occurrence of mycological resistance to conventional antifungal agents results in significant illness and death rates among immunodeficient patients. In addition, the underprivileged therapeutic results of conventional antifungal agents, besides the potential toxicity resulting from long term therapy necessitate the fabrication of efficient antimicrobial combinations. Hence, the objective of the present investigation is to synthesize, characterize and investigate the anticandidal action of green zinc oxide nanoparticles (ZnO-NPs) formulated using Camellia sinensis leaf extract against three candidal pathogens. The eco-friendly synthesized ZnO-NPs were characterized utilizing different physicochemical methods and their anticandidal potency was tested utilizing a disk diffusion assay. In this setting, the size of the biofabricated ZnO-NPs was detected using transmission electron microscope (TEM) micrographs, recording an average particle size of 19.380 ± 2.14 nm. In addition, zeta potential analysis revealed that the ZnO-NPs surface charge was -4.72 mV. The biogenic ZnO-NPs reveal the highest anticandidal activity against the C. tropicalis strain, demonstrating relative suppressive zones measured at 35.16 ± 0.13 and 37.87 ± 0.24 mm in diameter for ZnO-NPs concentrations of 50 and 100 μg/disk, respectively. Excitingly, Candida glabrata showed a high susceptibility to the biofabricated ZnO nanomaterials at both ZnO-NPs' concentrations (50 and 100 μg/disk) compared to the control. Moreover, the biosynthesized ZnO-NPs revealed potential synergistic effectiveness with nystatin and terbinafine antifungal agents against the concerned strains. The maximum synergistic efficiency was noticed against the C. glabrata strain, demonstrating relative synergistic percentages of 23.02 and 45.9%, respectively. The biogenic ZnO-NPs revealed no hemolytic activity against human erythrocytes revealing their biosafety and hemocompatibility. Finally, the high anticandidal effectiveness of biogenic ZnO-NPs against the concerned candidal pathogens, as well as potential synergistic patterns with conventional antifungal agents such as nystatin and terbinafine, emphasize the prospective application of these combinations for the fabrication of biocompatible and highly efficient antifungal agents.

Riboflavin Targets the Cellular Metabolic and Ribosomal Pathways of Candida albicans In Vitro and Exhibits Efficacy against Oropharyngeal Candidiasis.

Oropharyngeal candidiasis (OPC), which has a high incidence in immunocompromised and denture stomatitis patients, is commonly caused by Candida albicans infection and in some cases develops into disseminated candidiasis throughout the throat and esophagus, resulting in high mortality. New drugs are needed to combat OPC because of the limited treatment options currently available and increasing resistance to existing drugs. Here, we confirmed that riboflavin (RF), a cofactor of flavin adenine mononucleotide and flavin adenine dinucleotide, has broad-spectrum anti-Candida activity. The formation of C. albicans hyphae and biofilm was inhibited by RF. Mechanistically, RF disrupted membrane and cell wall integrity, as well as promoting reactive oxygen species and pyruvate accumulation. Furthermore, RF targeted multiple essential pathways via functional disruption of thiamine and RF metabolic pathways, central carbon metabolism, and ribosome metabolism. Similar to the results in vitro, the inhibitory effect of RF on C. albicans hyphae was confirmed in a mouse model of OPC. Moreover, after 5 consecutive days of intraperitoneal injection, RF exhibited therapeutic efficacy, as demonstrated by phenotype investigation, the fungal burden, and histopathological analysis. These findings revealed that RF exerts a multifaceted anti-Candida effect and has potential benefits in the treatment of OPC. IMPORTANCE Candida species are common pathogens in fungal infections, causing mucosal infection and invasive infection in immunodeficient patients. Given the limited classes of drugs and resistance to these drugs, new antifungal agents need to be developed. Drug repurposing is a potential method for antifungal drug development. This study demonstrated that riboflavin (RF) exhibited broad-spectrum anti-Candida activity. RF affected multiple targets involving the membrane and cell wall integrity, the accumulation of reactive oxygen species and pyruvate, and the altered metabolic pathways in C. albicans. Moreover, RF exhibited efficacy in the treatment of C. albicans in an oropharyngeal candidiasis mouse model. Taken together, the antifungal activity and the promising clinical application of RF were highlighted.

Advances and Challenges in Diagnostics of Toxoplasmosis in HIV-Infected Patients.

Toxoplasma gondii is a worldwide distributed protozoan parasite. This apicomplexan parasite infects one-third of the population worldwide, causing toxoplasmosis, considered one of the neglected parasitic infections. In healthy humans, most infections are asymptomatic. However, in immunocompromised patients, the course of the disease can be life-threatening. Human immunodeficiency virus (HIV)-infected patients have a very high burden of Toxoplasma gondii co-infection. Thus, it is essential to use modern, sensitive, and specific methods to properly monitor the course of toxoplasmosis in immunodeficient patients.

Advances in research on virulence factors of Acinetobacter baumannii and their potential as novel therapeutic targets.

Acinetobacter baumannii is a strictly aerobic, non-motile, non-fermenting, gram-negative bacillus. It is a highly infectious and invasive pathogen with high mortality and morbidity rates among immunodeficient patients. Due to increasing levels of drug resistance and the inefficiency of existing antimicrobial treatments, it is crucial to develop novel agents to control this pathogen. Several recent studies have investigated virulence factors that are associated with the pathogenesis of A. baumannii, and could thus serve as novel therapeutic targets. The present review comprehensively summarizes the current understanding of these virulence factors and their mechanisms in A. baumannii. We also highlight factors that could be potential therapeutic targets, as well as list candidate virulence factors for future researchers and clinical practitioners.

Primary Cardiac Burkitt’s Lymphoma- A Deadlock

Burkitt’s lymphoma is a high-grade, extremely aggressive form of B-cell non Hodgkin lymphoma with a very fast replication time (tumour doubling time of around 25 hours). The three forms of Burkitt’s lymphoma are documented which include endemic, sporadic, and immunodeficiency associated. It is enormously rare with less than 30 cases reported till date. Primary cardiac lymphoma is a rare cardiac neoplasm. The most common type is diffuse large B-cell lymphoma. Diagnosis is usually late and with poor prognosis. Primary cardiac lymphoma is more common in immunodeficient patients. This is a case of primary cardiac Burkitt’s lymphoma which was diagnosed in a 58-year-old immunocompetent male. The patient’s two-dimensional echocardiography and plain Computed Tomography (CT) scan of the chest revealed presence of massive pericardial effusion with mild to moderate bilateral pleural effusion. Cardiac Positron Emission Tomography (PET) CT revealed a soft tissue mass at atrioventricular groove which indicated either pericardial lymphoma or inflammatory serositis. The patient was opted for surgery, but the mass was noted involving the free wall of right ventricle including the diaphragmatic surface which extended onto atrioventricular groove and base of right atrial appendage. Thus, a decision to not proceed further with surgical repair was made. The histopathological and cytogenetic findings confirmed the presence of Burkitt's lymphoma. Later, it was discovered that the patient died within one month of diagnosis.

P334: Not all severe combined immunodeficiency patients are created equal and when rapid genetic testing matters

P334: Not all severe combined immunodeficiency patients are created equal and when rapid genetic testing matters

The examination of family functioning in immunodeficiency patients in the context of McMaster family therapy in Turkey

ABSTRACT Immunodeficiency diseases associated with the absence or dysfunction of any of the components that make up the immune system. These diseases may create difficulties for family functionality. The study aims to examine family functionality in the context of McMaster Family Therapy in families with immunodeficiency patients. The study include 153 family members from Immunodeficiency Patients Solidarity Platform in Turkey. The sociodemographic questionnaire and McMaster Family Assessment Device were used to collect data with respect to problem solving, communication, roles, affective responsiveness and involvement, behaviour control, and general functioning. The majority of the participants are married, females, university graduates and low income. Most of them have nuclear families and a diagnosis of primary immunodeficiency in children. Areas of non-healthy family functionality include affective involvement and behaviour control. Also, problem-solving, roles, and communication create risks in terms of dysfunction.

Interstitial Lung Disease in Immunocompromised Children.

The range of pulmonary complications beyond infections in pediatric immunocompromised patients is broad but not well characterized. Our goal was to assess the spectrum of disorders with a focus on interstitial lung diseases (ILD) in immunodeficient patients. We reviewed 217 immunocompromised children attending a specialized pneumology service during a period of 23 years. We assigned molecular diagnoses where possible and categorized the underlying immunological conditions into inborn errors of immunity or secondary immunodeficiencies according to the IUIS and the pulmonary conditions according to the chILD-EU classification system. Among a wide array of conditions, opportunistic and chronic infections were the most frequent. ILD had a 40% prevalence. Of these children, 89% had a CT available, and 66% had a lung biopsy, which supported the diagnosis of ILD in 95% of cases. Histology was often lymphocyte predominant with the histo-pattern of granulomatous and lymphocytic interstitial lung disease (GLILD), follicular bronchiolitis or lymphocytic interstitial pneumonitis. Of interest, DIP, PAP and NSIP were also diagnosed. ILD was detected in several immunological disorders not yet associated with ILD. Specialized pneumological expertise is necessary to manage the full spectrum of respiratory complications in pediatric immunocompromised patients.

CD8+ T Cells Trigger Auricular Dermatitis and Blepharitis in Mice after Zika Virus Infection in the Absence of CD4+ T Cells

Zika virus (ZIKV) became a public health concern when it re-emerged in 2015 owing to its ability to cause congenital deformities in the fetus and neurological complications in adults. Despite extensive data on protection, the interplay of protective and pathogenic adaptive immune responses toward ZIKV infection remains poorly understood. In this study, using a T-cell‒deficient mouse model that retains persistent ZIKV viral titers in the blood and organs, we show that the adoptive transfer of CD8+ T cells led to a significant reduction in viral load. This mouse model reveals that ZIKV can induce grossly visible auricular dermatitis and blepharitis, mediated by ZIKV-specific CD8+ T cells. Single-cell RNA sequencing of these causative CD8+ T cells from the ears shows an overactivated and elevated cytotoxic signature in mice with severe symptoms. Our results strongly suggest a role for CD8+ T-cell‒associated pathologies after ZIKV infection in CD4+ T-cell‒immunodeficient patients.

ASCENIV utilization in a primary immunodeficiency patient with recurrent viral infections

Primary immunodeficiency (PI) patients may still experience persistent viral and bacterial respiratory infections with ongoing treatments. We report a challenging case of a PI patient who experienced recurrent viral respiratory infections despite receiving standard immunoglobulin replacement therapy. The patient was subsequently managed with immune globulin intravenous, human-slra (ASCENIV™) that contains elevated antibodies against multiple respiratory pathogens. The patient demonstrated significant clinical improvement with a resolution of persistent and debilitating viral respiratory infections and associated sequela.

Effect of Early Bacillus Calmette-Guerin Vaccination of Pediatric Severe Combined Immunodeficiency Patients on the Outcome of Hematopoietic Stem Cell Transplantation Using a Reduced-Intensity Conditioning Regimen

The eminence of Bacillus Calmette-Guerin (BCG) vaccine in newborn vaccination programs has been conspicuous throughout the years, especially in low-income developing countries where tuberculosis is prevalent; however, application of the BCG vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as severe combined immunodeficiency (SCID). The present study aimed to evaluate whether the administration of BCG vaccine at birth could improve the outcomes of hematopoietic stem cell transplantation (HSCT) in pediatric patients with SCID. In this study, 30 SCID patients who underwent HSCT using a reduced-intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcomes of HSCT were evaluated in both non-BCG-vaccinated patients (n = 12) and BCG-vaccinated patients (n = 18). Our results show a higher incidence of acute graft-versus-host disease (aGVHD), but not of chronic GVHD, in the BCG-vaccinated patients, and a similar overall survival (OS) rate in the 2 groups. We speculate that the similar OS rate in the 2 groups, despite the risk of BGC vaccination, was because this group received an RIC conditioning regimen. There was no other difference between the 2 groups. Considering the effect of the BCG vaccine on HSCT outcome, we suggest that the administration of BCG vaccine be deferred until age 3 months so that APT testing without the interference of maternal antibodies can be performed. However, this study could benefit from a larger cohort to further validate our findings, as the possible reason for some factors not being statistically significant was our small sample size.

Knowledge, Attitudes, and Practices of Allergists/Immunologists Regarding Transition of Care for Primary Immunodeficiency Patients.

Only some allergists/immunologists provide care throughout the lifespan despite their training. Although transition of care (TOC) guidelines exist, research on provider perspectives on TOC for pediatric primary immunodeficiency (PID) patients is lacking. We aimed to characterize knowledge, attitudes, and practices and establish clinician needs using a needs assessment survey. The 15-min online survey was adapted from an existing rheumatology TOC survey and was emailed to the American Academy of Allergy Asthma and Immunology (AAAAI) and Clinical Immunology Society (CIS) members. Our primary hypothesis was that both AAAAI and CIS providers report being underprepared for TOC and would express interest in TOC resources and consensus. Forty-nine of 1250 eligible AAAAI and 67 of 698 eligible CIS participants completed the survey (4.8% vs 11.3% participation rate). Many (53.1% vs 59.7%) respondents transition their own patients but also retain adult patients (59.2% vs 52.2%). Many accepted transition patients (85.7% vs 92.5%). In total, 24.1% of respondents did not have a TOC policy while 18.9% have an informal policy. Only 25.0% were satisfied with their current practices while 43.9% agreed that a consensus statement would be useful. Despite a small sample size and high rate of unanswered questions, our findings show that TOC remains overlooked in our specialty and that providers want and need additional training and resources. There is a clear need to develop and evaluate the effectiveness of evidence-based TOC guidelines, resources, and best practices for PID patients.

Clinical and virological characteristics of viral shedding in children with norovirus gastroenteritis.

The correlation between the clinical manifestations and fecal viral load of norovirus (NoV) infection remains unknown. We established a SYBR® Green-based real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method to quantify NoV and then sequenced its genomes from the feces of patients admitted at the Chang Gung Memorial Hospital from 2017 to 2018. NoV GII.4 Sydney (n=21, 36.2%) and GII.P16-GII.2 (n=19, 32.8%), the two predominant genotypes found among 58 isolates, were closely related to the Taiwan variant 2012a cluster in the VP1 region and genotypes of China strain. An increase in viral load could be observed on Day 3 following the onset of NoV infection. The viral load then declined rapidly from days 10-15 but remained high for >1 month in a severe combined immunodeficiency patient. Significantly longer shedding was found in patients with fever (p=0.03) or infected by the GII.4 Sydney strain (p<0.01). The qRT-PCR-mediated method proposed in this work could quantify the viral load in patients with NoV infection. Significant viral shedding over a period of 2 weeks in children with acute gastroenteritis and >1 month in an immunodeficient patient was observed. Significantly longer shedding could be correlated with infection by the GII.4 Sydney strain and febrile patients.

Evaluation of Panfungal Polymerase Chain Reaction in Early Detection of Invasive Fungal Infections in Egyptian Patients with Hematological Malignancies.

The incidence of invasive fungal infections (IFIs) has increased owing to the rising number of immunodeficient patients. A case-control study was performed at the Ain Shams University Hospitals, Cairo, Egypt. The case group (n = 80) included 80 patients diagnosed with hematological malignancies, and the control group (n = 20) included 20 patients. All patients were tested for the presence of fungal species using blood culture and panfungal real-time polymerase chain reaction (RT-PCR). Fungal species differentiation was performed using high-resolution melting (HRM) PCR. There were 39 suspected cases of IFIs among the 80 patients. The panfungal RT-PCR detection rate was 51.3% (41/80). HRM-PCR identified that 51.2% of the fungal species were Candida albicans, 44.0% were non-Candida albicans, and 4.9% were Mucor. The blood cultures were positive for the presence of fungi in two patients with acute myeloid leukemia. The fungal detection rate using the panfungal RT-PCR technique was significantly higher than that using the blood culture technique (P < 0.001). RT-PCR using panfungal markers is sensitive, rapid, and superior to the blood culture technique to detect IFIs. HRM-PCR is a specific test for species identification.

Molnupiravir: From Hope to Epic Fail?

Molnupiravir has been the first oral antiviral authorized for COVID-19 outpatients, reporting extraordinary sales and preserved in vitro efficacy against Omicron sublineages so far. However, it has recently been associated with very poor clinical efficacy, the risk of creating novel SARS-CoV-2 variants of concern, and long-term risk for mutagenicity in humans. The latter two are severe concerns, especially in the indicated population, i.e., long-replicating, immunodeficient patients. We conclude that, at this point, alternative antivirals should be preferred over molnupiravir.