An international report on bacterial communities in esophageal squamous cell carcinoma.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Clinical outcomes and serologic response in solid organ transplant recipients with COVID-19: A case series from the United States.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features, disease course, and serologic response of COVID-19 among immunosuppressed patients such as solid organ transplant (SOT) recipients, who are at presumed risk for more severe disease, are not well characterized. We describe our institutional experience with COVID-19 among 10 SOT patients, including the clinical presentation, treatment modalities, and outcomes of 7 renal transplant recipients, 1 liver transplant recipient, 1 heart transplant recipient, and 1 lung transplant recipient. In addition, we report the serologic response in SOT recipients, documenting a positive IgG response in all 7 hospitalized patients. We also review the existing literature on COVID-19 in SOT recipients to consolidate the current knowledge on COVID-19 in the SOT population for the transplant community.

Cardiac Tropism of Borrelia burgdorferi: An Autopsy Study of Sudden Cardiac Death Associated with Lyme Carditis.

Fatal Lyme carditis caused by the spirochete Borrelia burgdorferi rarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology. Interstitial lymphocytic pancarditis in a relatively characteristic road map distribution was present in all cases. Cardiomyocyte necrosis was minimal, T cells outnumbered B cells, plasma cells were prominent, and mild fibrosis was present. Spirochetes in the cardiac interstitium associated with collagen fibers and co-localized with decorin. Rare spirochetes were seen in the leptomeninges of two cases by immunohistochemistry. Spirochetes were not seen in other organs examined, and joint tissue was not available for evaluation. Although rare, sudden cardiac death caused by Lyme disease might be an under-recognized entity and is characterized by pancarditis and marked tropism of spirochetes for cardiac tissues.

Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in the United Arab Emirates, April 2014.

Middle East respiratory syndrome coronavirus (MERS-CoV) infection causes an acute respiratory illness and is associated with a high case fatality rate; however, the pathogenesis of severe and fatal MERS-CoV infection is unknown. We describe the histopathologic, immunohistochemical, and ultrastructural findings from the first autopsy performed on a fatal case of MERS-CoV in the world, which was related to a hospital outbreak in the United Arab Emirates in April 2014. The main histopathologic finding in the lungs was diffuse alveolar damage. Evidence of chronic disease, including severe peripheral vascular disease, patchy cardiac fibrosis, and hepatic steatosis, was noted in the other organs. Double staining immunoassays that used anti-MERS-CoV antibodies paired with immunohistochemistry for cytokeratin and surfactant identified pneumocytes and epithelial syncytial cells as important targets of MERS-CoV antigen; double immunostaining with dipeptidyl peptidase 4 showed colocalization in scattered pneumocytes and syncytial cells. No evidence of extrapulmonary MERS-CoV antigens were detected, including the kidney. These results provide critical insights into the pathogenesis of MERS-CoV in humans.

Rickettsia parkeri Rickettsiosis, Arizona, USA.

In the United States, all previously reported cases of Rickettsia parkeri rickettsiosis have been linked to transmission by the Gulf Coast tick (Amblyomma maculatum). Here we describe 1 confirmed and 1 probable case of R. parkeri rickettsiosis acquired in a mountainous region of southern Arizona, well beyond the recognized geographic range of A. maculatum ticks. The likely vector for these 2 infections was identified as the Amblyomma triste tick, a Neotropical species only recently recognized in the United States. Identification of R. parkeri rickettsiosis in southern Arizona demonstrates a need for local ecologic and epidemiologic assessments to better understand geographic distribution and define public health risk. Education and outreach aimed at persons recreating or working in this region of southern Arizona would improve awareness and promote prevention of tickborne rickettsioses.

Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses.

Ebola viruses and Marburg viruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers, with case fatality rates in the range 25-90%. The diagnosis of filovirus using formalin-fixed tissues from fatal cases poses a significant challenge. The most characteristic histopathological findings are seen in the liver; however, the findings overlap with many other viral and non-viral haemorrhagic diseases. The need to distinguish filovirus infections from other haemorrhagic fevers, particularly in areas with multiple endemic viral haemorrhagic agents, is of paramount importance. In this review we discuss the current state of knowledge of filovirus infections and their pathogenesis, including histopathological findings, epidemiology, modes of transmission and filovirus entry and spread within host organisms. The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system, with release of pro-inflammatory cytokines, chemokines and growth factors, endothelial dysfunction, alterations of the innate and adaptive immune systems, direct organ and endothelial damage from unrestricted viral replication late in infection, and coagulopathy. Although our understanding of the pathogenesis of filovirus infections has rapidly increased in the past few years, many questions remain unanswered.

Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement--Connecticut, 2014.

In October 2014, a hospital in Connecticut notified CDC and the Connecticut Department of Public Health of a fatal case of gastrointestinal mucormycosis in a preterm infant. The infant, born at 29 weeks' gestation and weighing 1,400 grams (about 3 pounds), had developed signs and symptoms initially consistent with necrotizing enterocolitis approximately 1 week after birth. Exploratory laparotomy revealed complete ischemia of the gastrointestinal tract from the esophagus to the rectum; a portion of necrotic cecum was sent for microscopic examination. Following surgery, the infant developed multiple areas of vascular occlusion, including a large clot in the aorta, findings not usually associated with necrotizing enterocolitis. The infant died soon after. Histopathology results from the resected cecum revealed an angioinvasive fungal infection consistent with mucormycosis. Gastrointestinal mucormycosis is an extremely rare fungal infection caused by mold in the order Mucorales. It occurs predominantly in low birth weight infants, patients with diarrhea and malnutrition, and those receiving peritoneal dialysis; mortality is 85%. Local investigation revealed that the infant had received a dietary supplement, ABC Dophilus Powder, for 7 days, beginning on day 1 of life.

Rapid differentiation of estrogen receptor status in patient biopsy breast cancer aspirates with an optical nanosensor.

Breast cancer is a substantial source of morbidity and mortality worldwide. It is particularly more difficult to treat at later stages, and treatment regimens depend heavily on both staging and the molecular subtype of the tumor. However, both detection and molecular analyses rely on standard imaging and histological method, which are costly, time-consuming, and lack necessary sensitivity/specificity. The estrogen receptor (ER) is, along with the progesterone receptor (PR) and human epidermal growth factor (HER-2), among the primary molecular markers which inform treatment. Patients who are negative for all three markers (triple negative breast cancer, TNBC), have fewer treatment options and a poorer prognosis. Therapeutics for ER+ patients are effective at preventing disease progression, though it is necessary to improve the speed of subtyping and distribution of rapid detection methods. In this work, we designed a near-infrared optical nanosensor using single-walled carbon nanotubes (SWCNT) as the transducer and an anti-ERα antibody as the recognition element. The nanosensor was evaluated for its response to recombinant ERα in buffer and serum prior to evaluation with ER- and ER+ immortal cell lines. We then used a minimal volume of just 10 µL from 26 breast cancer biopsy samples which were aspirated to mimic fine needle aspirates. 20 samples were ER+, while 6 were ER-, representing 13 unique patients. We evaluated the potential of the nanosensor by investigating several SWCNT chiralities through direct incubation or fractionation deployment methods. We found that the nanosensor can differentiate ER- from ER+ patient biopsies through a shift in its center wavelength upon sample addition. This was true regardless of which of the three SWCNT chiralities we observed. Receiver operating characteristic area under the curve analyses determined that the strongest classifier with an AUC of 0.94 was the (7,5) chirality after direct incubation and measurement, and without further processing. We anticipate that further testing and development of this nanosensor may push its utility toward field-deployable, rapid ER subtyping with potential for additional molecular marker profiling.

Rapid Onsite Evaluation for Specimen Adequacy and Triage of Breast Masses in a Low-Resource Setting.

CONTEXT.­: Rapid onsite evaluation (ROSE) is critical in determining sample adequacy and triaging cytology samples. Although fine-needle aspiration biopsy (FNAB) is the primary method of initial tissue sampling in Tanzania, ROSE is not practiced. OBJECTIVE.­: To investigate the performance of ROSE in determining cellular adequacy and providing preliminary diagnoses in breast FNAB in a low-resource setting. DESIGN.­: Patients with breast masses were recruited prospectively from the FNAB clinic at Muhimbili National Hospital. Each FNAB was evaluated by ROSE for overall specimen adequacy, cellularity, and preliminary diagnosis. The preliminary interpretation was compared to the final cytologic diagnosis and histologic diagnosis, when available. RESULTS.­: Fifty FNAB cases were evaluated, and all were adequate for diagnosis on ROSE and final interpretation. Overall percentage of agreement (OPA) between preliminary and final cytologic diagnosis was 84%, positive percentage of agreement (PPA) was 33%, and negative percentage of agreement (NPA) was 100% (κ = 0.4, P < .001). Twenty-one cases had correlating surgical resections. OPA between preliminary cytologic and histologic diagnoses was 67%, PPA was 22%, and NPA was 100% (κ = 0.2, P = .09). OPA between final cytologic and histologic diagnoses was 95%, PPA was 89%, and NPA was 100% (κ = 0.9, P = <.001). CONCLUSIONS.­: False-positive rates of ROSE diagnoses for breast FNAB are low. While preliminary cytologic diagnoses had a high false-negative rate, final cytologic diagnoses had overall high concordance with histologic diagnoses. Therefore, the role of ROSE for preliminary diagnosis should be considered carefully in low-resource settings, and it may need to be paired with additional interventions to improve pathologic diagnosis.

A roadmap to establishing global oncology as a priority initiative within a National Cancer Institute-designated cancer center.

As the burden of cancers impacting low- and middle-income countries is projected to increase, formation of strategic partnerships between institutions in high-income countries and low- and middle-income country institutions may serve to accelerate cancer research, clinical care, and training. As the US National Cancer Institute and its Center for Global Health continue to encourage cancer centers to join its global mission, academic cancer centers in the United States have increased their global activities. In 2015, the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, responded to the call for international partnership in addressing the global cancer burden through the establishment of the Global Cancer Program as a priority initiative. In developing the Global Cancer Program, we galvanized institutional support to foster sustained, bidirectional, equitable, international partnerships in global cancer control. Our focus and intent in disseminating this commentary is to share experiences and lessons learned from the perspective of a US-based, National Cancer Institute-designated cancer center and to provide a roadmap for other high-income institutions seeking to strategically broaden their missions and address the complex challenges of global cancer control. Herein, we review the formative evaluation, governance, strategic planning, investments in career development, funding sources, program evaluation, and lessons learned. Reflecting on the evolution of our program during the first 5 years, we observed in our partners a powerful shift toward a locally driven priority setting, reduced dependency, and an increased commitment to research as a path to improve cancer outcomes in resource-constrained settings.

Assessment of Breast Pathology Reporting Needs and Development of Tumor Synoptic Templates in Sub-Saharan Africa.

CONTEXT.­: Breast pathology reports include many important details to guide clinical management. Reports with missing critical data elements are commonly seen in non-subspecialized pathology practices. The use of synoptic templates has been shown to improve pathology reports. Although synoptic templates are readily available by professional societies, many are not tailored to low-resource settings. OBJECTIVE.­: To perform an assessment of current breast pathology reporting at 3 referral hospitals in sub-Saharan Africa and design a locally adapted breast cancer synoptic template. DESIGN.­: We conducted semi-structured interviews with key stakeholders involved in breast cancer care including pathologists, radiologists, oncologists, and surgeons from Nigeria, Tanzania, and Mozambique. Moreover, each stakeholder reviewed a preliminary synoptic template that was compiled by using templates from the College of American Pathologists, Royal College of Pathologists, and International Collaboration on Cancer Reporting, and was asked to score each data element as essential, optional, or exclude. A locally adapted synoptic template was then designed from the needs assessment. Using the adapted templates, a retrospective review of breast cancer pathology reports from 2020 to 2022 was conducted to determine the completeness of reports at the 3 institutions. RESULTS.­: A total of 17 physicians were interviewed. Review of pathology reports revealed that none of the reports across all 3 sites contained all data elements considered essential by local physicians. CONCLUSIONS.­: There is an urgent need to improve breast pathology reporting in sub-Saharan Africa. Development and implementation of synoptic templates in collaboration with key stakeholders has the potential to improve pathology reporting practices in low-resource settings.

Monoamniotic monochorionic twins discordant for noncompaction cardiomyopathy.

Occasionally "identical twins" are phenotypically different, raising the question of zygosity and the issue of genetic versus environmental influences during development. We recently noted monochorionic-monoamniotic twins, one of which had an isolated cardiac abnormality, noncompaction cardiomyopathy, a condition characterized by cardiac ventricular hypertrabeculation. We examined the prenatal course and subsequent pathologic correlation since ventricular morphogenesis may depend on early muscular contraction and blood flow. The monochorionic-monoamniotic female twin pair was initially identified since one fetus presented with increased nuchal translucency. Complete heart block was later identified in the fetus with nuchal translucency who did not survive after delivery. In contrast, the unaffected twin had normal cardiac studies both prenatally and postnatally. Pathologic analysis of the affected twin demonstrated noncompaction of the left ventricle with dysplasia of the aortic and pulmonary valves. Dissection of the cardiac conduction system disclosed atrioventricular bundle fibrosis. Maternal lupus studies, amniocentesis with karyotype, and studies for 22q11.2 were normal. To test for zygosity, we performed multiple STR marker analysis and found that all markers were shared even using nonblood tissues from the affected twin. These studies demonstrate that monozygotic twins that are monochorionic monoamniotic can be discordant for cardiac noncompaction. The results suggest further investigation into the potential roles of pathologic fibrosis, contractility, and blood flow in cardiac ventricle development.

Comparison of low-cost phantoms for ultrasound-guided fine-needle aspiration biopsy training.

INTRODUCTION: Phantoms and simulators are widely accepted methods to gain valuable experience and confidence for inexperienced trainees prior to seeing their patient and for refining their skills. A phantom model that is durable, simple, and inexpensive to produce and use would be ideal to train practitioners in ultrasound-guided fine-needle aspiration biopsy (USFNA) technique. MATERIALS AND METHODS: In this study, we systematically compared several low-cost phantom models including gelatin, extra firm tofu, canned cooked pork, ballistics gel, and chicken breast for their haptic properties, echogenicity, teaching utility, and overall performance based on a Likert scale (1-5; 5 = best). Nine cytopathologists and cytopathology fellows who perform FNA regularly evaluated these models and completed the survey. RESULTS: The gelatin phantom, with a gelatin to water ratio of 1:8 by weight, was found to be the best for USFNA practice and overall performance, followed by the 1:10 gelatin phantom. Tofu and chicken breast phantoms were also good low-cost alternatives that needed only a few minutes of total preparation time. CONCLUSIONS: Low-cost, homemade phantoms can serve as excellent alternatives to commercial phantoms for practicing and teaching USFNA.

Evaluation of Women With a Positive Urine Cytology and no Demonstrable Disease in the Urinary Tract.

Urinary cytology is indispensable both for the evaluation of gross hematuria and surveillance of patients with urothelial neoplasms. A positive urine cytology usually indicates the presence of urothelial carcinoma somewhere in the urinary tract. However, in women, it may also signal urothelial carcinoma involvement of the lower gynecologic tract or be the presenting sign for a primary cancer of the lower gynecologic tract or rectum. Guidelines for the evaluation of women with a positive cytology and normal urinary tract are lacking. We present a review of the current literature with case scenarios to bring clinicians attention to this diagnostic dilemma.

Human Papillomavirus-Associated Head and Neck Malignancies in Sub-Saharan Africa: A Systematic Review.

PURPOSE: The proportion of head and neck cancers (HNCs) with human papillomavirus (HPV) positivity in sub-Saharan Africa (SSA) is poorly characterized. Characterizing this has implications in staging, prognosis, resource allocation, and vaccination policies. This study aims to determine the proportion of HPV-associated HNC in SSA. MATERIALS AND METHODS: This systematic review included searches from PubMed, EMBASE, Web of Science, African Index Medicus, Google Scholar, and African Journals Online. All English publications reporting the proportion of HNC specimens from SSA patients who tested positive for HPV and/or p16 were included. Study quality was assessed using the National Institutes of Health Quality Assessment Tool for Case Series Studies. RESULTS: In this systematic review of 31 studies and 3,850 patients, the overall p16 positivity was 13.6% (41 of 1,037 patients tested) with the highest proportion among oropharyngeal cancers (20.3%, 78 of 384 patients) and the overall HPV polymerase chain reaction positivity was 15.3% (542 of 3,548 samples tested) with the highest proportion among nasopharyngeal cancers (16.5%, 23 of 139 patients). Among the 369 HPV strains detected, the most common genotypes were HPV 16 (226 patients, 59.2%) and HPV 18 (78, 20.4%). CONCLUSION: HPV was found to be associated with a significant proportion of HNC in SSA. The genotypes reported suggest that the nine-valent vaccine and gender-neutral vaccination policies should be considered. Given that these studies may not accurately capture prevalence nor causation of HPV in HNC subsites, additional research is needed to provide a more thorough epidemiologic understanding of HPV-associated HNC in SSA, including risk factors and clinical outcomes.

A Genomic Analysis of Esophageal Squamous Cell Carcinoma in Eastern Africa.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) comprises 90% of all esophageal cancer cases globally and is the most common histology in low-resource settings. Eastern Africa has a disproportionately high incidence of ESCC. METHODS: We describe the genomic profiles of 61 ESCC cases from Tanzania and compare them to profiles from an existing cohort of ESCC cases from Malawi. We also provide a comparison to ESCC tumors in The Cancer Genome Atlas (TCGA). RESULTS: We observed substantial transcriptional overlap with other squamous histologies via comparison with TCGA PanCan dataset. DNA analysis revealed known mutational patterns, both genome-wide as well as in genes known to be commonly mutated in ESCC. TP53 mutations were the most common somatic mutation in tumors from both Tanzania and Malawi but were detected at lower frequencies than previously reported in ESCC cases from other settings. In a combined analysis, two unique transcriptional clusters were identified: a proliferative/epithelial cluster and an invasive/migrative/mesenchymal cluster. Mutational signature analysis of the Tanzanian cohort revealed common signatures associated with aging and cytidine deaminase activity (APOBEC) and an absence of signature 29, which was previously reported in the Malawi cohort. CONCLUSIONS: This study defines the molecular characteristics of ESCC in Tanzania, and enriches the Eastern African dataset, with findings of overall similarities but also some heterogeneity across two unique sites. IMPACT: Despite a high burden of ESCC in Eastern Africa, investigations into the genomics in this region are nascent. This represents the largest comprehensive genomic analysis ESCC from sub-Saharan Africa to date.

Evaluation of Human Epidermal Growth Factor Receptor 2 Expression in Gastric and Gastroesophageal Cancers in Tanzania.

CONTEXT.­: The incidence of human epidermal growth factor receptor 2 (HER2) positivity in gastric cancers differs widely across various populations and is unknown in many low-resource settings. OBJECTIVE.­: To evaluate the rates of HER2 positivity in gastric and gastroesophageal adenocarcinoma at a national referral hospital in East Africa. We also assessed the association between HER2 overexpression and patient clinicopathologic characteristics. DESIGN.­: A retrospective review of cases diagnosed as either gastric or gastroesophageal adenocarcinoma between 2013 and 2017 was performed at Muhimbili National Hospital in Dar es Salaam, Tanzania. Of 1205 specimens meeting inclusion criteria, stratified random sampling was conducted to select 150 cases for HER2 immunohistochemistry and clinicopathologic analysis. RESULTS.­: The median age of patients was 56.5 years, with 65.3% (98 of 150) of the cohort composed of male patients, and 34.7% (52 of 150) of female patients. HER2 overexpression was identified in 6.0% (9 of 150) of cases. Approximately half of the tumors (51.3%; 77 of 150) were intestinal-type gastric adenocarcinoma, and 36.0% (54 of 150) were moderately differentiated. Intestinal-type (P = .01) and well-differentiated tumors (P = .001) were associated with HER2 overexpression. CONCLUSIONS.­: HER2 overexpression was primarily seen in intestinal-type and well-differentiated tumors. Therefore, prioritizing HER2 testing for patients with intestinal-type, well-differentiated, or moderately differentiated gastric and gastroesophageal adenocarcinomas may be appropriate in Tanzania in efforts to allocate testing for patients who are most likely to benefit from trastuzumab therapy.

Histologic detection of Helicobacter pylori by the immunohistochemical method using anti-Helicobacter pylori polyclonal antibody: A cross-sectional study of patients with gastric pathologies at the Muhimbili National Hospital in Dar-es-salaam, Tanzania.

BACKGROUND AND STUDY AIM: Immunohistochemistry is one of the superior methods and is regarded as the gold standard for the detection of Helicobacter pylori. We aimed to detect the presence of Helicobacter pylori in gastric biopsies among patients at the Muhimbili National Hospital from January 2012 to December 2016. Also, we determined the predictors of Helicobacter pylori infection. PATIENTS AND METHODS: Retrospectively, we retrieved the tissue blocks of gastric biopsies at the Central Pathology Laboratory of the patients with different gastric pathologies at the Muhimbili National Hospital from January 2012 to December 2016. Helicobacter pylori were detected using anti-Helicobacter pylori polyclonal antibodies. Binary logistic regression analysis was done to determine the predictors of Helicobacter pylori infection. A two-tailed p < 0.05 was considered significant. RESULTS: The prevalence of detection of Helicobacter pylori was 37.1% (63/170) using immunohistochemistry compared to 32.4% (55/170) using histology. Peptic ulcer disease, the absence of gastric cancer, and chronic gastritis were the predictors of Helicobacter pylori infection in our study (AOR = 0.2, 95% CI = 0.06-0.70, p = 0.011, AOR = 3.23, 95% CI = 1.02-10.29, p = 0.047, AOR = 0.32, 95% CI = 0.12-0.87, p = 0.025, respectively). CONCLUSION: In this study, Helicobacter pylori infection was associated with the presence of peptic ulcer disease, chronic gastritis, and the absence of gastric cancer. The rate of detection of Helicobacter pylori infection was higher in tissue blocks of elderly patients than in those of young patients. Also, gastric cancer was more prevalent in old female patients.

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19.

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) in some individuals, while the majority remain asymptomatic. Natural killer (NK) cells play an essential role in antiviral defense. NK cell maturation and function are regulated mainly by highly polymorphic killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands. Herein, we tested our hypothesis that the individualized KIR and HLA class I ligand combinations that control NK cell function determine the outcome of SARS-CoV-2 infection. Methods: We characterized KIR and HLA genes in 200 patients hospitalized for COVID-19 and 195 healthy general population controls. Results: The KIR3DL1+HLA-Bw4+ [Odds ratio (OR) = 0.65, p = 0.03] and KIR3DL2+HLA-A3/11+ (OR = 0.6, p = 0.02) combinations were encountered at significantly lower frequency in COVID-19 patients than in the controls. Notably, 40% of the patients lacked both of these KIR+HLA+ combinations compared to 24.6% of the controls (OR = 2.04, p = 0.001). Additionally, activating receptors KIR2DS1+KIR2DS5+ are more frequent in patients with severe COVID-19 than patients with mild disease (OR = 1.8, p = 0.05). Individuals carrying KIR2DS1+KIR2DS5+ genes but missing either KIR3DL1+HLA-Bw4+ combination (OR = 1.73, p = 0.04) or KIR3DL2+HLA-A3/11+ combination (OR = 1.75, p = 0.02) or both KIR3DL1+HLA-Bw4+ and KIR2DL2+HLA-A3/11+ combinations (OR = 1.63, p = 0.03) were more frequent in the COVID-19 cohort compared to controls. Conclusions: The absence of KIR3DL1+HLA-Bw4+ and KIR3DL2+HLA-A3/11+ combinations presumably yields inadequate NK cell maturation and reduces anti-SARS-CoV-2 defense, causing COVID-19. An increased frequency of KIR2DS1+KIR2DS5+ in severe COVID-19 patients suggests vigorous NK cell response triggered via these activating receptors and subsequent production of exuberant inflammatory cytokines responsible for severe COVID-19. Our results demonstrate that specific KIR-HLA combinations that control NK cell maturation and function are underlying immunogenetic variables that determine the dual role of NK cells in mediating beneficial antiviral and detrimental pathologic action. These findings offer a framework for developing potential host genetic biomarkers to distinguish individuals prone to COVID-19.