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BackgroundHumoral and cellular immune responses to SARS-CoV-2 vaccination among immunosuppressed patients remain poorly defined, as well as variables associated with poor response.MethodsWe performed a retrospective observational cohort study at a large Northern California healthcare system of infection-naïve individuals fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) with clinical SARS-CoV-2 interferon gamma release assay (IGRA) ordered between January through November 2021. Humoral and cellular immune responses were measured by anti-SARS-CoV-2 S1 IgG ELISA (anti-S1 IgG) and IGRA, respectively, following primary and/or booster vaccination.Results496 immunosuppressed patients (54% female; median age 50 years) were included. 62% (261/419) of patients had positive anti-S1 IgG and 71% (277/389) had positive IGRA after primary vaccination, with 20% of patients having a positive IGRA only. Following booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Factors associated with low humoral response rates after primary vaccination included anti-CD20 monoclonal antibodies (P&nbsp

ImportanceData on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited.ObjectiveTo determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response.DesignRetrospective observational cohort study.SettingLarge healthcare system in Northern California.ParticipantsThis study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection.Exposure(s)Immunosuppressive diseases and therapies.Main Outcome(s) and Measure(s)Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination.Results496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (PPP=.002), and B cell lymphoma (P=.004); those associated with low rates of cellular response included S1P receptor modulators (PPP=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose.Conclusions and RelevanceCellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.

Malaria is critical to rule out in febrile returned travelers. We evaluated the performance of the Alethia Malaria loop-mediated isothermal amplification (LAMP) assay for rapid one-time malaria screening using nucleic acid amplification testing. Retrospective analysis of 51 archival blood specimens collected from 32 patients with malaria and 25 uninfected controls showed Malaria LAMP assay to have sensitivity of 100% (95% CI 93.0-100) and specificity of 100% (95% CI 86.7-100) using blood smear microscopy as the reference standard. Prospective evaluation of Malaria LAMP as a single screening test in 205 patients identified 4 (1.95%) positives which were all confirmed as Plasmodium falciparum by PCR, with parasitemia quantified as0.1% (n = 2), 1.0% (n = 1), and 4.6% (n = 1). Alternative diagnoses were found in 129 of 201 (64.2%) of LAMP-negative patients, and no patient was subsequently diagnosed with malaria. The Malaria LAMP offers a sensitive and rapid stand-alone screening alternative in non-endemic settings.

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including 3rd dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is less after infection compared to all vaccines evaluated, but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks post-vaccination in some cases. SARS-CoV-2 antibody specificity, breadth and maturation are affected by imprinting from exposure history, and distinct histological and antigenic contexts in infection compared to vaccination., Human antibody responses to SARS-CoV-2 differ between vaccination and infection, with vaccination (regardless of vaccine type) inducing more productive lymph node germinal center responses and a broader range of IgG neutralizing antibodies capable of recognizing viral variants.

Dengue and COVID-19 co-circulation presents a diagnostic conundrum for physicians evaluating patients with acute febrile illnesses, both in endemic regions and among returning travelers. We present a case of a returning traveler from Pakistan who, following repeated negative SARS-CoV-2 tests, was found to have a Dengue virus serotype 2 infection.

We report persistent severe acute respiratory syndrome coronavirus 2 infection in a patient with HIV/AIDS; the virus developed spike N terminal domain and receptor binding domain neutralization resistance mutations. Our findings suggest that immunocompromised patients can harbor emerging variants of severe acute respiratory syndrome coronavirus 2.

Characterization of cell-mediated and humoral immune responses to SARS-CoV2 mRNA vaccine has implications for protective immunity in immunocompromised patients. However, studies have demonstrated poor humoral response to SARS-CoV2 mRNA vaccine in immunocompromised patients and data on cellular immune response are currently lacking. Here we compared immune response after 2-dose vaccination in 100 immunocompromised patients (solid organ transplant recipients, hematologic malignancy, autoimmune condition, and primary immunodeficiency) and 16 immunocompetent healthy healthcare workers. We find that 100% (CI=80.6-100%) of immunocompetent individuals show positive cell-mediated and humoral immune response post vaccination while only 50% (CI=40.4-59.6%) of immunocompromised patients show humoral immune response and 69% (CI=59.4-77.2%) have a positive cell-mediated immune response. 21% of immunocompromised patients have no humoral immune response or cell-mediated immune response and thus are likely vulnerable to SARS-CoV2 infection. Monitoring of immune response in immunocompromised populations, particularly in high-risk immunocompromised patients (solid organ transplant recipients, patients with severe autoimmunity, and those ≥50 years), with clinical IGRA and serological assay after vaccination may identify patients who may benefit from revaccination or prophylactic monoclonal antibody therapy to prevent COVID-19 in this patient population

The clear cell variant of solid pseudopapillary neoplasm (ccSPN) of the pancreas was first described in 2006. In this article, we report a case of this rare variant and review the few published reports. Both the current and previous reports show that ccSPN has several morphologic differences from conventional SPN, including clear vacuoles, fewer pseudopapillary formations, more solid/diffuse architecture, less hemorrhage, and fewer cholesterol clefts. Some of these features peculiar to ccSPN, such as solid/diffuse architecture, have been proposed to suggest aggressive behavior, though reports of ccSPN are rare and often have limited clinical follow-up. ccSPN also appears to occur more frequently in males than conventional SPNs. These clinical and pathologic features lead to unique set of differential diagnostic considerations for ccSPN, including metastatic renal cell carcinoma, perivascular epithelial cell tumor, and clear cell variants of other carcinomas. These unique features, atypical differential, and uncertain prognostic ramifications all make ccSPN an important variant to be aware of and report.

Numerous tuberculosis (TB) deaths remain undetected in low-resource endemic settings. With autopsy-confirmed tuberculosis as our standard, we assessed the diagnostic performance of Xpert MTB/RIF Ultra (Ultra; Cepheid) on nasopharyngeal specimens collected postmortem.From October 2016 through May 2019, we enrolled pediatric and adult medical deaths to a prospective autopsy study at two referral hospitals in northern Tanzania with next-of-kin authorization. We swabbed the posterior nasopharynx prior to autopsy and tested the samples later by Ultra. At autopsy we collected lung, liver, and, when possible, cerebrospinal fluid for mycobacterial culture and histopathology. Confirmed tuberculosis was defined as Mycobacterium tuberculosis complex recovery by culture with consistent tissue histopathology findings; decedents with only histopathology findings, including acid-fast staining or immunohistochemistry, were defined as probable tuberculosis.Of 205 decedents, 78 (38.0%) were female and median (range) age was 45 (0,96) years. Twenty-seven (13.2%) were found to have tuberculosis at autopsy, 22 (81.5%) confirmed and 5 (18.5%) probable. Ultra detected M. tuberculosis complex from the nasopharynx in 21 (77.8%) of 27 TB cases (sensitivity 70.4% [95% confidence interval {CI} 49.8-86.2%], specificity 98.9% [95% CI 96.0-99.9%]). Among confirmed TB, the sensitivity increased to 81.8% (95% CI 59.7-94.8%). Tuberculosis was not included as a death certificate diagnosis in 14 (66.7%) of the 21 MTBc detections by Ultra.Nasopharyngeal Ultra was highly specific for identifying in-hospital tuberculosis deaths, including unsuspected tuberculosis deaths. This approach may improve tuberculosis death enumeration in high-burden countries.

Background Laboratory-based methods for SARS-CoV-2 antibody detection vary widely in performance. However, there are limited prospectively-collected data on assay performance, and minimal clinical information to guide interpretation of discrepant results. Methods Over a 2-week period, 1080 consecutive plasma samples submitted for clinical SARS-CoV-2 IgG testing were tested in parallel for anti-nucleocapsid IgG (anti-N, Abbott) and anti-spike IgG (anti-S1, EUROIMMUN). Chart review was conducted for samples testing positive or borderline on either assay, and for an age/sex-matched cohort of samples negative by both assays. CDC surveillance case definitions were used to determine clinical sensitivity/specificity and conduct receiver operating characteristics curve analysis. Results There were 52 samples positive by both methods, 2 positive for anti-N only, 34 positive for anti-S1 only, and 27 borderline for anti-S1. Of the 34 individuals positive for anti-S1 alone, 8 (24%) had confirmed COVID-19. No anti-S1 borderline cases were positive for anti-N or had confirmed/probable COVID-19. The anti-N assay was less sensitive (84.2% [95% CI 72.1-92.5%] vs 94.7% [95% CI 85.4-98.9%]) but more specific (99.2% [95% CI 95.5-100%] vs 86.9% [95% CI 79.6-92.3%]) than anti-S1. Abbott anti-N sensitivity could be improved to 96.5% with minimal effect on specificity if the index threshold was lowered from 1.4 to 0.6. Conclusion Real-world concordance between different serologic assays may be lower than previously described in retrospective studies. These findings have implications for the interpretation of SARS-CoV-2 IgG results, especially with the advent of spike antigen-targeted vaccination, as a subset of patients with true infection are anti-N negative and anti-S1 positive.

Intravascular large B-cell lymphoma (IVLBCL) is a rare and deadly malignancy involving the growth of lymphoma cells within vessel lumina of all organ types. IVLBCL is further divided into the hemophagocytic Asian variant and a classical Western variant. Both variants are difficult to diagnose by imaging, and although diagnostic criteria have been developed to guide workup, histopathological examination remains imperative. Treatment of IVLBCL remains difficult given the high mortality of the disease, but rituximab has emerged as a promising therapeutic option when combined with various cytotoxic regimens. The two main variants of IVLBCL generally manifest in their respective Asian or Western populations, and crossover between ethnicities is rare. We present the second described case of Asian-variant IVLBCL in an African American individual.

Lung adenocarcinoma can have a varied appearance at presentation. Solid, ground-glass, or part-solid and part-ground-glass nodules are commonly seen [1]. Multifocal areas of consolidation that are peribronchovascular and contain air bronchograms may also be identified [3]. Multiple discrete nodules, or the so-called miliary pattern, are rare, with few cases reported in the literature [3, 10, 12, 14]. This pattern is more commonly reported as multifocal or diffuse adenocarcinoma, and detailed data regarding the incidence has not yet been studied in depth. However, in one case report of 73 patients with adenocarcinoma, 14 presented with multifocal disease, though only one had innumerable discrete nodules [19, 22]. In another study examining 548 patients with non-small cell lung cancer, 504 patients presented with a dominant lesion (stage I disease) and 44 with multifocal disease. Of the 44 patients, 18 had multifocal adenocarcinoma [2]. Some have suggested that the miliary pattern of adenocarcinoma may be produced by bone or liver metastases that continually seed the lung, though this has yet to be verified [10]. Because the miliary pattern is much less common, it may be confused for other entities, such as tuberculosis. Non-small cell lung cancer metastasizes to the bone in approximately 15–40% of cases, mostly involving the axial skeleton [11, 16]. Appendicular metastases are more common proximal to the knee and elbow, though more distal involvement is reported [5, 9, 11, 15, 18, 20, 21]. Extremity metastases are often initially misdiagnosed as benign entities such as infection due to presenting symptoms of local redness, pain, and swelling. Generally, a bony metastasis on radiograph appears as a lytic lesion and may be centered in the cortex (cookie-bite lesion). There may or may not be a demonstrable soft tissue mass [7]. Tuberculous and malignant involvement of the bone is often indistinguishable on imaging, particularly in the spine, where MRI findings can be similar [4, 13, 17, 23]. Diagnosis of tuberculous spread to the bone in general is often difficult, with an average delay in diagnosis of 16–19 months [4]. The musculoskeletal system is involved in 1–3% of cases of tuberculosis. The femur, tibia, and small bones of the hands and feet are often affected [6]. Typically, the metaphyses are involved, with radiographic features that include osteopenia and poorly defined lytic lesions with minimal surrounding sclerosis [4]. Our goal is to highlight the importance of maintaining a broad differential when evaluating a patient with confounding risk factors and imaging findings. Premature diagnoses may lead to delays in appropriate management [13]. Ultimately, tissue sampling may be necessary in providing a definitive, timely diagnosis.

Background Accurate detection and identification of invasive fungal pathogens relies on concordance of several complementary laboratory techniques, including fungal culture, serology, and histopathologic identification. Histopathologic stains such as the Gomori methenamine silver stain (GMS) are used to highlight fungal cell wall in tissue specimens. We sought to determine the diagnostic performance of histopathology fungal stains as compared to fungal culture for diagnosis of invasive fungal tissue infection at tertiary medical centers with dissimilar patient populations. Methods We performed a retrospective review of all surgical pathology specimens with reported GMS results and concurrent fungal culture at Keck Medical Center (Keck) and Los Angeles County + USC Medical Center (LAC). Ratios of GMS diagnostic performance were compared using chi-squared analyses, with fungal culture as the gold standard for detection. Results Of 1347 LAC surgical pathology specimens stained with GMS to evaluate for fungal infection, 229 (17.0%) had concurrent tissue specimens submitted for fungal culture. Of 1546 Keck GMS-stained surgical pathology specimens, 358 (23.2%) had concurrent tissue for fungal culture. GMS stain performance at LAC showed a sensitivity of 53.7% (95% CI: 37.4-69.3%) and specificity of 90.4% (95% CI: 85.2-94.2%). At Keck, GMS showed a sensitivity of 64.1% (95% CI: 52.4-74.7%), specificity of 88.9% (95% CI: 84.7-92.4%), without significant difference in performance between sites, (p=0.27) and (p=0.62), respectively. Among filamentous fungi, GMS false negative frequency at LAC was 5.3% (10/190) and 4.0% (11/277) at Keck, without significant difference (p=0.51). A subset of pathology reports suggested the fungus genus based on histologic morphology. Of 10 LAC pathology specimens with fungal genus specified, 2 (20.0%) reports gave the incorrect genus and 8/18 (44.4%) reports at Keck gave incorrect genus as per concurrent culture isolate result. Table 1. Diagnostic performance of GMS histopathology stain on surgical pathology specimens compared to tissue fungal culture at LAC and Keck Medical Centers from July 2015 through December 2018. Conclusion GMS stain had low-to-moderate sensitivity when compared to fungal tissue culture. Increased submission of concurrent tissue for fungal culture is likely to improve detection. When genus level identification was attempted, fungal forms were incorrectly identified in about one-third of histopathology specimens. Disclosures All Authors: No reported disclosures

Rapid diagnosis and treatment of an infected joint are paramount in preserving orthopedic function. Here, we present a brief review of the many challenges associated with the diagnosis of both septic arthritis and prosthetic joint infections. We also discuss the many laboratory tests currently available to aid in the accurate diagnosis of joint infection, as well as emerging diagnostics that may have future utility in the diagnosis of these challenging clinical entities.

Malakoplakia is a rare granulomatous disease that most commonly occurs in the urinary tract. It is characterized by sheets of histiocytes with granular basophilic inclusions and Michaelis-Gutmann bodies. We present an exceedingly rare case of malakoplakia of the thyroid in a 54-year-old Caucasian woman on immunosuppressive therapy for renal transplant performed in 1994.

Background Bone and Joint Infections (BJI) have high morbidity and are difficult to treat infections. Culture-based diagnosis is limited in its ability to recover fastidious bacteria and because several organisms can be involved; culture times of up to two weeks may be necessary for certain bacteria. The sensitivity of culture is also negatively impacted by antibiotics received before surgery. Alternatively, molecular methods offer a promising improvement for the diagnosis of BJI. The goal of this study was to evaluate a development version of Biofire® Bone and Joint Infection (BJI) Panel (bioMerieux SA, BioFire Diagnostics, LLC) using synovial fluid samples. Methods 121 synovial fluid specimens were collected from patients with suspected bone and joint infection in a pilot evaluation. All specimens were collected and tested in culture by the sites using their standard of care practices; in parallel, a leftover volume of 200 µL was tested on the BJI panel. BJI panel results were then compared with culture and discordant results were investigated using a comparator assay (PCR/sequencing). Results 49 synovial fluid specimens (40%) were positive by culture vs. 72 with the BJI panel (59%). Of the 97 positive detections by the BJI panel, 58 were concordant with culture; the 39 additional organism detections were in majority confirmed by PCR/sequencing. Lastly, two false negative results corresponding to the same sample are under investigation. Conclusion The BJI Panel was able to identify most of the pathogens detected by culture. The majority of additional detections observed were confirmed by PCR/sequencing. While sites are currently enrolling more synovial fluids samples, these preliminary data suggest that a multiplexed molecular test may be more sensitive than culture to detect pathogens in synovial fluid specimens. The data presented in this abstract have not been reviewed by FDA or other regulatory agencies for In Vitro Diagnostic use. Disclosures B. Pons, bioMerieux: Employee, Salary. C. Jay, bioMerieux: Employee, Salary. T. Martin, bioMerieux: Employee, Salary. I. Sothier, bioMerieux: Employee, Salary. H. Savelli, bioMerieux: Employee, Salary. B. Kensinger, bioFire a bioMerieux company: Employee, Salary. F. Laurent, BioFire (bioMerieux company): Investigator, Research support. L. Abad, BioFire (bioMerieux company): Investigator, Research support. C. Murphy, BioFire (bioMerieux company): Investigator, Research support. A. Craney, BioFire (bioMerieux company): Investigator, Research support. B. Schmitt, BioFire (bioMerieux company): Investigator, Research support. A. Waggoner, BioFire (bioMerieux company): Investigator, Research support. S. Butler-Wu, BioFire (bioMerieux): Investigator, Research support. C. Costales, BioFire (bioMerieux company): Investigator, Research support. J. Bien-Bard, BioFire (bioMerieux): Investigator, Research support. J. Mestas, BioFire (bioMerieux): Investigator, Research support. J. Esteban, BioFire (bioMerieux): Investigator, Research support. L. Salar-Vidal, BioFire (BioMerieux company)): Investigator, Research support. A. Harrington, BioFire (bioMerieux company): Investigator, Research support. S. Collier, BioFire (BioMerieux Company): Investigator, Research support. A. Leber, BioFire (bioMerieux company): Investigator, Research support. K. Everhart, BioFire (bioMerieux company): Investigator, Research support. J. M. Balada-Llasat, BioFire (bioMerieux company): Investigator, Research support. J. Horn, BioFire (bioMerieux company): Investigator, Research support. S. Magro, bioMerieux: Employee, Salary. K. Bourzac, BioFire a bioMerieux company: Employee, Salary.