Branda, John A.

ABSTRACT Current laboratory testing for Lyme disease (LD) relies on serology. We evaluated the performance of standard two-tiered testing (STTT) and modified two-tiered testing (MTTT) algorithms using samples obtained from well-characterized patients with early LD in the U.S. East Coast and Upper Midwest. Participants with signs and symptoms of early LD (cases) and controls were enrolled by Lyme Disease Biobank. We compared the performance of four FDA-cleared STTT or MTTT algorithms using serum samples from 251 participants (107 cases, 69 with a convalescent draw; 144 endemic controls). At the initial blood draw, algorithm sensitivity ranged from 22% to 36%, with specificity ranging from 98% to 100%. MTTT algorithms showed higher sensitivity compared with STTT algorithms ( P ≤ 0.05). One STTT algorithm was less sensitive than the other ( P = 0.035), and there was no significant difference in sensitivity between MTTT algorithms. There was also discordance between algorithms; only 22 of the 45 samples classified as laboratory confirmed by Lyme Disease Biobank testing were positive using all algorithms evaluated. Likelihood of positive two-tiered serology among cases with a suspected erythema migrans (EM) skin lesion increased with longer lesion duration and/or when presenting with >1 constitutional symptom. Participants with suspected EM without constitutional symptoms were unlikely to test positive by any algorithm evaluated. Testing convalescent samples did not improve LD detection, and seroconversion was rare. While MTTT confirmed more early LD cases than STTT, all two-tiered algorithms evaluated were insensitive in this population. Novel diagnostics that improve laboratory confirmation for early LD are urgently needed. IMPORTANCE This study confirms that two-tiered serologic testing algorithms are insensitive in early Lyme disease, particularly within the first 2 weeks after symptom onset or when erythema migrans is not accompanied by constitutional symptoms. It also demonstrates that seroconversion is rare after antibiotic treatment. These results highlight the need for novel diagnostics for early Lyme disease that do not rely on serologic testing.

Abstract Rationale The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non–COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

Modified two-tiered testing (MTTT) algorithms for Lyme disease (LD), which involve the sequential use of orthogonal enzyme immunoassays (EIAs) without immunoblotting, are acceptable alternatives to standard two-tiered testing (STTT; EIA followed by immunoblots) provided the EIAs have been FDA-cleared for this intended use. We evaluated four Zeus Scientific LD EIAs used in two distinct MTTT algorithms for FDA review.

ABSTRACT We present a case of tenosynovitis caused by a novel, slowly growing, nonchromogenic, nontuberculous mycobacterium (NTM). Originally misidentified as Mycobacterium tuberculosis complex, the NTM cross-reacts with the M. tuberculosis complex nucleic acid hybridization probe, a M. tuberculosis gamma interferon release assay, and is closely related to M. tuberculosis by 16S rRNA gene sequencing.