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Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome-associated Coronavirus 2 (SARS-CoV-2), has become a global threat to public health. COVID-19 is more pathogenic and infectious than the prior 2002 pandemic caused by SARS-CoV-1. The pathogenesis of certain disease manifestations in COVID-19 such as diffuse alveolar damage (DAD) are thought to be similar to SARS-CoV-1. However, the exact pathogenesis of COVID-19 related deaths remains poorly understood. The aim of this article was to systematically summarize the rapidly emerging literature regarding COVID-19 autopsies. A meta-analysis was also conducted based on data accrued from preprint and published articles on COVID-19 (n=241 patients) and the results compared with postmortem findings associated with SARS-CoV-1 deaths (n=91 patients). Both autopsy groups included mostly adults of median age 70 years with COVID-19 and 50 years with SARS-CoV-1. Overall, prevalence of DAD was more common in SARS-CoV-1 (100.0%) than COVID-19 (80.9%) autopsies (P=0.001). Extrapulmonary findings among both groups were not statistically significant except for hepatic necrosis (P

PURPOSE The purpose of this study was to report a case of microsporidial endotheliitis masquerading as graft rejection after deep anterior lamellar keratoplasty (DALK). METHODS A 36-year-old man visited the clinic with complaints of blurred vision, redness, pain, watering, and whitish appearance of the black portion of his left eye. On evaluation, there was diffuse stromal edema with epithelial defect and hypopyon. Microbial keratitis resolved with macular grade scar. He underwent DALK. After 3 years, he presented with complaints of sudden diminution of vision in the same eye for 10 days. His unaided visual acuity was counting finger 1 meter. The clinical findings were circumcorneal congestion, diffuse graft edema, Descemet membrane folds, and diffuse keratic precipitates. A presumptive diagnosis of left eye graft rejection was made. Topical steroids were administered. There was significant improvement within a week. However, at 1 month, there was an increase in graft edema after the steroids were tapered. At this point, a diagnosis of endotheliitis of viral origin was made. He was then administered oral antivirals and steroids. There were 2 such waxing and waning episodes of graft edema before the graft failed. Patient underwent penetrating keratoplasty with cataract extraction with intraocular lens implantation. RESULTS The previous donor and host Descemet endothelium complex was sent for histopathology and polymerase chain reaction. Both histology and polymerase chain reaction were positive for microsporidia. CONCLUSIONS Microsporidial endotheliitis may present as graft rejection. There should be a suspicion of microsporidial infection in cases of features mimicking as endothelial rejection after DALK.

PURPOSE To report endotheliitis as an early, key presenting sign of Acanthamoeba keratitis in patients who are soft contact lens wearers. METHODS We report 4 cases of patients presenting with pain, red eye, and reduction in vision in the context of soft contact lens wear. On examination, the predominant clinical finding was that of endotheliitis, localized fusiform stromal edema with corresponding keratic precipitates, anterior chamber inflammation, and minimal epithelial and anterior stromal signs. The classical signs of Acanthamoeba keratitis were not present. RESULTS All 4 cases were clinically diagnosed as Acanthamoeba endotheliitis; corneal scrapes were negative; case 1 was polymerase chain reaction positive, and case 3 underwent confocal microscopy that showed double-walled cysts, suggesting Acanthamoeba. All responded well to anti-Acanthamoeba medication alone with 3 cases achieving complete resolution with minimal anterior stromal scarring by 7 weeks. Case 1 had steroid treatment before being seen at our unit and had a prolonged course of treatment with complete resolution by 4 months. CONCLUSIONS It is imperative to have a high index of suspicion for Acanthamoeba in patients presenting with pain and endotheliitis in the context of contact lens wear, even in the absence of classical signs.

The involvement of the vascular endothelium in the complications of coronavirus disease 2019 is now recognized. Chief among these are pulmonary endotheliitis, cytokine storm, endotoxic shock, and cardiovascular collapse. This Perspectives article is focused on therapeutical strategies to reduce the risk of these complications by targeting the vascular endothelium as a part of the overall treatment of coronavirus disease 2019.

Purpose To report a case of conjunctival epithelial ingrowth after penetrating keratoplasty. Methods A 57-year-old woman with herpetic corneal keratitis, endotheliitis, and bullous keratopathy underwent penetrating keratoplasty (PKP) and secondary cataract surgery. One month after cataract surgery, an epithelial ingrowth was observed at the 5 o'clock donor host junction. Ingrowth extended into the anterior chamber and along the iris surface by 9 months. Another PKP was performed, and the excised graft was submitted for histopathology. Results The graft showed CK13-positive and CK3-negative cells lining the endothelial surface, indicating the conjunctival origin of ingrown epithelium. Ten months postoperatively, no recurrence of ingrowth was observed. Conclusions We experienced a rare case of conjunctival epithelial ingrowth after penetrating keratoplasty. There was no recurrence of the ingrowth after surgical removal, and the conjunctival origin may explain the relatively benign course of the complication.

PURPOSE To report the clinical outcome and postoperative course of Descemet membrane endothelial keratoplasty (DMEK) in irreversible corneal edema due to herpes simplex virus (HSV) endotheliitis. METHODS This is a retrospective, noncomparative, interventional case series. Nineteen eyes of 19 patients underwent standard DMEK combined with cataract surgery (triple DMEK) between May 2016 and April 2018. All patients received perioperative oral acyclovir (ACV) and prednisolone. Patients were followed up on day 1, on day 7, at 1 month, and then at 3 monthly intervals. Preoperative and postoperative best spectacle-corrected visual acuity (BSCVA), graft clarity, pachymetry, and endothelial cell loss after 1 year were recorded. Postoperative complications and HSV recurrence were noted until the last follow-up visit. RESULTS All eyes were phakic with variable grades of cataract with a preoperative BSCVA of 1.0 logarithm of the minimum angle of resolution or worse. The mean follow-up period was 19.3 ± 5.4 months. After 1 year, 14 (73.7%) eyes achieved a BSCVA of 0.3 or better. Seventeen (89.5%) patients had a clear graft at the last visit without any rejection episode. One graft failed after 16 months. After 3 months, the mean pachymetry reduced from 667.1 ± 62.1 to 512.8 ± 27.1 μm (P < 0.001). The mean endothelial cell loss after 1 year was 36.7 ± 13.4%. Three (15.8%) eyes had recurrence: one with recurrent endotheliitis and 2 with dendritic keratitis despite oral ACV, which responded to oral valacyclovir and ACV eye ointment. One patient had re-recurrence of endotheliitis after 20 months. CONCLUSIONS DMEK in persistent corneal edema after HSV endotheliitis remains challenging but has encouraging outcomes. The postoperative course may be complicated by HSV recurrence. Prophylactic oral antivirals for 1 year or more and topical antivirals are useful for the prevention of recurrence.

PURPOSE To describe an alternative surgical approach, femtosecond laser-assisted deep lamellar Descemet membrane endothelial keratoplasty (Femto-DL-DMEK), for the treatment of corneal endothelial diseases associated with posterior stromal scarring. METHODS Case report of a 52-year-old man with pseudophakic bullous keratopathy and posterior corneal scarring secondary to viral endotheliitis who underwent Femto-DL-DMEK. The surgical technique was as follows: First, a manual lamellar dissection plane was created at approximately 75% to 85% depth through a 5.0-mm superior scleral incision. One week later, using a femtosecond laser, an intersecting posterior side cut of 8.2 mm diameter was created. Subsequently, the dissected posterior recipient disk was removed from the anterior chamber through a 3.2-mm limbal incision. Finally, an 8.0-mm DMEK graft was placed. RESULTS The patient's uncorrected distance visual acuity improved from 20/200 (0.15; decimal) preoperatively to 15/25 (0.6) after surgery; corrected distance visual acuity improved from 20/200 (0.15) to 20/25 (0.9) with a residual refraction of +1.0-0.50 at 140 degrees. Endothelial cell count was 2062 cell/mm 6 months after surgery. No intra- or postoperative complications were noted. CONCLUSIONS As long as the anterior and mid-stroma are unaffected, those with endothelial diseases associated with opacification of the posterior stroma can benefit from endothelial keratoplasty through a Femto-DL-DMEK procedure, avoiding all well-known drawbacks of penetrating keratoplasty.

PURPOSE To observe the pathological changes in dendritic cells (DCs) and inflammatory cells in the corneal epithelium and endothelium using in vivo confocal microscopy during the management of herpetic endotheliitis. METHODS A total of 110 eyes with herpetic endotheliitis were included. All patients were treated with antiviral agents combined with glucocorticoids. Changes in corneal edema were observed using slit-lamp microscopy and anterior segment optical coherence tomography. DCs and inflammatory cells in the epithelium and endothelium were detected using in vivo confocal microscopy before treatment and at 1 to 2 weeks and 1 and 3 months after treatment. Recurrence was monitored for 2 years. The contralateral normal eyes were evaluated as controls. RESULTS Mean density of DCs decreased at 1 month after treatment (100 ± 14 cells/mm) compared with before treatment (148 ± 26 cells/mm, P < 0.001). At 3 months, DCs returned to small and dendritiform reflective corpuscular cells at a density of 44 ± 11 cells/mm (P < 0.001), and the mean density of endothelial cells (2011 ± 173 cells/mm) was significantly lower than in controls (2472 ± 233 cells/mm, P = 0.002). Inflammatory cells residing in the epithelium were significantly reduced in number and disappeared at 1 to 2 weeks, and those at the endothelial surface almost disappeared at 1 month. There was no relapse during the follow-up evaluation. CONCLUSIONS DCs and inflammatory cells in the epithelial and endothelial cell layers of the cornea changed constantly in density, morphology, and distribution during the therapeutic process of herpetic endotheliitis. Adequate understanding of these alterations may help to guide the management of this disease.

PURPOSE There is currently limited information regarding the outcomes of endothelial keratoplasty in eyes with cytomegalovirus (CMV) endotheliitis. We report the results of Descemet stripping automated endothelial keratoplasty (DSAEK) for endothelial failure secondary to CMV. METHODS This is a retrospective review of 4 eyes of 4 patients with CMV endotheliitis and DSAEK. CMV was confirmed in each case by a positive aqueous tap on qualitative polymerase chain reaction. The clinical characteristics of the patients and postoperative outcomes were studied. RESULTS The mean age of the 4 patients was 69.6 ± 8.1 years. Two were ethnically Vietnamese, 1 Chinese, and 1 Lebanese. All were immunocompetent. Three eyes had presented with hypertensive uveitis and 1 with bullous keratopathy. Twelve DSAEKs were performed in total in the 4 eyes. Five grafts were performed without any perioperative treatment with oral valganciclovir. All subsequently failed after a mean of 8.0 ± 3.8 months. Seven grafts were managed with oral valganciclovir; 2 of these grafts failed after 18 and 37 months, and 1 graft had primary graft failure. Four grafts are currently surviving, despite an episode of CMV reactivation in 2 grafts. CONCLUSIONS In cases of unexplained corneal decompensation or early graft failure after uncomplicated DSAEK, a diagnosis of CMV infection must be considered. Subsequent management of DSAEK in such cases remains challenging. The postoperative course can be complicated by CMV reactivation, which may masquerade either as graft rejection or graft failure. Long-term treatment with oral valganciclovir or topical ganciclovir may be required to decrease graft failure rates.

To investigate the clinical characteristics of viral endotheliitis after keratoplasty, we evaluated clinical parameters in individuals with anterior chamber inflammation after keratoplasty classified according to the absence or presence of DNA from various viruses in aqueous humor.A total of 29 eyes of 27 subjects with anterior chamber inflammation after keratoplasty were enrolled in the study. The subjects were classified into the herpes simplex virus (HSV) group (7 patients, 8 eyes), cytomegalovirus (CMV) group (6 patients, 6 eyes), varicella zoster virus group (2 patients, 2 eyes), and nonviral group (12 patients, 13 eyes) on the basis of detection of viral DNA in aqueous humor. The interval between keratoplasty and the onset of inflammation, changes in intraocular pressure (IOP), and corneal manifestations of inflammation were retrospectively reviewed.Sixteen of the 29 eyes developed anterior chamber inflammation within 2 years after keratoplasty. IOP during active inflammation was significantly increased in the HSV and CMV groups compared with preinflammation values, and the increased IOP was significantly ameliorated in association with resolution of inflammation. Linear-type keratoprecipitates were frequently detected in the HSV (5 of 8 eyes), CMV (3 of 6 eyes), and nonviral (6 of 13 eyes) groups. Corneal edema was also commonly observed in the HSV (7 of 8 eyes) and nonviral (13 of 13 eyes) groups.Changes in IOP and corneal manifestations may provide a basis for differentiation of viral endotheliitis from allograft rejection and among viral pathogens in individuals with anterior chamber inflammation after keratoplasty, and they may thus allow initiation of appropriate treatment before viral DNA is identified.

We present a unique case involving a 6-year-old female with a unilateral corneal endotheliitis-like finding, who was ultimately found to have a form of anterior diffuse infiltrating retinoblastoma with no evidence of retinal involvement. The patient's presumed endotheliitis was initially treated with topical dexamethasone and oral acyclovir without improvement. She then underwent multiple fine-needle aspirations of anterior chamber fluid, which were negative for abnormal findings of viral polymerase chain reaction, viral cultures, and flow cytometry. Months after initial presentation, an anterior chamber angle mass developed and a biopsy identified retinoblastoma cells. The patient underwent plaque radiotherapy of the cornea and systemic chemotherapy. The patient regained good vision and is tumor-free at 13 months. Anterior inflammation is a rare form of masquerade syndrome associated with retinoblastoma; however, it tends to be associated with diffuse posterior segment retinoblastoma when it does occur. Diffuse anterior retinoblastoma is a rare form of retinoblastoma with no apparent focus in the retina. Ultimately, our patient developed an anterior chamber angle lesion, which was biopsied and proven to be retinoblastoma. Unusual corneal endotheliitis-like findings in children that are not responsive to conventional treatment should raise the clinician's suspicion of malignancy, even when no retinal lesion is detected.

Corneal endotheliitis was first reported as an autoimmune disease by Khodadoust in 1982. Thereafter, herpes simplex virus (HSV) was detected as a causative agent, and corneal endotheliitis was classified as an infectious disease. However, most primary corneal endotheliitis had been idiopathic. In 2006, cytomegalovirus (CMV) DNA was detected in a case of corneal endotheliitis, and other reports on CMV endotheliitis from Asian countries established it as a new clinical entity. Limited studies have reported clinical findings, and the pathogenesis of HSV and CMV corneal endotheliitis is unknown. Therefore, this review describes what is currently known about the pathogenesis of HSV and CMV endotheliitis by way of previously reported case studies and basic research. In addition, we review work by our own group regarding the role of Toll-like receptor 9 and the results of transcriptome analysis after HSV infection in an in vitro model using immortalized human corneal endothelial cells. It is critical to diagnose corneal endotheliitis early to provide effective treatment with ganciclovir or valganciclovir and prevent the loss of corneal endothelial cells. Therefore, we hope that these in vitro results may provide further information to help elucidate the in vivo pathogenesis of HSV and CMV endotheliitis.

Rationale To report a case of herpes simplex virus (HSV) linear endotheliitis in a 57-year-old male who had underwent keratoplasty 10 years ago. The characteristic linear keratic precipitates (KPs) resembled the Khodadoust line in graft rejection. The differential diagnosis is essential, because the treatment regimen is different between HSV linear endotheliitis and graft rejection. Patient concerns The patient developed a sudden onset of ocular pain and a decrease in visual acuity in his right eye. The patient had received penetrating keratoplasty in the eye 10 years ago. Diagnoses The ocular disease was evaluated using several ocular examinations, including best-corrected visual acuity (BCVA), intraocular pressure, slit lamp examination, fundus examination, and aqueous humor tap. Characteristic linear endothelial KPs were found both in the host cornea and graft cornea. Stromal edema was evident in both the donor and recipient corneas. The aqueous humor was sampled for viral polymerase chain reaction (PCR) analysis. The sample was investigated for the possible presence of HSV I, HSV II, cytomegalovirus, and varicella zoster virus. The PCR was positive for HSV I and negative for HSV II, cytomegalovirus, and varicella zoster virus. Interventions The patient was treated with both antiviral and steroid treatments for 1 month. Thereafter, prophylactic antiviral treatment was continued. Outcomes The subjective symptoms had improved and the cornea edema and the linear endothelial KPs had disappeared. The BCVA improved from 20/200 to 20/80. Lessons HSV linear endotheliitis is the most severe form of HSV endotheliitis. This case showed characteristic endothelial KPs, which were different from the Khodadoust line of graft rejection.

Rationale: Autoimmune hepatitis (AIH) is characterised by interface hepatitis. However, some acute cases exhibit atypical centrilobular necrosis with mild portal inflammation. Detailed histological and ultrastructural analyses of acute AIH are limited. Patient concerns: A 44-year-old female was admitted to our hospital with jaundice, general fatigue and liver dysfunction. Her transaminase levels were elevated, her immunoglobulin G level was 1735 mg/dL and her anti-nuclear titres were ×80. Diagnosis: AIH was diagnosed, and histochemical examination of a liver biopsy showed the presence of atypical histological features of prominent centrilobular necrosis and central vein and hepatic sinusoidal endotheliitis. Electron microscopy showed that dendritic cells (DCs) and lymphocytes were attached to disrupted liver sinusoidal endothelial cells (LSECs) in hepatic sinusoids and that DCs attached to LSECs via pseudopods in the central vein. Interventions and outcomes: The patient was started on 40 mg/day prednisolone to control the hepatic inflammation. Her aspartate and alanine aminotransferase levels started declining after prednisolone was initiated. Three weeks later, these levels had normalised. The dosage of prednisolone was gradually decreased as liver function improved. The patient remains under observation and continues to receive 2.5 mg prednisolone. Lessons: An important marker of acute AIH may be the presence of activated DCs in the hepatic sinusoids and central vein.

PURPOSE To evaluate the expression of CXCL9, -10, and -11 chemokines in the aqueous humor of patients with herpetic endotheliitis. METHODS Aqueous humor was collected from 26 patients with herpetic endotheliitis and 21 control subjects. The concentrations of CXCL9, -10, and -11 in the aqueous humor were measured with enzyme-linked immunosorbent assays. The correlation between chemokine levels and clinical parameters of disease severity was analyzed. Flow cytometry was performed to count CXCR3 cells and CXCR3CD4 cells in the aqueous humor. RESULTS The concentrations of CXCL9, -10, and -11 were 429.08 ± 297.41 pg/mL, 23,102.49 ± 15,964.95 pg/mL, and 258.25 ± 103.25 pg/mL in patients with herpetic endotheliitis and 16.84 ± 16.73 pg/mL (P < 0.01), 188.45 ± 183.43 pg/mL (P < 0.01), and 7.32 ± 6.45 pg/mL (P < 0.01) in control subjects, respectively. Aqueous chemokine levels correlated significantly with keratitic precipitates and corneal edema in patients with herpetic endotheliitis. The mean percentages of CXCR3 and CXCR3CD4 cells were higher in herpetic endotheliitis patients compared with the controls. CONCLUSIONS Expression of CXCL9, -10, and -11 chemokines and their receptor CXCR3 increases in the aqueous humor of patients with herpetic endotheliitis. Chemokine levels are associated with the clinical severity of the disease.

Sneddon syndrome is a rare systemic vasculopathy affecting the skin as livedo racemosa and the central nervous system as stroke. A 31-year-old man with a history of livedo racemosa presented with a partial left third nerve palsy. Skin biopsy showed signs of endotheliitis with obliteration of dermal blood vessels due to intimal proliferation and fibrin thrombi consistent with Sneddon syndrome. The patient was treated with platelet antiaggregant therapy with complete resolution of his third nerve palsy. Clinicians should be aware of Sneddon syndrome because prompt diagnosis and treatment may prevent potential morbidity and mortality.

PURPOSE To specify confocal scan features of keratic precipitates (KPs) in uveitic eyes of various etiologies. METHODS Confocal scan was performed on 129 eyes of 93 patients with different types of uveitis to characterize the morphologic features of KPs. The study included Fuchs heterochromic iridocyclitis (FHIC) in 50 eyes, idiopathic granulomatous uveitis in 27, herpetic anterior uveitis in 10, pars planitis associated with endotheliitis in 9, Vogt-Koyanagi-Harada syndrome in 8, multiple sclerosis-related uveitis in 7, sarcoidosis in 3, acute anterior uveitis not associated with HLA B27 in 3, acute retinal necrosis in 2, psoriatic uveitis in 2, chronic endophthalmitis in 2, sclerouveitis in 2, HLA B27-associated anterior uveitis in 2, sympathetic ophthalmia in 1, and toxoplasmosis in 1. The differences in types of KPs between various uveitic groups were analyzed. RESULTS Mean age of the patients was 32.5 +/- 11.2 (range, 14-67) years, and 58 (62.36%) were female. Bilateral involvement was observed in 36 cases (38.7%). Stippled and globular KPs were predominantly observed in almost all types of uveitis. With comparing the infectious versus noninfectious uveitis, dendritiform KPs were almost more common in infectious uveitis (P = 0.053) and smooth-rounded KPs were significantly more common in noninfectious uveitis (P = 0.000). Dendritiform KPs were observed more commonly in nongranulomatous uveitis than in the granulomatous ones (P = 0.005). Smooth-rounded KPs were more common in chronic uveitis than in the acute forms (P = 0.000). Predominant morphologies of KPs in FHIC were dendritiform (80.0%) and infiltrating (78.0%). The most commonly observed morphologies of KPs in intermediate uveitis were dendritiform (56.3%) and smooth rounded (56.3%). Cruciform KPs were more frequently seen in cases with FHIC (60.0%). In bilateral cases, the morphologic features were similar. CONCLUSIONS Morphologic features of KPs in various types of uveitis are diverse. Stippled and globular KPs may be observed in almost all types of uveitis. Certain types of KPs are more frequently associated with specific forms of uveitis, that is, smooth-rounded KPs may be an indicative of a granulomatous uveitis and infiltrating and dendritiform in infectious uveitis. Confocal scan may play a potential important role in identification of underlying mechanisms in complex forms of uveitis.

Herpetic keratitis is manifested in various corneal disorders, for example, dendritic keratitis, persistent epithelial defect, disciform keratitis, and endotheliitis. In this paper, we report on the quantity of herpes simplex virus (HSV) genome in tears from patients with various types of herpetic keratitis in an attempt to understand the role of HSV in these conditions.We collected tear samples from both eyes of 56 consecutive patients with herpetic keratitis who visited Kinki University Hospital between June 2000 and May 2002. All patients had unilateral herpetic keratitis: epithelial keratitis in 27 eyes; persistent epithelial defect in 6; active disciform stromal keratitis in 14; silent stromal keratitis in 6; and endotheliitis in 3. We measured levels of HSV genome in these tear samples using a real-time polymerase chain reaction (PCR) method.In epithelial keratitis, HSV DNA was detected in all 27 samples from affected eyes (6.4 +/- 4.4 x 10(5) copies/sample). In persistent epithelial defect, HSV DNA was detected in all 6 samples from affected eyes (8.5 +/- 3.3 x 10(4) copies/sample). In active disciform stromal keratitis, HSV DNA was detected in 8 of the 14 affected eyes (1.4 +/- 1.1 x 10(5) copies/sample including zero values in negative samples). HSV DNA was not detected in samples from unaffected eyes or eyes affected by silent stromal keratitis or endotheliitis.Real-time PCR is a useful method for quantifying HSV DNA in tear samples from patients with herpetic keratitis. Using this method, we demonstrate that HSV reproduction occurs in persistent epithelial defect and disciform stromal keratitis.

Veno-occlusive disease (VOD) can develop in association with the administration of cytotoxic chemotherapeutic agents and irradiation. In solid-organ transplant settings, azathioprine has been implicated as a predisposing factor. VOD with fatal outcome occurred in a post liver-transplant recipient who had never been exposed to any agents that have the potential to induce VOD. At onset, the disease manifested clinically as gross ascites and progressive jaundice and was observed after clinically diagnosed acute graft rejection. The disease was confirmed by histologic examinations. Histologic studies of biopsy samples from this patient revealed that most small hepatic veins less than 300 microm in diameter were affected, exhibiting concentric intimal thickening with sparse inflammatory cells. A few of the hepatic veins exhibited active endotheliitis with occasional extension of inflammation to neighboring centrilobular areas. Despite intensified immunosuppression, the observed fibrous obliterative changes were irreversible. Although the cause of VOD in this patient is tentative, the damage to the endothelium, associated with acute rejection, is likely to be attributable. VOD deserves recognition as one of the causes for liver dysfunction and persistent ascites after liver transplantation.

Treatment of acute cellular rejection (ACR) is associated with increased viral load, more severe histologic recurrence, and diminished patient and graft survival after liver transplantation for hepatitis C virus (HCV). Recurrence of HCV may be difficult to distinguish histologically from ACR . Because the immunologic mechanisms of ACR and HCV recurrence are likely to differ, we hypothesized that ACR is associated with the expression of a specific subset of immune activation genes that may serve as a diagnostic indicator of ACR and provide mechanistic insight into the pathophysiology of ACR and recurrence of HCV. The goal of the study was to study intragraft gene expression patterns in ACR and during recurrence of HCV in HCV-infected recipients. High-density microarrays were used to determine relative intragraft gene expression in two groups of HCV-infected liver transplant recipients: four with steroid responsive ACR by Banff criteria and four age- and gender-matched HCV-infected recipients with similar necroinflammatory activity but without histological criteria for rejection (no cholangitis or endotheliitis). Immunosuppression was similar in both groups. Other etiologies of graft dysfunction were excluded by ultrasound, cholangiography, and cultures. High-quality total RNA was extracted from snap frozen liver biopsies, reverse transcribed, labeled with biotin, and fragmented according to established protocol. Twenty-five genes were relatively overexpressed, and 15 were relatively underexpressed by ≥twofold in the ACR when compared with the HCV group. ACR was most notably associated with the relative overexpression of genes associated with major histocompatibility complex I and II, insulin-like growth factor–1 expression, apoptosis induction, and T-cell activation. In HCV-infected liver transplant recipients, ACR is associated with an intragraft gene expression profile that is distinct from that seen during recurrence of HCV. These experiments provide evidence that alloimmunity, as indicated by expression of T-cell activation and apoptosis-inducing genes, is less important in recurrence of HCV than in ACR. Further studies are required to determine whether gene expression profiles, either intragraft or in serum, can be used for the diagnosis and differentiation of ACR from recurrence of HCV. ( Liver Transpl 2002;8:814-821. )

Background. Graft losses due to leaks, bleeding, thrombosis, infections, and early pancreatitis are grouped together under the category of technical failure. Among these complications, massive vascular thrombosis continues to be the most important cause of early graft loss due to technical failure. Pathological evaluation of most allografts lost early in the posttransplantation period shows vascular thrombosis with associated proportional parenchymal necrosis. The morphological findings in allografts that are considered to be lost due to technical failure has not been systematically addressed. In particular, the role of acute rejection in early graft loss has not been well studied. Methods. Seventy-four consecutive pancreas graft pancreatectomies were studied histologically to evaluate for thrombosis (recent versus organized), type of vessel involved by thrombosis (arteries, veins, or both), acute rejection grade, chronic rejection grade, endotheliitis, transplant arteritis, coagulation necrosis, acute pancreatitis, presence of infectious organisms, transplant (obliterative) arteriopathy, neoplasia, relative proportions of alpha and beta islet cells, and immunoglobulin and complement deposition. The histological findings were correlated with donor and recipient data as well as clinical presentation. Results. In 23 out of 39 grafts lost in the first 4 weeks posttransplantation, the only pathological changes found were vascular thrombosis and bland ischemic parenchymal necrosis. In these cases, no underlying vascular pathology or any other specific histological change was identified. Most of these grafts (78%) were lost in less than 48 hr and all in the first 2 weeks posttransplantation. Massive vascular thrombosis occurring in an otherwise histologically normal pancreas was the most common cause of graft loss in the first 4 weeks posttransplantation (59%). In most of the remaining cases (33%), although the clinical presentation suggested technical failure, there was clear histological evidence that the massive thrombosis resulted from vascular injury due to immune damage (acute and hyperacute rejection). Increased incidence of early graft thrombosis was seen in grafts from older donors and longer cold ischemia times. After the first month posttransplantation, graft pancreatectomies revealed a wider variety of pathological processes that included severe acute rejection, combined acute and chronic rejection, chronic rejection, and infections. Acute and chronic vascular thrombosis in large and small vessels was commonly seen at all times posttransplantation; chronic, organized thrombosis was strongly associated with chronic rejection. Conclusions. (a) Early acute thrombosis occurring in a histologically normal pancreas defines a true technical failure. This study showed that acute rejection leading to massive thrombosis, which clinically simulates technical failure, results in a significant proportion of early graft losses. (b) Systematic histological evaluation of failed grafts is absolutely necessary for the accurate classification of the cause of graft loss. (c) There is morphological evidence that chronically ongoing thrombosis is an important, common, contributing factor for late graft loss.

Purpose To report the clinical course of a rare case of bilateral herpetic linear endotheliitis. Methods A 70-year-old man presented with bilateral circumferential bullous edema with stromal edema progressing centrally in the left cornea and bilateral sensorineural hearing impairment simultaneously. Serum immunoglobulin G (IgG) and IgM antibodies against herpes simplex virus type 1 (HSV1) were tested for, and aqueous humor from both eyes was examined separately using polymerase chain reaction for the presence of HSV1 DNA. Results Serum antibody titers against HSV1 were positive. In the polymerase chain reaction, the aqueous humor showed HSV1 DNA in both eyes. Forty milligrams of prednisolone was given per day and 200 mg of oral acyclovir was given 4 times daily, but corneal edema progressed. After penetrating keratoplasty surgery in the left eye, recurrent herpetic endotheliitis also seemed to occur. Conclusions HSV-1 may cause bilateral corneal linear endotheliitis and hearing impairment simultaneously. Linear endotheliitis should be regarded as a manifestation of HSV1 corneal infection. There is a poor prognosis, and severe corneal edema can result if aggressive treatment is not used.

All 684 post-orthotopic liver transplantation (OLT) liver biopsies performed at the Royal Free Hospital (RFH) between 1988 and 1993, from 120 patients, were reviewed in order to try to define the relative importance of the histological features of immunosuppressionresponsive cellular rejection. Twenty histological features considered to be possible contributors to the diagnosis of cellular rejection were documented in a binary (presentlabsent) fashion. These features in 106 biopsy specimens obtained 1 to 8 days after OLT were analyzed using stepwise logistic discriminant analysis. All clinical and treatment records were reviewed, and each biopsy specimen was assigned to a diagnostic category depending on these records and follow-up information. Important determinants of the histological diagnosis of cellular rejection (which occurred in 84 of the 106 cases) were moderate/severe mixed portal inflammation, eosinophils, endotheliitis, and bile duct damage. When these all occurred together, the odds of rejection increased 3.6-fold. The original histological diagnosis was recorded, and each biopsy specimen showing cellular rejection was regraded according to the specific criteria of Snover et al., Demetris et al., and a novel RFH scoring system. The latter consists of evaluating portal inflammation, endotheliitis, eosinophils, and bile duct damage, each on a 0 to 3 scale (none, mild, moderate, or severe, respectively) and summation. The resulting cellular rejection score thus can range from 0 to 12. The agreement between the different scoring systems was analyzed using K statistics, and there was good concordance (K, 0.64 to 0.78), despite different histological criteria being used to derive each score. Each system showed a similar degree of sensitivity (87% to 96%). The specificity ranged from 59% to 77%. We conclude that the histological diagnosis of cellular rejection relies mainly on the previously described features of mixed portal inflammation, endotheliitis, eosinophils, and duct damage. There is scope for unification and simplification of the existing grading systems, which depend on differing criteria, and we suggest one such scheme.

We report the first two cases of apparent azathioprine hepatotoxicity occurring after liver transplantation. The two patients exhibited jaundice, elevated serum transaminase activities and histopathological features of sinusoidal congestion and centrilobular hepatocellular degeneration 17 and 61 days after transplantation. After withdrawal of azathioprine, liver test results improved immediately in both patients. Recurrence of liver injury after another challenge with azathioprine was seen in the first case. Previously, fatal venoocclusive disease occurring after kidney transplantation had been attributed to azathioprine. Irreversible venoocclusive disease and the reversible hepatotoxicity described in this report (i.e., sinusoidal congestion with centrizonal necrosis) most likely represent different stages of hepatic endotheliitis caused by azathioprine. Thus early diagnosis of azathioprine hepatotoxicity is of great importance. (HEPATOLOGY 1991;14:806–810).

Hepatic allograft rejection is presently classified into acute and chronic rejection based on histological features, timing and reversibility. However, because features of both types of rejection can occur at any time, and in many combinations, the terms "acute" and "chronic" seem inappropriate in some instances. Thus the term "cellular rejection" better defines the histological features of portal hepatitis, nonsuppurative destructive cholangitis and endotheliitis, which are independent of time and response to therapy. Similarly, because progressive bile duct destruction leading to a decrease in the number of interlobular and septal bile ducts is the major histological feature of "chronic rejection," the term "ductopenic rejection," defined as the loss of bile ducts in 50% or more of portal tracts independent of time and reversibility, seems more appropriate. The pathogenesis of cell-mediated rejection has not been completely explained; however, direct immunocytic attack on small bile ducts and small arteries appear to be the major feature. The process may lead to bile duct loss ("ductopenia"). The pathogenetic role of foam-cell arteritis resulting in ischemic bile duct injury and the role of humoral mechanisms in causing ductopenic rejection awaits further clarification. In the past, irreversible ductopenic rejection occurred in approximately 10% of all patients who underwent their first liver transplantation; this figure, however, appears to be decreasing. The clinical features of irreversible rejection include persistent and progressive cholestasis; rising serum levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase; and a decrease in hepatic synthetic function. Ductopenic rejection can occur early (2 to 5 wk after liver transplantation) but most often develops between 6 wk and 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

PURPOSE We propose a nomenclature for classification of herpes simplex virus (HSV) keratitis. We hope that a more consistent classification system will lead to a better understanding of the disease processes, thus resulting in improved diagnosis, treatment, and patient outcomes. METHODS A review of the literature was performed to evaluate current HSV classification systems. These systems were evaluated in the context of both current clinical and basic science studies and our own clinical observations. RESULTS The proposed classification system is based on the anatomy and pathophysiology of the specific presentations of HSV keratitis. Anatomically, the primary level of corneal involvement, whether epithelium, stroma, or endothelium, must be elucidated. Pathophysiologically, the cause of the inflammation. whether immunologic, infectious, or neurotrophic, must be determined. There are four major categories of HSV keratitis. (1) Infectious epithelial keratitis, which is made up of cornea vesicles, dendritic ulcer, geographic ulcer, and marginal ulcer. (2) Neurotrophic keratopathy, which includes punctate epithelial erosions and neurotrophic ulcer. (3) Stromal keratitis, which is subdivided into necrotizing stromal keratitis and immune stromal keratitis. (4) Endotheliitis, which has three clinical presentations: disciform, diffuse, and linear. CONCLUSION We believe that by categorizing cases of HSV keratitis by their primary anatomic and pathophysiologic etiologic characteristics, clinicians can better understand and therefore treat all types of HSV keratitis. The four main categories of HSV keratitis are infectious epithelial keratitis, neurotrophic keratopathy, stromal keratitis, and endotheliitis. Each of these is subdivided to more specific clinical presentations.

Herpes simplex virus (HSV) infection is one of the leading causes of corneal blindness. This study compared the clinical, virologic, and immunopathologic features of primary and recurrent murine models of herpes simplex keratitis (HSK) in the National Institutes of Health (NIH) inbred mouse strain. Primary infection resulted in multiple epithelial dendrites, followed by diffuse stromal opacification, symptoms that do not mimic what is seen in human HSK. In contrast, recurrent infection presented clinical features that included microdendrites, focal stromal opacities, disciform endotheliitis, and corneal neovascularization, which were similar to those observed in human disease. Immunohistochemical characterizations indicated that the number and duration of T cells and macrophages in recurrent HSK resemble those observed in primary disease. Results also indicated that the amount of infectious virus detected in the cornea during primary and recurrent disease was similar. However, when corneas were stained for HSV-1 antigens, mice with primary HSK displayed diffuse HSV antigen expression throughout the cornea, whereas HSV antigens were more focally distributed in recurrent disease. These data suggest that the clinical differences between the recurrent and primary herpetic keratitis may, in part, reflect the different distribution of HSV-1 antigens within the cornea.

60 patients were studied 3 months to 4 years after pregnancy. All had high pressure, gross proteinuria, and edema. In many cases, typical glomerular lesions and proteinuria disappeared rapidly. When arteriolar lesions are of grade I or II, they progressively disappear or remain unchanged and blood pressure returns to normal values. When arteriolar lesions are of grade III (endotheliitis, hyperplasia and edema of the media and subendothelial deposits), blood pressure remains at a high level or increases, without changes during the time of observation of the arteriolar lesion or of renal function.