Acyclovir reduces the duration of fever in patients with infectious mononucleosis-like illness.

Acyclovir is known for its antiviral activity against some pathogenic viruses such as the Epstein-Barr virus (EBV) that causes infectious mononucleosis (IM) and IM-like illness. Therefore, we empirically administered acyclovir to patients with suspected EBV-IM and IM like-illness, upon their admission to our hospital. We admitted 25 patients, who were hospitalized for fever and lymphadenopathy, to the Tohoku University Hospital Infectious Disease Ward. As part of treatment, 8 of these patients were given acyclovir (750 mg/day) with their consent and were assigned to the acyclovir group; the remaining 17 patients were assigned to the control group. The mean age of acyclovir patients (all men) was 42±5.2 years, and that of control patients (13 men and 4 women) was 31±3.0 years. The cause of illness was confirmed as EBV-IM in 6 patients (1, acyclovir; 5, control), and remained unknown for the other 19 IM-like illness patients (7, acyclovir; 12, control). A shorter duration of hospitalization and fever was observed in the acyclovir compared to that in the control patients (hospitalization duration: 16±3.7 vs. 27±7.7 days, P=0.36; fever duration: 4.5±1.8 vs. 18±6.5 days, P=0.04). Additionally, serum amyloid A (SAA) levels were lower in acyclovir than that in control patients (98±37 vs. 505±204 µg/mL, P=0.02). Therefore, we propose that acyclovir is a potential therapeutic agent for both EBV-IM and IM like-illnesses. Future studies should further examine its mechanism of action.

Quinolone-induced upregulation of osteopontin gene promoter activity in human lung epithelial cell line A549.

Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin (62%), gatifloxacin (82%), sparfloxacin, (79%), and sitafloxacin (60%). Enhancement of OPN secretion was shown to be due to the effect of quinolones on the OPN gene promoter activity. We also examined the role of quinolones on apoptosis and found that sparfloxacin decreased the late apoptosis of A549 cells, but garenoxacin did not show the antiapoptotic effect. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation.

Distinct clinical features in nontuberculous mycobacterial disease with or without latent tuberculosis infection.

Nontuberculous mycobacteria (NTM) diseases are in the face of a progressive increase even in immune-competent subjects, and the clinical features of NTM diseases are heterogenous. The decision to institute treatment of the patients should be made after a period of follow up, because therapy is often prolonged, and frequently ineffective. The reasons why some patients develop severe NTM diseases are not clear. Here we observed the involvement of latent tuberculosis infection (LTBI) in clinical and laboratory features of NTM diseases. We evaluated various tuberculosis-related inflammatory markers including osteopontin (OPN), pentraxin-3 (PTX-3), and soluble IL-2 receptor (sIL-2R) in NTM infected patients with or without LTBI. Eight NTM and 5 tuberculosis (TB) patients, and 5 healthy subjects were enrolled. Polymerase Chain Reaction (PCR) analysis confirmed the absence of tuberculosis specific gene (RD1 region), among clinical isolates from NTM patients. Interferon-γ (IFN-γ) release assay (IGRA) using Early Secreted Antigenic Target-6 (ESAT-6) and CFP-10, the RD1-encoded protein, was employed for determining LTBI. IGRA was positive in 4/8 NTM (NTM with LTBI, 50%) and 5/5 TB patients. Only 2 of 4 NTM with LTBI were under chemotherapy among all NTM patients, and others were followed up. The plasma levels of OPN, PTX3 and sIL-2R were significantly higher in NTM patients with LTBI than in those without LTBI (P < 0.05). The two patients under therapy showed the highest OPN levels that persisted after treatment. The increased inflammatory levels in NTM patients with LTBI indicate enhanced inflammatory reaction. Extensive therapy may be necessary in such patients.

Improved inhaler handling after repeated inhalation guidance for elderly patients with bronchial asthma and chronic obstructive pulmonary disease.

Accurate evaluation of inhaler handling is essential for improved treatment of bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD). Many studies have described the correlation between age, inhalation guidance, and procedure improvement. Elderly patients should receive proper inhalation guidance. This was a retrospective open cohort study conducted at a single hospital with outpatient open pharmacies that provided inhalation guidance to patients of BA and COPD. A total of 525 cases were included in the study. The median age was 71 years with no significant difference between genders (males: 71 ± 16.0 years; females: 72 ± 16.1 years; P = .24). There were 226 males (43.0%) and 299 females (57.0%; P = .03). BA was significantly more prevalent than COPD (P < .001). There was no significant difference in dry powder inhaler (DPI) and pressurized metered-dose inhaler (pMDI) visits in those <60 years of age (P = .23). pMDI was used significantly more often than DPI in those aged 60 to 90 years of age (P < .001). In both <70 and >70 years of age, the most common error with DPI use was improper inhalation speed, which reduced (improved) at the third visit. Gargling errors were most common with DPI use at the second visit and with pMDI at the first visit in both age groups, which subsequently reduced rapidly. Continuous repeated guidance steadily and significantly decreased errors with all devices (P < .001 for DPI, pMDI, and soft mist inhaler). Elderly cases (>70 years of age) should undergo continuous repeated guidance to reduce inhalation errors like inhalation speed and gargling errors.

Two Cases of COVID-19-Related Deaths Unaccounted for: A Call for Action.

Coronavirus disease 2019 (COVID-19) high-risk survivors experience long-term COVID-19 symptoms. Hence, these individuals require early and ubiquitous respiratory rehabilitation to avoid malnutrition. We report the case of a 93-year-old woman who recovered from moderate II severity (pneumonia requiring oxygen). The patient, after prolonged hospitalization, demonstrated low severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity and showed no COVID-19 respiratory symptoms for more than 72 hours. Subsequently, the patient became debilitated and lost her appetite without dysphagia, dysgeusia, and smell disorder, developed nosocomial pneumonia as a sequela of acute COVID-19 and died. We also report the second case of an 84-year-old man diagnosed with moderate II COVID-19 severity. After recovery, the patient was frail due to the previous onset of COVID-19 and worsened during his stay at home, losing appetite without dysphagia, dysgeusia, and smell disorder, and dying of senility as the official cause. Recovered COVID-19 appears to be a health risk by malnutrition without anorexia and depression, among other conditions. A proven rehabilitation program for each phase of the disease is required for better lung function and nutritional status.

A case of Sjögren's syndrome with worsening of pleural effusion due to steroid discontinuation.

The etiology of Sjögren's syndrome (SS) remains unclear and is associated with many other autoimmune diseases. In particular, symptoms of SS are not apparent when steroids are already being administered for other autoimmune diseases. This report documents a case of autoimmune hepatitis with SS, which was diagnosed on the basis of the worsening of unilateral pleural effusion after the discontinuation of steroids as well as the manifestation of symptoms, such as dry mouth. Adrenal insufficiency due to the discontinuation of steroids was assumed to be the cause of the worsening, rather than infection stress, because no indicators of infectious diseases were observed. The diagnosis of SS was confirmed via lip biopsy examination and anti-SS antibody positivity. Re-administration of steroids rather than antibiotics drastically reduced the pleural effusion and improved the dry mouth symptom. SS with pleural effusion in a case of autoimmune disease was reported to show both unilateral and bilateral pleural effusion predominantly containing lymphocytes. SS with pleural effusion may be more common than expected and should be differentiated from traditional SS. Moreover, biopsy examination should be considered if necessary because the condition might remain latent when steroids are administered.

Malnutrition, Airflow Limitation and Severe Emphysema are Risks for Exacerbation of Chronic Obstructive Pulmonary Disease in Japanese Subjects: A Retrospective Single-Center Study.

Background: Different characteristics of patients with chronic obstructive pulmonary disease (COPD) between Western and Japanese populations have been reported. Risk factors for COPD exacerbation have been reported in Western countries but have not been studied in Japan. Patients and Methods: We retrospectively examined risk factors for COPD exacerbation. A total of 156 Japanese patients were enrolled, and the records of 136 patients were analyzed. Results: In the exacerbation group (n=60), body mass index, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), the FEV1/FVC ratio (FEV1/FVC), the percent predicted values of FEV1 (%FEV1), and serum total protein (TP) and albumin concentrations were lower, and age, mortality rate, frequency of common cold and pneumonia, COPD severity rankings, modified Medical Research Council (mMRC) dyspnea score, and proportions of patients with severe emphysema (>50% of low attenuation area) and receiving long-term oxygen therapy were higher than those in the nonexacerbation group (n=76). However, the proportion of patients with a greater number of eosinophils (≥200/µL and/or ≥2%) and the exhaled nitric oxide concentration did not differ between the two groups. In the univariate analysis, the risk factors for exacerbation were age; long-term oxygen therapy; low FVC, FEV1, FEV1/FVC and %FEV1; high COPD severity ranking and mMRC score; severe emphysema; hypoproteinemia (<6.5 g/dL); hypoalbuminemia (<3.5 g/dL); leukocytosis; lymphocytopenia; and anemia. In the multivariate analysis, the risk factors were hypoalbuminemia, hypoproteinemia and low FEV1. Additionally, in patients in the exacerbation-induced mortality subgroup, age, exacerbation frequency, mMRC score and the proportion of patients with lymphocytopenia were higher, and FVC, %FVC, FEV1, serum TP concentration and the lymphocyte number were lower than those in the exacerbation survival subgroup. Conclusion: Malnutrition, airflow limitation and severe emphysema were risks for exacerbation and mortality associated with infection in Japanese patients with COPD.

Efavirenz-induced neurological symptoms in rare homozygote CYP2B6 *2/*2 (C64T).

Some of the HIV-1-infected patients who were given highly active anti-retroviral therapy (HAART) including efavirenz (EFV) presented adverse central nervous system (CNS) symptoms such as fatigue and insomnia. The incidence of adverse CNS symptoms is associated with hepatic cytochrome P450 isozymes (CYP2B6) polymorphisms. For example, CYP2B6 *6 (G516T and A785G) and *7 (G516T, A785G and C1459T) prolonged the EFV half-life despite discontinuation of EFV. CYP2B6 *2/*2 (C64T) is extremely rare and there have been no data describing the EFV plasma concentrations in C64T homozygous patients, who developed adverse CNS symptoms. C64T homozygous possibly has some catalytic defects.

Properties of anti-gp41 core structure antibodies, which compete with sera of HIV-1-infected patients.

To determine the correlation between the immunoreaction against the core structure of human immunodeficiency virus type (HIV-1) transmembrane protein gp41 epitopes and the disease progression, it is essential to evaluate the anti-core structure antibody epitopes and the humoral immunity against the epitopes. For this purpose we evaluated monoclonal antibodies (mAbs) against the gp41 core structure such as mAbs 50.69, 98.6 and T26, by Western blotting (WB) and flow cytometry. WB showed mAbs 50.69 and 98.6 bound to both monomeric and oligomeric gp41, and mAb T26 exclusively bound to oligomeric gp41. We evaluated the sera from Pneumocystis pneumonia patients (PCP; n=7) and long-term survivors (LTS; n=7). Competition assay with sera and mAbs for binding to H9 cells infected with HIV-1 IIIB virus was done using flow cytometry. The results revealed that PCP sera as well as LTS sera inhibited the binding of all the three mAbs, and the PCP sera inhibited mAb T26 binding more efficiently than LTS. Therefore, PCP patients retain competing immunity to antibodies against not only the shared epitopes of the core structure (binding sites of mAbs 50.69 and 98.6) but also against oligomeric gp41 specific epitope (binding site of mAb T26).

A case of Manila type Mycobacterium tuberculosis infection in Japan.

A 76-year-old Japanese woman contracted a Mycobacterium tuberculosis (TB, Manila type) infection in Japan, despite never having traveled. However, her son was treated for TB in the Philippines 3 years before he stayed at her house. Spoligotyping allows us to identify the TB genotype and identify the route of infection.

Thrombin activates envelope glycoproteins of HIV type 1 and enhances fusion.

To elucidate the roles of serine proteases, including thrombin, in HIV infection, we treated H9 cells infected with HIV-1 LAI virus (H9/IIIB) with four different proteases (thrombin, cathepsin G, trypsin and chymotrypsin) and observed their effects on functional epitopes on both gp120 and gp41 by using flow cytometry. Monoclonal antibodies (MAbs) against the V3 loop, V2 loop, CD4 binding site, coreceptor binding site and gp41 were used. It was found that trypsin decreased the binding of all MAbs except for one MAb against the V3 loop (IIIB-V3-21). Chymotrypsin and cathepsin G did not show any remarkable effect on the antigen expression. On the other hand, thrombin decreased the reactivities of two out of four anti-V3 MAbs and increased the exposure of functional gp120 epitopes including the coreceptor binding site and CD4 binding site. Thrombin also increased the expression of 2F5 antigen (a neutralizing epitope of gp41) but had no effect on other gp41 epitopes. The effect of trypsin or thrombin on HIV-induced cell fusion was examined through co-culturing H9/IIIB and MAGI cells. Trypsin slightly inhibited fusion. Fusion was significantly enhanced in a dose-dependent manner by thrombin, and a 280% increase at 5 U/ml (P < 0.001) was observed. In conclusion, thrombin, one of the major inflammatory molecules in blood, facilitates HIV-induced cell fusion, probably by activating gp120.

The N-terminal of the V3 loop in HIV type 1 gp120 is responsible for its conformation-dependent interaction with cell surface molecules.

The V3 loop of HIV-1 gp120 plays an important role in the interaction of the viral envelope with cellular coreceptors and/or with other cell surface molecules. To clarify this interaction we used a panel of monoclonal antibodies (MAbs) against V3 loop and synthetic looped V3 peptides V3-BH10, V3-ADA, and V3-89.6, derived from the V3 regions of the BH10 clone of IIIB (X4-tropic), ADA (R5-tropic), and 89.6 (R5X4-tropic), respectively. A linear mutant peptide, V3-BH10/CA, was also synthesized as a control. Biotinylated V3-BH10, -BH10/CA, and-ADA were also made. The binding abilities of the biotinylated and nonbiotinylated peptides to various types of cells were investigated by using flow cytometry. Subsequently, the principal region of the V3 loop involved in cell surface binding was analyzed by using MAbs against the tip (447-52D and 694-98D), N-termini (IIIB-V3-21) or C-termini (IIIB-V3-01) of the V3 loop in flow cytometry and enzyme-linked immunoabsorbent assay. We demonstrate that looped V3 peptides of both X4 and R5X4 HIV (V3-BH10 and V3-89.6) can bind to various types of cells irrespective of their CD4 and/or coreceptor expression in a conformation-dependent manner. In contrast, the V3 loop of R5 HIV (V3-ADA) can scarcely bind to the cells. Using MAbs whose epitopes cover the entire V3 loop we found that MAb IIIB-V3-21 can react with platebound but not cell-bound peptides, and the MAb blocked biotin-V3-BH10 binding suggesting that the N-terminal of the V3 loop interacts directly with cell surface molecule(s).

A man from South Asia presenting with abdominal pain.

The diagnosis of abdominal tuberculosis (TB) is challenging due to the non-specific clinical presentation and frequent failure to detect the pathogen. A young Bangladeshi man presented to the Emergency Outpatient department with constipation and burning abdominal pain that was localised primarily in the epigastrium. Although the infectious agent was not detected, findings of histological examination were helpful in guiding the treatment strategy. As a good clinical practice, it is important to consider abdominal TB as a possible diagnosis in such cases, particularly when a patient has previously been residing in a high TB burden country. Thus, appropriate diagnosis and early antituberculous therapy are essential for achieving a positive outcome.

Characterization of a CD4-independent clinical HIV-1 that can efficiently infect human hepatocytes through chemokine (C-X-C motif) receptor 4.

OBJECTIVE: HIV-1 isolates are prominently CD4-dependent and, to date, only a few laboratory-adapted CD4-independent strains have been reported. Therefore, whether CD4-independent viruses may exist in HIV-1-infected patients has remained unclear. Here, we report the successful isolation of a CD4-independent clinical HIV-1 strain, designated SDA-1, from the viral quasispecies of a therapy-naive HIV-1 and Pneumocystis jirovecii pneumonia patient in the late-stage of AIDS with extremely low CD4 cell count (CD4 = 1/microl). We characterized this virus and further explored whether it could infect or induce pathological effects in human hepatocytes. DESIGN AND METHODS: To determine coreceptor usage and CD4-independent infection, the HIV-1 envelope (Env)-pseudotypes and Env-chimeric viruses were used. RESULTS: SDA-1 was able to infect CD4 cell lines through either chemokine (C-X-C motif) receptor 4 or CCR5. It still maintained the ability to infect CD4 cells through multiple coreceptors of chemokine (C-X-C motif) receptor 4, chemokine (C-C motif) receptor 5, chemokine (C-C motif) receptor 3 and chemokine (C-C motif) receptor 8. Productive infection by SDA-1 was noted in both CD4-negative hepatoma cells and primary cultured human hepatocytes. Moreover, we demonstrated that SDA-1 could efficiently infect human hepatocytes on both static and mitotic phases through chemokine (C-X-C motif) receptor 4, without inducing apoptotic cell death. CONCLUSION: The present study provides evidence that emergence of CD4-independent HIV-1 virus in vivo may occur in HIV-1-infected patients. In addition, these results shed light on the mechanisms involved in liver damage in HIV-1-infected individuals, which could have important implications concerning the range of mutability and the pathogenesis of AIDS.

Systemic sarcoidosis associated with double cancers of the esophagus and stomach.

To discriminate between sarcoidosis and sarcoid reaction in the lymphadenopathy of malignancy is sometimes clinically important. We describe a case of sarcoidosis associated with double cancers of the esophagus and stomach. A patient who six months previously was found to have early gastric cancer, was then found to have esophagus cancer. The chest radiography demonstrated bilateral hilar lymphadenopathy. Pathological analysis of the lymph nodes and lungs showed non-caseating epithelioid cell granuloma, revealing the existence of sarcoidosis. The findings suggest that the possibility of systemic sarcoidosis should be considered in cases with established malignancy and newly disclosed radiographic findings.

Competitive study of monoclonal antibodies against the HIV-1 Gp41 core structure.

Monoclonal antibodies (MAbs) 50.69, 98.6, and T26 bind specifically to the core structure of the human immunodeficiency virus type 1 (HIV-1) envelope transmembrane glycoprotein (gp41). To clarify the specificity of the anti-core structure MAbs, we performed competitive assays using the MAbs to the H9 human T cell line infected with the IIIB strain of HIV-1 (H9/IIIB). Bound MAb 50.69 inhibited MAb 98.6 binding unidirectionally. The reason for the unidirectional cross competition between MAbs 50.69 and 98.6 is not clear, but these results help to define the antigenic structure of gp41 on the surface of infected cells.

Activation of gp120 of human immunodeficiency virus by their V3 loop-derived peptides.

V3 loop peptides from three different human immunodeficiency virus type 1 (HIV-1) strains were synthesized. BH10, ADA, and 89.6 strains whose infections are dependent on CXCR4, CCR5, and both, respectively, were selected. Co-transfection of luciferase reporter gene and corresponding envelope genes (HXB2, ADA, and 89.6) generate pseudotype viruses (HXB2/Luc, ADA/Luc, and 89.6/Luc). The effects of each peptide on the infection of U87 cells expressing CD4 and one of the coreceptors with all pseudotype viruses were evaluated. V3 loop peptide from BH10 (V3-BH10) alone increased the HXB2/Luc infection by 93% at 10 microM. Both V3-ADA and V3-89.6 enhanced ADA/Luc infection by 38% and by 55% at 10 microM, respectively. For 89.6/Luc infection, only V3-89.6 enhanced the infections on both target cells. V3-BH10 modulated the epitopes of coreceptor binding site and V2 loop of gp120 on HIV-1 IIIB infected H9 cells, indicating that V3 loop peptide activates viral gp120 and enhances infectivity.