Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in China

BACKGROUND: While human cases of highly pathogenic avian influenza A (H5N1) virus infection continue to increase globally, available clinical data on H5N1 cases are limited. We conducted a retrospective study of 26 confirmed human H5N1 cases identified through surveillance in China from October 2005 through April 2008. METHODOLOGY/PRINCIPAL FINDINGS: Data were collected from hospital medical records of H5N1 cases and analyzed. The median age was 29 years (range 6-62) and 58% were female. Many H5N1 cases reported fever (92%) and cough (58%) at illness onset, and had lower respiratory findings of tachypnea and dyspnea at admission. All cases progressed rapidly to bilateral pneumonia. Clinical complications included acute respiratory distress syndrome (ARDS, 81%), cardiac failure (50%), elevated aminotransaminases (43%), and renal dysfunction (17%). Fatal cases had a lower median nadir platelet count (64.5 x 10(9) cells/L vs 93.0 x 10(9) cells/L, p = 0.02), higher median peak lactic dehydrogenase (LDH) level (1982.5 U/L vs 1230.0 U/L, p = 0.001), higher percentage of ARDS (94% [n = 16] vs 56% [n = 5], p = 0.034) and more frequent cardiac failure (71% [n = 12] vs 11% [n = 1], p = 0.011) than nonfatal cases. A higher proportion of patients who received antiviral drugs survived compared to untreated (67% [8/12] vs 7% [1/14], p = 0.003). CONCLUSIONS/SIGNIFICANCE: The clinical course of Chinese H5N1 cases is characterized by fever and cough initially, with rapid progression to lower respiratory disease. Decreased platelet count, elevated LDH level, ARDS and cardiac failure were associated with fatal outcomes. Clinical management of H5N1 cases should be standardized in China to include early antiviral treatment for suspected H5N1 cases

The Role of Amino Acid Metabolism of Tumor Associated Macrophages in the Development of Colorectal Cancer

Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment (TME). Previous studies have shown that TAMs play a dual role in the development of colorectal cancer and promote the additional exploration of the immune escape of colorectal cancer. Studies have confirmed that macrophages utilize amino acid metabolism under the stimulation of some factors released by tumor cells, thus affecting the direction of polarization. Therefore, we investigated the effect of amino acid metabolism on macrophage function and the involved mechanism. Based on the comprehensive analysis of the GSE18804 GEO dataset and amino acid metabolism pathway, we identified the eight key enzymes of amino acid metabolism in colon TAMs, namely, ACADM, ACADS, GPX4, GSR, HADH, HMGCL, HMGCS1 and IDH1. We then evaluated the expression, survival analysis and relationship of clinicopathological features with these eight key enzymes. The results supported the critical role of these eight genes in colorectal cancer. Macrophages phagocytose tumor cells, and these eight key enzymes were identified in combination with GPX4, a critical protein of ferroptosis, suggesting that the change in the expression of these eight key enzymes in TAMs may be involved in the regulation of colorectal cancer through cell death. Correlation analysis of three programmed cell death (PCD) marker genes indicated that these eight key enzymes may cause macrophage death through pyroptosis, leading to immune escape of colorectal cancer. We also investigated the regulation of ACADS in CRC using flow cytometry, qPCR and ELISAs, which demonstrated that an ACADS deficiency polarizes TAMs to M2 macrophages. In summary, the present study revealed the relationship between amino acid metabolism and the cell death of macrophages, providing a new research direction for the molecular mechanism of macrophage polarization

Comparison of demographic and clinical features of 17 fatal and 9 nonfatal H5N1 cases, China.

*<p>Medians were compared between fatal and survival cases with the Wilcoxon rank sum test. For categorical variables, percentages of cases in each category were compared with Fisher's exact test.</p>†<p>NA demotes not applicable.</p>‡<p>Two fatal H5N1 cases had underlying medical conditions, including a 24-year-old pregnant woman <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002985#pone.0002985-Shu1" target="_blank">[28]</a> and a 16-year-old male with a 10-year history of minimal change glomerulopathy. Two surviving H5N1 cases had underlying medical conditions, including a 26-year-old pregnant woman and a 44-year-old female with a ten-year history of chronic bronchitis [unpublished data, China CDC].</p>#<p>A higher proportion of cases survived that received any antiviral treatment compared to those that did not receive antivirals (67% [8/12 patients] vs 7% [1/14 patients], p = 0.003), and with a positive linear association: the Gamma coefficient equals 0.664 (p = 0.005) which indicate a positive correlation between antiviral therapy and disease outcome.</p>$<p>High-dose corticosteroid use was defined as ≥250 mg hydrocortisone or equivalent intravenous (IV) administration daily. For children <13 years old, high-dose corticosteroid use was defined as ≥5 mg hydrocortisone or equivalent IV/kg/day.</p>¶<p>[]: Indicates denominators for testing of fewer cases than full group.</p

Initial chest radiographic findings and progression during hospitalization of 26 H5N1 cases, China.

*<p>NA demotes not applicable</p

Progression of pulmonary disease in chest radiographs from adult (35-year-old male, Panels A day 6 and B day 23 of illness) and pediatric (6-year-old male, Panels C day 6 and D day 14 of illness) H5N1 cases.

<p>Progression of pulmonary disease in chest radiographs from adult (35-year-old male, Panels A day 6 and B day 23 of illness) and pediatric (6-year-old male, Panels C day 6 and D day 14 of illness) H5N1 cases.</p

Laboratory findings of 26 H5N1 cases^* on initial testing, at hospital admission, and during hospitalization, China.

*<p>Indicates denominators for testing of fewer cases than full group.</p>†<p>Abbreviations and normal range: WBC, white blood cell, 4.0–10.0×10⁹ cells per L, leukopenia (abnormal) was defined as leukocyte count less than 4×10⁹ per L; LYM, lymphocyte count, 0.8–4.0×10⁹ cells per L, lymphopenia (abnormal) was defined as lymphocyte count less than 0.8×10⁹ per L; PLT, platelet count, 100–300×10⁹ platelets per L, thrombocytopenia (abnormal) was defined as platelet count less than 100×10⁹ per L.</p>‡<p>Abbreviations and normal range: ALT, alanine aminotrasferase, 0.0–45.0 U/L; AST, aspartate aminotransferase, 0–45 U/L; Albumin, 35.0–55.0g/L; Creatinine, 36.0–144.0 µmol/L; CK, creatine kinase, 25–190 U/L, abnormal was defined as >130 IU/L for males and >110 IU/L for females; CK-MB, creatine phosphokinase isoenzymes, 0–25 U/L; LDH, Lactic dehydrogenase, 110–250 U/L; Plasma glucose concentration, 3.33–5.55 mmol/L for <15 years, 3.89–5.83 mmol/L for adults (16–59 years), 4.44–6.38 mmol/L for age >60 years, hyperglycemia (abnormal) was defined as plasma glucose concentration above the upper limit.</p>#<p>Abbreviations and normal range: PT, prothrombin time, 11–13 second, abnormal was defined as 3 seconds longer than the upper range of normal; APTT, activated partial thromboplastin time, 26–36 second, abnormal was defined as 3 seconds longer than the upper range of normal; FIB, fibrinogen, 2.0–4.0 g/L, abnormal was defined as <2.0 g/L.</p>§<p>Normal ranges: total protein (below 120 mg/L); red blood cells (0 to 1 per average high powered field [HPF×400)); white blood cells (1–4 per HPF×400)</p>¶¶<p>NA demotes not applicable.</p