The Role of PCSK9 in Infectious Diseases.

BACKGROUND: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, in particular regarding its role in lipid metabolism, cardiovascular risk but also its role in innate immunity. Increasing evidence is available on the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, as well as in the regulation of host response to bacterial infections, mainly sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. OBJECTIVE: Aim of this paper is to review available published literature on the role of PCSK9 in a wide array of infectious diseases. CONCLUSION: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients for the treatment of HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Finally, a loss of function in the PCSK9-encoding gene has been reported to possibly reduce mortality in malaria infection.

INFECTIOUS PATHOLOGIES AFFECTING KIDNEY TRANSPLANT RECEPIENTS: A SINGLE CENTRE PROSPECTIVE OBSERVATIONAL STUDY

Introduction: Kidney transplant recipients (KTRs) have to receive lifelong immunosuppressive therapy. Consequently they are predisposed to life threatening infections. Even though the data on infectious pathologies have been described in KTRs, the data on long term sequalae of such diseases is lacking. Methods: In this single high volume centre we followed up 100 KTRs, who presented to us with signs of infections. Patients presenting with acute drug reaction or toxicity, malignancy, and auto-immune disorders were excluded. Results: Majority of the patients were male (80%) with a median age of 47years and the median duration of follow up is 34 months. Comorbidites were present in majority of patients in the form of hypertension (83%), Diabetes (11%), heart disease (7%). Amongst infections prior to kidney transplant, TB (28%), HCV (11%) and HBV (1%) were the predominant. 33% patients had acute graft dysfunction, which on biopsy showed mostly ATN and was managed conservatively. However one patient had features of CMV viremia, which was managed with iv Valganciclovir. During follow up 57% of patients presented to us with at least one episode of infection, while 24% patients had 3 more episodes of infection during the follow up period. First episode of infection occurred after a median duration of 10 months. The most common infections were UTI (40%), acute gastroenteritis (35%), CMV infections (10%),pyelonephritis (5%), bacterial pneumonia (5%) protozoal infections (2%), COVID (2%). Most of the infections were managed successfully however 10% patients had graft dysfunction and are on maintenance hemodialysis. Conclusions: Infections in KTRs are a serious debilitating condition which affect graft function. Prompt and aggressive treatment is warranted for graft survival. No conflict of interest

ADULT-ONSET STILL'S DISEASE AND MACROPHAGE ACTIVATION SYNDROME FOLLOWING COVID-19 PNEUMONIA

CASE: A 41-year-old woman with recent COVID-19 pneumonia presented to the hospital with several months of fever, polyarthralgia, and weight loss. She reported waxing and waning shoulder, elbow, wrist, hip, knee, and ankle pain without identifiable triggers. She had no pertinent medical or family history. Vital signs were only notable for fever of 40C which recurred daily. Exam revealed tenderness to palpation of multiple joints;her skin had no rash, purpura, or nodules. Hepatosplenomegaly and axillary lymphadenopathy were noted. Infectious workup was negative for bacterial, viral, fungal, mycobacterial, parasitic, and protozoal infections. Initial studies demonstrated hemoglobin 8.2 mg/dL, lymphopenia, and aspartate transaminase 58 U/L. Flow cytometry, excisional lymph node biopsy, and bone marrow biopsy were negative for lymphoproliferative disease. Rheumatologic workup revealed elevated ferritin, triglycerides, Interleukin-6, soluble Interleukin-2 receptor (sIL-2R), and “C-X-C Motif Chemokine Ligand 9” (CXCL9);extensive rheumatologic serologies were otherwise negative. Her clinical picture was consistent with Macrophage Activation Syndrome (MAS). She also met diagnostic criteria for Adult-Onset Still's Disease (AOSD) given arthralgia, fever, lymphadenopathy, splenomegaly, abnormal liver function test (LFT), and otherwise negative workup. Her presentation suggested COVID-19 triggered AOSD which triggered MAS. We administered intravenous immune globulin (IVIG) and high-dose steroids. She clinically improved and was discharged with oral steroids. She returned to the hospital two months later for fever, arthralgia, and faint, evanescent rash with elevated erythrocyte sedimentation rate, C-reactive protein, ferritin, lactate dehydrogenase, and LFT consistent with an AOSD flare. She received intravenous steroids and Anakinra. Symptoms resolved, and she was discharged with plans to continue Anakinra and oral steroids. At followup, she had resolution of all symptoms. IMPACT/DISCUSSION: COVID-19 has many chronic complications, including triggering of underlying rheumatic disease. This sequence of events suggests that COVID-19 Pneumonia triggered an underlying diagnosis of AOSD. AOSD should be considered in the differential diagnosis of patients with quotidian fever and arthralgia following COVID-19 infection. AOSD is a diagnosis of exclusion and requires ruling out infectious, malignant, and rheumatic etiologies. AOSD may trigger MAS, a dysregulated immune response to underlying inflammation, and should be considered in patients with suspected infection refractory to treatment who have fever, splenomegaly, cytopenias, and elevated ferritin, triglycerides, sIL-2R, and CXCL9. CONCLUSION: COVID-19 has many chronic complications. AOSD may manifest after COVID-19 infection and should be considered in the differential diagnosis of patients with persistent fever and arthralgia. MAS should be suspected in patients with systemic inflammation refractory to treatment. AOSD may cause MAS.

Challenges and Promises for Obtaining New Antiprotozoal Drugs: What’s Going Wrong?

Infections by protozoa can cause some of the most serious human diseases, particularly in tropical regions. However, the number of available drugs used to treat such diseases tends to be limited with relatively high toxicity, and the vast majority of such drugs were developed in the 1920s to 1970s. The development of antiprotozoal drugs has been hindered owing in part to: (1) the highly complicated life cycles of such organisms and their ability to avoid innate immune defences;(2) challenges associated with culturing such organisms particularly in different phases of their growth and amplification;and (3) a lack of investment in biomedical research aimed at developing treatments for tropical diseases that do not tend to affect more affluent countries. Indeed, only three new drugs have entered into clinical trials in recent times, highlighting the tremendous gap in knowledge that should be bridged to more effectively treat protozoal infections.

Serum Calprotectin Levels in Dogs with Diarrhea

Background: Diarrhea induced by infectious factors may lead to significant health problems in dogs. Canine parvovirus (CPV), canine coronavirus (CCV), canine distemper virus (CDV), Giardia spp., Escherichia coli (E. coli), and Salmonella spp. are the important infectious agents that may induce diarrhea in dogs. The present study aimed to investigate the effect of CPV, CCV, CDV, Giardia spp., E. coli, and Salmonella spp. infections on the change in serum calprotectin (Calp) concentration. Materials, Methods & Results: A total of 30 dogs were enrolled in the study. The study dogs were divided into 3 groups. Healthy animals as confirmed by clinical examination and animals negative for the specified pathogens were placed in Group 1. Animals infected by one or more agents, including CPV, CCV, CDV, and Giardia spp., but negative for E. coli or Salmonella spp. were placed in Group 2. Finally, animals positive for E. coli or Salmonella spp. and infected or not infected by one or more agents, including CPV, CCV, CDV, and Giardia spp., were placed in Group 3. Stool samples and rectal and conjunctival swab samples were collected to investigate the etiologic agents that induced diarrhea. Blood samples were collected through vena cephalica antebrachii for hematological and biochemical examinations. The samples were obtained via routine clinical examinations at the Prof. Dr. Servet Sekin outpatient clinic at Dicle University Veterinary Faculty. CPV, CCV, CDV, and Giardia spp. diagnoses were made based on immunochromatographic test kits. The bacteriological analysis of stool samples was used to diagnose E. coli and Salmonella spp. infection. Serum Calp concentrations were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The analysis of swab and stool samples by immunochromatographic rapid diagnosis kits and microbiological methods showed that 5 animals were infected with CPV, 10 with CCV, 6 with CDV, 3 with Giardia spp., 12 with E. coli, and 2 with none of the specified agents. Total leukocyte count (WBC), lymphocyte (Lym - %), and granulocyte (Gra - %) values were higher in the diarrheal dogs when compared with the control group. In the biochemical examination of serum samples, total bilirubin (TBIL) and phosphorus (P) levels were higher and sodium (Na) levels were lower in Group 3 when compared to the control group (P = 0.025, 0.024, and 0.018, respectively). Total protein (TP) and albumin (Alb) values were lower in Group 2 compared to Groups 1 and 3 [P = 0.001 and 0.019 for TP, P = 0.000 and 0.01 for Alb, respectively]. There was a statistically significant difference in creatine kinase (CK) levels between Group 1 and Group 2 (P = 0.013). Serum Calp level was higher in the E. coli infected group (Group 3) compared to the other groups, no significant differences were noted between the groups (P > 0.05). Discussion: In conclusion, to the best of authors knowledge, this study is the first to evaluate serum Calp levels in dogs with diarrhea induced by viral, bacterial, and protozoan infections. The Calp level was higher in the sick dogs that were infected by at least one agent, including CPV, CCV, CDV, and Giardia spp., and were at the same time E. coli positive when compared with the control group and the group without E. coli infections. It was concluded that new studies could be useful to reveal the diagnostic importance of serum Calp concentration in dogs with diarrhea and that these results may contribute to future studies in this area.