Viral Infections Lecture

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Viral Infections Lecture

  1. 1. Viral Infections In Which Cardiovascular Manifestations Predominate OST 524 Cardiovascular System M. J. Patterson, MD, PhD
  2. 2. Myocarditis-Pericarditis • Etiology: cardiotropism • Pathology • Clinical features • Diagnosis • Immunity • Epidemiology • Prophylaxis and treatment
  3. 3. Viral Infections with Involvement of the Hematopoeitic and Lymphatic Systems • Epstein Barr Virus (EBV): Infectious mononucleosis • EBV: Burkitt's lymphoma • Human herpes HHV6, HHV7, HHV8 • Human Parvovirus B19: transient aplastic anemia • Bone marrow failure • Malignant association - other
  4. 4. CMV and cardiovascular disease
  5. 5. Cardiac Malformations as Part of Rubella Embryopathy • Etiology: vascular endothelial tropism
  6. 6. Myocarditis - Pericarditis • Etiology – Virus should always be part of the differential diagnosis of primary acute myocarditis – Clinical evidence suggesting involvement of the heart has been reported for essentially all known viruses – Cardiotropism: viral receptor substances
  7. 7. Myocarditis - Pericarditis • Etiology – Most commonly incriminated viruses: enterovirus 30 nm, RNA: Coxsackie B, Coxsackie A, ECHO, polio • Cox B esp 2,3,4,5 • Cox A • ECHO – Occasionally myopericardial involvement in course of any viral infection • often manifested only by EKG modification • does not necessarily imply an anatomic alteration of the myocardium
  8. 8. Viruses That Have Been Shown to Cause Myocarditis • Common – Coxsackievirus A – Coxsackievirus B – Echovirus – Human immunodeficiency virus – Influenza • Less Common – Adenovirus family – Arbovirus – Epstein-Barr virus – Herpes simplex virus type 1 – Human cytomegalovirus – Measles virus – Respiratory syncytial virus – Rubella virus – Varicella-zoster virus
  9. 9. Myocarditis - Pericarditis • Pathology – Relatively nonspecific – Cardiac lesions: dilation and hypertrophy, esp. of left ventricle, edema, interstitial infiltrate of mononuclear cells, isolated necrosis of myocardial fibers, inflammation and necrosis resulting in foci for sclerosis – Diffuse cellular necrosis in other organs in coxsackie infections – Pericarditis rarely occurs without clinical or histologic evidence of myocarditis – Immune-mediated pathology
  10. 10. Circulation 89:2422, 1994
  11. 11. Inflammatory Cytokines Cytokine Principal Cell of Origin Principal Action IL-2 Activated T cell Autocrine T-cell growth factor. Stimulates production of IL-2, TNF-α, Activates natural killer cells IL-1 Activated macrophages, endothelial cells Stimulates T-cell activation. Induction of inflammatory metabolites. Activates endothelial cells and stimulates cytokine production. IL-6 Monocytes, macrophages, T cells, endothelial cells Stimulates differentiation of B cells. Stimulates production of plasma proteins by hepatocytes. INF Activated T cells Activates monocytes. Increases production of oxygen radicals by macrophages. Increases expression of MHC class I and II antigens. TNF- α Activated macrophages Activates endothelial cells. Stimulates production of cytokines. Can induce direct lysis of some cell types. IL-8 Activated macrophages, lymphocytes, endothelial cells Chemo-attractant for neutrophils and causes neutrophil stimulation.
  12. 12. Myocarditis - Pericarditis • Clinical features: relatively rare form of heart disease in U.S., generally acute and benign – Occurrence - a disease of newborns and infants; sometimes older children, occasionally in adults – Antecedent URI---1-30d before symptoms refer to heart – subacute or chronic cardiopathy
  13. 13. Signs and Symptoms of Viral Myocarditis • Symptoms – Fatigue – Dyspnea – Palpitation – Chest pain – Syncope • Signs – Pericardial rub – Sinus tachycardia – Atrial or ventricular arrhythmias – Conduction disturbances – Cardiomegaly – Right or left S3 or S4 gallop sounds – Congestive heart failure
  14. 14. New England Journal of Medicine 343:1391 2000
  15. 15. Infectious Causes of Pericarditis • Bacterial – Actinomyces – Bacteroides fragilis – Borrelia burgdorferi – Brucella – Campylobacter – Chlamydia – Enterococcus sp. – Escherichia coli – Fusobacterium nucleatum – Haemophilus influenzae – Klebsiella pneumoniae – Legionella – Listeria monocytogenes – Mycobacterium avius-intracellulare – Mycobacterium tuberculosis – Mycoplasma pneumoniae – Neisseria gonorrhea – Neisseria meningitis – Nocardia asteroides – Peptostreptococcus – Pseudomonas aeruginosa – Prevotella sp. – Salmonella – Staphylococcus aureus – Streptococcus pneumoniae – Streptococcus (group C)
  16. 16. Infectious Causes of Pericarditis • Viral – Adenovirus – Coxsackie A – Coxsackie B – Cytomegalovirus – Echovirus – Epstein Barr virus – Hepatitis B – Herpes simplex – HIV – Influenza – Mumps – Varicella Zoster • Fungal – Aspergillus – Blastomyces dermatitidis – Candida – Coccidioides Immitis – Cryptococcus neoformans – Histoplasma capsulatum • Parasitic – Entamoeba histolytica – Schistosoma – Toxocara canis – Toxoplasma gondii
  17. 17. Noninfectious Causes of Pericarditis • Collagen vascular diseases – Rheumatic fever – Rheumatoid arthritis – Scleroderma – CREST syndrome – Systemic lupus erythematosus – Sarcoidosis – Sjögren's syndrome – Mixed connective tissue disease – Vasculitis, including temporal arteritis – Polyarteritis • Drug-induced – Minoxidil – Bleomycin – Procainamide – Hydralazine – Azathioprine • Inflammatory bowel disease – Ulcerative colitis – Crohn’s disease
  18. 18. Noninfectious Causes of Pericarditis • Neoplastic – Primary (benign or malignant) – Metastatic to pericardium • Other – Fabry’s disease – Uremia – Löffler's syndrome – Thalassemia – Acute myocardial infarction – Kawasaki’s Disease – Dissection aortic aneurysm – Post-radiation – Pregnancy • Other – Myxedema – Dego's disease – Cardiac Injury • Traumatic • Dressler’s syndrome – Stevens-Johnson syndrome – Polymyositis – Dermatomyositis – Behçet's syndrome – Addisonian crisis – Gout – Whipple’s disease
  19. 19. Criteria for Diagnosis of Myopericarditis • ECG manifestation – ST-T or T wave changes or – Low QRS voltage or – A-V conduction defects or – Intraventricular conduction defects • Plus 2 or more symptoms – Precordial left-sided chest pain – Signs and symptoms of congestive heart failure – Cardiomegaly – Fever – Pericardial friction rub
  20. 20. Myocarditis - Pericarditis • Diagnosis – Appropriate specimens for viral diagnosis • Isolation of agent: pericardial fluid, T.S., R. S. first few days of illness, heart tissue at autopsy or biopsy • Serology: 4-fold rise in titre by neutralization, complement fixation, hemagglutination inhibition; allows identification of a specific recent infection which is circumstantial evidence with a high index of suspicion when correlated with clinical findings. – Etiological diagnosis of viral carditis is difficult
  21. 21. Disease Category: Myocarditis-pericarditis Source Viral Agents Usually Sought Throat Swab Rectal Swab CSF Urine Pericardial Fluid Other Enterovirus ++ +++ - - ++ * Myxovirus +++ - - - ++ * Paramyxovirus +++ - - - ++ * • *Because it is frequently very difficult to isolate and/or associate these agents with the disease in question, it is emphasized that serological tests are particularly important to insure a diagnosis. • N.B. In general, it is important to remember that viral shedding often diminishes rapidly after the onset of illness; therefore, it is important to attempt to collect specimens as early as possible - including an acute serum sample.
  22. 22. Criteria for Viral Myocarditis • High-order association – Isolation of virus from myocardium, endocardium or pericardial fluid or – Demonstration of viral antigen in the myocardium endocardium or pericardium by immunofluorescent or immunoperoxidase assay, etc.
  23. 23. Criteria for Viral Myocarditis • Moderate-order association – Isolation of virus from pharynx or feces, and a fourfold rise in type-specific neutralizing, hemagglutination-inhibiting or complement-fixing antibodies or – Isolation of virus from pharynx or feces, and a concomitant titer in serum of 1/32 or more of type-specific IgM-neutralizing or hemagglutination-inhibiting antibodies.
  24. 24. Criteria for Viral Myocarditis • Low-order association – Isolation of virus from pharynx or feces. – A fourfold rise in type-specific neutralizing, hemagglutination inhibiting, or complement-fixing antibodies – A single serum with a titer of 1/32 or greater of type- specific IgM neutralizing or hemagglutination inhibiting antibodies
  25. 25. Histologic Criteria for the Classification of Viral Myocarditis (“Dallas Criteria”) • Initial Biopsy – Active myocarditis with or without fibrosis • Presence of inflammatory infiltrate and damage of adjacent myocytes • Frank necrosis that may consist of vacuolization, irregular cellular outlines, and cellular disruption with lymphocytes closely applied to the cell surface • Uninvolved myocardium often appears normal – Borderline myocarditis (may require biopsy) • Inflammatory infiltrate or myocyte damage not seen on light microscopy • Diagnostic changes evident on additional cuts of original biopsy, which suggest active myocarditis and do not require a repeat biopsy – No evidence of myocarditis
  26. 26. Histologic Criteria for the Classification of Viral Myocarditis (“Dallas Criteria”) • Subsequent Biopsies – Ongoing myocarditis • Degree of abnormality is equal to or worse than that of the original biopsy – Resolving myocarditis • Inflammatory infiltrate is less and repair is evident – Resolved myocarditis • No remaining inflammatory infiltrate and no evidence of persistent cellular necrosis
  27. 27. Myocarditis - Pericarditis • Immunity: – Need to see 4-fold rise due to ubiquity of the agents and persistence of titers – Chronicity postulated due to lesions representing an immune response
  28. 28. Myocarditis - Pericarditis • Epidemiology: – Season: random through year – Spread: fecal-oral and respiratory – Age – Other factors: • Physical exercise • Nutrition • Volume load on circulatory system • Pregnancy • Sex • Corticosteroids • Diabetes
  29. 29. The Journal of Experimental Medicine 143:1239, 1976
  30. 30. Myocarditis - Pericarditis • Prophylaxis and treatment: – Chronic sequelae constitute an argument for search for specific treatment and prevention – Controlled studies of effects of therapeutic measures are needed – Bed rest and supportive therapy
  31. 31. Proposed Therapies of Postviral and Idiopathic Myocarditis Category Therapy Comment Conventional therapy of congestive heart failure Digitalis and diuretics Digitalis may decrease interleukin- 1β and tumor necrosis factor-α Angiotensins-converting enzyme inhibitors and angiotensin-II receptor antagonists May have a direct immunomodulatory effect Bed rest, β-blockers Both beneficial and deleterious effects in murine models Immunosuppressive therapy Corticosteroids Documented use in humans Cyclosporine Documented use in humans Azathioprine Documented use in humans FK506 OKT3 Documented use in humans Many others
  32. 32. Proposed Therapies of Postviral and Idiopathic Myocarditis Category Therapy Comment Immunomodulatory therapy Gamma globulin Documented use in humans Coxsackie B3 vaccine FK565 Immunostimulant action inhibits replication Immunoadsorption Antiviral therapy Ribavirin Interferon Anticytokine therapy Anti-tumor necrosis factor antibody Vesnarinone One of several phosphodiesterase inhibitors that inhibit cytokine release Amiodarone Miscellaneous Margatoxin One of several T-cell potassium-channel blockers Calcium antagonists May prevent microvascular spasm N-monomethyl-l- arginine Inhibition of nitric oxide synthesis may prevent myocyte injury and reversible depression
  33. 33. Viral Infections with Involvement of the Hematopoietic and Lymphatic Systems
  34. 34. Epstein-Barr Virus, Infectious mononucleosis • EBV herpes group virus, lymphotropic – 1889 Pfeiffer - "drusenfieber" - glandular fever – 1968 - Henle's: after long history attributed an essential virus role in the disease to a virus of the herpes group – EB virus = Epstein Barr virus, a herpes type virus named for cell line in which it was first detected – Transforms (i.e., releases from normal regulatory control) human B lymphocytes which then interact with the T lymphocytes (atypical lymphs of mono)
  35. 35. New England Journal of Medicine 343:482 2000
  36. 36. New England Journal of Medicine 343:483 2000
  37. 37. JAMA 278:511, 1997
  38. 38. Various Forms of Infection by EB Virus in Man • Productive replicative infection – Virus replication leading to cell death (as in the oropharynx of some infected individuals) • Nonproductive infection – Can be activated to productive cycle • Latent infection – Virus genome express to give LYDMA and EBNA (as in peripheral B cells of all infected individuals) • Malignant transformation – Virus genome expressed to give early antigen and cell changes of malignancy (as in BL showing LYDMA, EBNA, EMA, and NPC showing EBNA) • In marmosets EB virus certainly induces malignant transformation with EBNA expression to give malignant lymphomas
  39. 39. Pediatrics in Review 7:36, 1985
  40. 40. Clinical Findings in Heterophile Antibody- Positive Infectious Mononucleosis No. of Patients 270 56,200 100 100 Symptoms (% of patients) •Sore throat 88 70 NS NS •Malaise 50 43 NS 76 •Headache 62 37.5 NS 55 •Nausea, vomiting, anorexia 27 7.1 NS 43 •Myalgia 21 12.5 NS NS
  41. 41. Clinical Findings in Heterophile Antibody- Positive Infectious Mononucleosis No. of Patients 270 56,200 100 100 Signs (% of patients) •Fever 65 97.5 94 79 •Lymphadenopathy >90 100 94 95 •Pharyngitis 85 83 NS 91 •Exudative 63 22 69 49 •Splenomegaly 50 NS 63 51 •Palpebral edema 18 36 11 5 •Palatal petechiae 47 25 NS 13 •Rash 25 3 15 12 •Jaundice 10 8 8 0
  42. 42. Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Symptoms Number of Patients Malaise 9 Fever 8 Chills 6 Myalgia 6 Sore throat 5 Headache 4 Anorexia 3 Abdominal pain 2
  43. 43. Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Signs Number of Patients Pharyngeal erythema 5 Lymphadenopathy 5 Rash 5 Splenomegaly 3 Hepatomegaly 0 Exudative pharyngitis 0
  44. 44. Clinical Disorders Associated Etiologically with Epstein-Barr Virus Primary infection Evidence for etiology (+ to ++++) •Infectious mononucleosis ++++ •Congenital infection with fetal abnormalities ++++ •Acute neurologic disease (Guillain Barré, Bell’s Palsy, meningoencephalitis) +++ •Acquire agammaglobulinemia, aplastic anemia, lymphoma +++ •Lymphoproliferative lesions including lymphomas in renal and other organ transplant recipients ++ •Tonsillopharyngitis ++ •Thrombocytopenia ++ •Pneumonia ++ •Reye’s syndrome ++ •Hemophagocytic syndrome + •Acute arthritis +
  45. 45. Clinical Disorders Associated Etiologically with Epstein-Barr Virus Reactivated infection Evidence for etiology (+ to ++++) •Lymphoproliferative lesions including lymphomas in renal and other organ transplant recipients ++ •Burkitt’s lymphoma, nasopharyngeal carcinoma ++ •Chronic mononucleosis or chronic (symptomatic) EBV infection ++ •Rheumatoid arthritis + •Acquired immunodeficiency syndrome (AIDS) and AIDS-related complex +
  46. 46. Complications of Infectious Mononucleosis • Neurologic – Meningoencephalitis – Aseptic meningitis – Guillain-Barré syndrome – Facial or other peripheral nerve paralysis – Transverse myelitis – Optic neuritis – Seizures – Coma – Acute psychosis – Acute cerebellar ataxia • Hematologic – Autoimmune hemolytic anemia – Thrombocytopenic purpura – Granulocytopenia – Pancytopenia – DIC
  47. 47. Complications of Infectious Mononucleosis • Cardiac – Myocarditis – Pericarditis • Respiratory – Pharyngeal edema with airway obstruction – Interstitial pneumonia – Pleuritis • Hepatic – Cholestatic jaundice – Massive hepatic necrosis causing liver failure • Splenic Rupture
  48. 48. Signs and Symptoms of Hemophagocytic Lymphohistiocytosis Organ System Clinical Findings Laboratory Findings General Fever, edema Bone Marrow Anemia Hemophagocytosis, cytopenia ≥ 2 lines Immune system Splenomegaly, lymphadenopathy ↓ Natural killer cell activity, ↑ serum cytokines, ↑ soluble IL-2 receptor Liver Jaundice, hepatomegaly ↑ Triglycerides, ↓ fibrinogen, ↑ ferritin, ↑ LDH, coagulopathy, ↑ transaminases, ↑ bilirubin, DIC Lungs Cough Infiltrates on chest x-ray Skin Generalized maculopapular rash CNS Irritability, stiff neck, seizure, CN palsy, ataxia ↑ Protein in CSF, hemophagocytosis in CSF
  49. 49. “Chronic Mononucleosis” Clinical Findings and Reported Complaints Among 39 Patients with Suspected Chronic Infectious Mononucleosis Complaint Patients No. (%) Fatigue 29 (74) Nervous system 28 (73) Depression 27 (70) Pharyngitis 25 (64) Fever 24 (63) Lymphadenopathy 23 (59) Myalgia 21 (56) Complaint Patients No. (%) Dyslogia 20 (53) Arthritis/arthralgia 19 (51) Splenomegaly 9 (22) Weight loss 9 (22) Rash 5 (12) Hepatomegaly 4 (10)
  50. 50. CFS due to stress and unknown factors Lake Tahoe CFS ? Stress + EBV-related CEBV Severe CEBV (high VCA, EA, absent EBNA-1 Antibodies) CMV HIVHHV-6 Lyme disease
  51. 51. Timeline graph from 1800 to the present of other diseases with symptoms very similar to CFS 1800 1850 1900 1950 2000 Chronic Fatigue Syndrome Postviral Fatigue Syndrome Chronic Candidiasis Chronic Mononucleosis, Chronic EBV Total Allergy Syndrome Myalgic Encephalomyelitis, Epidemic Neuromyasthenia Hypoglycemia Chronic Brucellosis Da Costa's Syndrome Neurasthenia Febricula, Vapors
  52. 52. Summary of the Working Definition of CFS • Major criteria – Persistent or relapsing fatigue or easy fatigability that does not resolve with bed rest and is severe enough to reduce average daily activity by ≥ 50 – Satisfactory exclusion of other chronic conditions, including preexisting psychiatric disease
  53. 53. Summary of the Working Definition of CFS • Minor criteria – Mild fever (37.5-38.0ºC oral if document by patient) or chills – Sore throat – Lymph node pain in anterior or posterior cervical or axillary chains – Unexplained, generalized muscle weakness – Muscle discomfort, myalgia – Prolonged (≥ 24 h) generalized fatigue after previously tolerable levels of exercise – New generalized headaches – Migratory, noninflammatory arthralgia – Neuropsychologic symptoms: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate or depression – Sleep disturbance – Patient description of initial onset of symptoms as acute or subacute
  54. 54. Summary of the Working Definition of CFS • Physical findings (documented by physician at least twice ≥ 1 month apart) – Low-grade fever (37.6-38.6ºC oral or 37.8-38.8ºC rectal) – Non-exudative pharyngitis – Palpable or tender anterior or posterior cervical or axillary lymph nodes (<2 cm diameter)
  55. 55. Epstein-Barr Virus, Infectious mononucleosis • Laboratory diagnosis – Blood smear with "atypical" lymphocytes – Heterophile agglutination (nonspecific reaction with abs which agglutinate HRBC or SRBC) – Anti EB virus abs
  56. 56. Clinical and laboratory manifestations of infectious mononucleosis. The predominant symptoms, signs, laboratory changes and EB virus-specific serologic findings during classic infectious mononucleosis are depicted in four panels. Arrow A indicates asymptomatic prodrome; arrow B, peak of clinical illness; and arrow C, early convalescence, during which the EB virus-associated neuropathies usually occur. Pediatrics in Review 7:37, 1985
  57. 57. Disorders Associated with >20% Atypical Lymphocytes • EBV mononucleosis • Viral hepatitis • CMV mononucleosis
  58. 58. Disorders Associated with <20% Atypical Lymphocytes • Infections – Mumps – Varicella – Rubeola – Rubella – Roseola infantum (HHV6) – Herpes simplex – Herpes zoster – Influenza – Tuberculosis – Brucellosis – Toxoplasmosis – Syphilis – Smallpox – Malaria – Babesiosis – RMSF – Ehrlichiosis
  59. 59. Disorders Associated with <20% Atypical Lymphocytes • Non-Infectious – Drug hypersensitivity reactions – Drug fever – Dermatitis herpetiformis – Radiation therapy – Stress – Lead intoxication
  60. 60. Interpretation of EBV Serology IgG-VCA IgM-VCA EBV Nuclear Antigen EBV Early Antigen No evidence of infection <10 <10 <2 <10 Acute infection >10 ≥10 <2 ≥20 Convalescent infection >10 Variable >2 Variable Remote past infection ≥10 <10 >2 ≤20
  61. 61. EBV Toxoplasmo sis Rubella HIV CMV HHV-6 HAV/HBV Physical Findings •Pharyngitis ++ (exudative/ non-exudative) + (non- exudative) + (non- exudative) ± (non- exudative) + (non- exudative) + (non- exudative) ± (non- exudative) •Lymphadenopathy Bilateral posterior cervical/genera lized lymph- adenopathy Unilateral single node involvement Occipital postauricula r generalized lymph- adenopathy Localized node enlargement generalized lymph- adenopathy Bilateral posterior cervical/ generalized lymph- adenopathy Bilateral posterior cervical adenopathy None/mild general adenopathy •Splenomegaly +++ ± - - ± ± - Lab Abnormalities •Leukopenia + - ± + + ± •Atypical lymphocytosis 20% <5% <5% - ≥ 20% <10% <5% • ↑SGOT/SGPT + ± - - + + +++ •Thrombocytopenia + - ± + + ± - •Mono spot + -* -* -* -* -* -* *rarely false positive Mono spot test
  62. 62. Epstein-Barr Virus, Infectious mononucleosis • Epidemiology: – Children and young adults – Droplet spread probably – Communicability period and incubation period
  63. 63. Epstein-Barr Virus, Infectious mononucleosis • Immunity: – EB virus (or one closely related antigenically) might operate in an opportunistic way whenever it finds actively proliferating lymphocytes
  64. 64. Epstein-Barr Virus, Infectious mononucleosis • Prophylaxis and treatment: – Symptomatic and supportive – Acyclovir – Corticosteroids
  65. 65. Burkitt's disease • African lymphoma starting as jaw or orbital tumor, then involvement of maxillary bones, kidneys, ovaries, thyroid, parotid • Epidemiology – Central Africa – Case concentration: children 7-8 years old • Associated etiology – Herpes-group virus: EB virus (from cell line of a Burkitt lymphoma established by Epstein and Barr) – DNA, 180 nm enveloped
  66. 66. Annual Review of Microbiology 31:424, 1977
  67. 67. Other • HHV 6, HHV7, HHV8 • Human Parvovirus B19: transient aplastic crisis • Bone marrow failure • Malignant association
  68. 68. Hematology of Infancy and Childhood 4th Edition Vol 1:222, 1993 Mechanisms of virus-induced bone marrow failure. EBV = Epstein-Barr virus CMV = cytomegalovirus CTL = cytotoxic lymphocyte HGF = hematopoietic growth factor HSC = hematopoietic stem cell
  69. 69. Infectious Causes of Cancer Clinical Infectious Diseases 32:679, 2001
  70. 70. Established Association Between an Infectious Agent and a Malignancy Pathogen Malignancy Helicobacter pylori Gastric carcinoma Helicobacter pylori Mucosal-associated lymphoid tissue Schistosoma haematobium Bladder cancer HTLV-1 Adult T-cell leukemia/lymphoma HTLV-11 Hairy cell leukemia HBV Liver cancer HHV-8 Kaposi sarcoma EBV Lymphoproliferative disorders EBV Nasopharyngeal carcinoma EBV Burkitt’s lymphoma HPV Anogenital carcinoma, cervical cancer
  71. 71. CMV and cardiovascular disease
  72. 72. Cardiac Malformations as Part of Rubella Embryopathy • Rubella virus predilection for vascular endothelium: patent ductus arteriosus, atrial septal defect, ventricular septal defect, lesions of myocardial fibers, alterations in renal arteries, pulmonary artery stenosis, and also thrombocytopenic purpura

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