HEPADNAVIRIDAE (see previous discussion) HERPESVIRIDAE Virus Characteristics + Large dsDNA + Enveloped, icosahedral + Derives envelope from nuclear membrane Intranuclear inclusion bodies + Establishes latency Viruses of Medical Importance + Herpes simplex virus 1 and 2 (HSV) + Varicella-zoster virus (VZV) + Epstein-Barr virus (EBV) + Cytomegalovirus (CMV) + Human herpesvirus 6 (HHV-6) + Human herpesvirus 8 (HHV-8) Figure Il-4-16. Herpesvirus 310 KAPLAN) MEDICAL Chapter 4 e Medically Relevant Viruses HSV-1 and HSV-2 Reservoir: juman mucosa and ganglia ‘Transmission: close personal contact (ie. kissing, sexual contact) Y establishes infection in the mucosal epithelial cells and rus travels up the ganglion to establish lifelong, nce of Pathogenesis: HS leads to formation of vesicle latent infection; stress triggers reactivation of virus in nerve and recurre vesicles Diseases: Rule of thumb is that HSV-1 infections generally occur above the waist and HSV-2 infections generally occur below the waist. HSV-1. Key Vignette Clues HSV-1 and HSV-2 Cold sores/genital vesicles Keratoconjunctivitis Meningoencephalitis/ encephalitis Neonatal disseminated/encephalitis, Teanck smear, Cowdry type A inclusion bodies Scanned with CamScanner310 KAPLAN) MEDICAL Chapter 4 # Medically Relevant Viruses HSV-1 and HSV-2 Key Vignette Clues human mucosa and ganglia Hv-1 and HSV-2 : close personal contact (ie., kissing, sexual contact) © Cold sores/genital vesicles HSV establishes infection in the mucosal epithelial cells and + Keratoconjunctivitis leads to formation of vesicles; virus travels up the ganglion to establish lifelong latent infection; stress triggers reactivation of virus in nerve and recurrence of * Meningoencephalitis/ vesicles encephalitis Diseases: Rule of thumb is that HSV-1 infections generally occur above the * Neonatal waist and HSV-2 infections generally occur below the waist. disseminated/encephalitis, © Tzanck smear, Cowdry type A HSV-1 inclusion bodies * Gingivostomatitis and cold sores: blister-like lesions on oral mucosa; latent in trigeminal ganglion + Keratoconjunctivitis: generally with lid swelling and vesicles; possible dendritic ulcers; if untreated and repeat attacks, possible blindness + Encephalitis: fever, headache, confusion; focal temporal lesions and perivascular cuffing; if untreated, 70% mortality rate; most common cause of viral encephalitis in U.S. HSV-2 * Genital infections: painful genital vesicles; systemic effects include fever, malaise, myalgia; latency in sacral nerve ganglia + Neonatal herpes: infection occurs during passage through infected birth canal; usually severe, ie., disseminated with liver involvement and high mortality; encephalitis, high mortality; skin, eyes, mouth) Diagnosis * Oral lesions: clinical cephalitis: PCR on CSF; large numbers of RBCs in CSF + Genital infections: Tzanck smear to show formation of multinucleated giant cells and Cowdry type A intranuclear inclusions has been largely replaced by immunofluorescent staining, which can distinguish HSV-1 from HSV-2 ‘Treatment: Acyclovir, a nucleoside analog that is only activated in cells infected with HSV-1, HSV-2 or VZV. (This is because the virus thymidine kinase is required to activate the drug by placing the first phosphate on the drug, followed by the phosphorylation via cellular enzymes.) In cases of acyclovir resistance (caused by a mutation in the thymidine kinase), use famciclovir, valacyclovir, or penciclovir, Scanned with CamScannerKAPLAN) MEDICAL 311 Key Vignette Clues viv * Chickenpox: unvaccinated child with asynchronous rash * Shingles: elderty with unilateral vesicular rash that follows dermatome ‘© Tzanck smear with Cowdry type A intranuclear inclusions and. syncytia Key Vignette Clues EBV * Young adult with fever, lymphadenopathy, splenomegaly + Downey type il atypical T lymphocytes reach 70% in blood * Heterophile (monospot) positive 312 KAPLAN) MEDICAL Varicella Zoster Virus (VZV) Reservoir: human mucosa and nerves ‘Transmission: respiratory droplets Pathogenesis: VZV enters the respiratory tract + replicates in local lymph nodes — primary viremia — spleen and liver —> secondary viremia — skin (rash) — latent in the dorsal root ganglia. Reactivation of virus due to stress or immunocompromise causes vesicular lesions and severe nerve pain. Diseases + Chickenpox ~ Fever, pharyngitis, malaise, rhinitis ~ Asynchronous rash = One of 5 “classic” childhood exanthems; less common due to vaccina- tion + Shingles ster Pain and vesicles restricted to one dermatome Fifth or sixth decade of life ~ Reactivation of latent infection Diagnosis + Tzanck smear—Cowdry type A, intranuclear inclusions + Antigen detection by PC! Treatment + Healthy adults with shingles—oral acyclovir + Immunocompromised—IV acyclovir + Aspirin contraindicated due to associat n with Reye syndrome Prevention + Live, attenuated vaccine, booster for 60-year-old to prevent shingles + VZIG (varicella-zoster immunoglobulin) for postexposure prophylaxis of the immunocompromised Epstein-Barr Virus (EBV) Reservoir: humans Transmission: saliva, 90% of adult population is seropositive Scanned with CamScanner312 KAPLAN) MEDICAL Chapter 4 » Medically Relevant Viruses Pathogenesis + Virus infects nasopharyngeal epithelial cells, salivary and lymphoid tissues latent infection of B cells (EBV binds to CD21 and acts as, a B-cell mitogen) — results in production of atypical reactive T cells (Downey cells), which may constitute up to 70% of WBC count + Heterophile antibodies are produced (due to B cell mitogenesis) Diseases + Heterophile-positive mononucleosis, “kissing disease’: fatigue, fever, sore throat, lymphadenopathy, splenomegaly; latency in B cells + Lymphoproliferative disease: occurs in immunocompromised patients; T cells can't control B-cell growth + Hairy oral leukoplakia: hyperproliferation of lingual epithelial cells; ‘occurs in AIDS patients Malignancies + Burkitt lymphoma: cancer of the maxilla, mandible, abdomen; Africa; malaria cofactor; AIDS patients; translocation juxtaposes c-myc one gene to a very active promoter such as immunoglobulin gene promoter + Nasopharyngeal carcinoma: Asia (most common cancer in southern China); tumor cells of epithelial origin + Hodgkin and non-Hodgkin lymphoma Diagnosis: heterophile-antibody positive (IgM_ antibodies that recognize Paul-Bunnell antigen on sheep and bovine RBCs) ‘Treatment: symptomatic, for uncomplicated mononucleosis Cytomegalovirus (CMV) Reservoir: humans ‘Transmission: saliva, sexual, parenteral, in utero Pathogenesis: CMV infects salivary gland epithelial cells and establishes a persistent infection in fibroblasts, epithelial cells, and macrophages; latency in mononuclear cells + Cytomegalic inclusion disease: most common in utero infection in U:S.; ranges from infected with no obvious defects to severe disease characterized by jaundice, hepatosplenomegaly, thrombocytic purpura ("blueberry muffin baby”), pneumonitis, and CNS damage to death *+ Mononucleosis (children and adults): heterophile-negative mononucleosis Key Vignette Clue: MV ‘+ Heterophile-negative ‘mononucleosis in children and adults + Neonate with jaundice, hepatosplenomegaly, thrombocytic purpura ‘© Owl-eye intranuclear inclusion bodies in biopsy KAPLAN) MEDICAL Scanned with CamScannerMicrobiology Key Vignette Clu HHV-6 Infant with Fever — lacy body rash Key Vignette Clues HHV-8 AIDS patient with sarcoma + Immunocompromised patients + Interstitial pneumonitis to severe systemic infection (due to reactiva- tion in transplanted organ or AIDS patient) + CMV retinitis common in AIDS patients + Gl disease common in AIDS patients Diagnosis + Owl-eye inclusion (“sight-o-megalo-virus”) in biopsy material and urine + Basophilic intranuclear inclusions + Serology, DNA detection, virus culture ‘Treatment: supportive for healthy patients; ganciclovir/foscarnet + human immunoglobulin for immunocompromised (AIDS and transplant patients) (resistance to ganciclovir through UL97 gene) Prevention: safe sex; screening of blood and organ donors HHV-6/7 Reservoir: humans ‘Transmission: respiratory droplets Pathogenesis: replicates in peripheral blood mononuclear cells Disease: roseola (exanthem subitum); fever for 3-5 days followed by lacy body rash Diagnosis: clinical ‘Treatment: symptomatic HHV-8 (Kaposi sarcoma-associated herpesvirus KSHV) Reservoir: humans ‘Transmission: sexual contact, saliva, vertical, transplantation Pathogenesis: gene turns on vascular endothelial growth factor (VEGF); plays direct role in development of Kaposi sarcoma; latent in B cells and glandular epithelial cells Disease: Kaposi sarcoma linical; serology, PCR Diagnosi ‘Treatment: none Scanned with CamScannerTable II-4-10. Herpesvirus Infections Pu men eo Clinicat Pest) Peat eed ec Hsv-1 Mucosa Gingivostomatitis, Trigeminal ganglia _| Cold sores HSV-2___| Mucosa Genital herpes, neonatal herpes _| Sacral ganglia Genital herpes vv Mucosa Chickenpox Dorsal root ganglia | Shingles (zoster) EBV ‘Mucosal ‘Mononucleosis (heterophile @) | B cells ‘Asymptomatic epithelial cells, shedding of virus, Beells cmv ‘Mononuclear | Mononucleosis (heterophile -), | Mononuclear cells | Asymptomatic cells, epithelial | cytomegalic inclusion disease shedding of virus cells HHv-6 | Mononuclear —_| Roseola infantum ‘Mononuclearcells | Asymptomatic cells, shedding of virus HHv-s | Dermis Fever, rash B cells, glandular | Kaposi sarcoma epithelial cells POXVIRIDAE Virus Characteristics + Large dsDNA, enveloped + Complex morphology + Replicates in the cytoplasm + Potential biowarfare agent Viruses of Medical Importance + Variola + Vaccinia (vaccine strain) + Molluscum contagiosum + Orf + Monkeypox Figure tI-4-17. Poxvirus Scanned with CamScannerFigure ll--17. Poxvirus KAPLAN) MEDICAL 315 a art Ile Microbiology Key Vignette Clues Variola/Smallpox + Virus extinct ‘© Synchronous rash begins in ‘mouth + face and body © Guamieri bodies (intracytoplasmic inclusions) Key Vi Molluscum Contagiosum © Young adult (wrestling, swim team) ‘© Umbilicated warts ‘© Eosinophilic cytoplasmic inclusion bodies Variola/Smallpox Reservoir: humans; Variola has 1 serotype making eradication (1979) possible ‘Transmission: respiratory route Pathogenesis + Via inhalation, the virus enters the upper respiratory tract and disseminates via lymphatics —+ viremia + After a secondary viremia, the virus infects all dermal tissues and internal organs + Classic “pocks” Disease + 5-17 day incubation + Prodrome of flu-like illness for 2-4 days + Prodrome followed by rash, which begins in mouth and spreads to the face, arms and legs, hands, and feet and can cover entire body within 24 hours + All vesicles are in same stage of development (synchronous rash) Diagnosis: clinical; Guarnieri bodies found in infected cells (intra ytoplasmic) ‘Treatment: supportive care Prevention: live, attenuated vaccine Molluscum contagiosum Reservoir: humans Transmission: direct contact (sexual) and fomites Pathogenesis: replication in dermis Disease: single or multiple (<20) benign, wart-like tumors; molluscum bodies in central caseous material (eosinophilic cytoplasmic inclusion bodies) linical (warts are umbilicated); eosinophilic cytoplasmic inclusion Treatment: self-limiting in healthy persons; ritonavir, cidofovir for immunocompromised —_——— , Scanned with CamScannerCHAPTER Herpesviruses and Other DNA Viruses 4.2 fia A ‘The members of Herpesviridae possess the following properties: ‘Nuclele acid: * Large (150-200 nm size), spherical in shape with icosahedral symmetry Crlergiiore orl mn ‘+ Tegument: I is an amorphous, asymmetric structure present between the capsid and | @soNAwheh replicates by roling envelope ‘+ Establish latent or persistent infections in their hosts and undergo periodic reactivation Possess dsDNA and replicates by rolling circle mechanism. Beane Duration of replication Site of ‘Transmission: ‘Subfamily | (Cytopathology) latency | Species + HSV Dect contac with ‘Alpha Short (12-18 hours) Neurons | Herpes simplex veus ype 1 and2| |. fiswie' sounds or Cytyie Varioala-zoster vius verteal mode. Beta | Long (>24 hours), Gytomegalic | Gands, | Cylomegalovius Kidneys Long ( 26 hours) TFeells | Human herpesvinus 6 end 7 Lymphoproterative ‘Gamme | Variobe, Lymphoprlferatie | B-Cell | Epstein-Bar vius and Human herpesvirus 8 Pas Properties Herpes simplex virus-t Herpes simplex virus-2 ‘Transmission Direct contact with mucosa or abraded skin ‘Sexual mode or vertical mode Latency ‘Tigeminal ganglia Sacral ganglia ‘Age aflected ‘Young chiléren Young aduts| ‘Anibody distribution in adults_| Present in 70-90% of people Present in 20% of people ‘Common manifestations |» Oralfacial mucosal lesions + Genital iesions + Encephaltis, meningtis and ocular lesions + Skin lesions: Below the waist +_Skin lesions: Above the waist +_Neonatal Herpes oa (CAM) Forms smaller pocks Forms larger pocks ‘Chick embryo fibroblast Does not grow well Replicates well Newrovirulence Less More Drug resistance Less More “Antigenic homology HSV 1 and 2 show > 80% antigenic homology ‘Genomic sequence homctogy | HSV 1 and 2 show > 50% homology in the genomic sequence Clinical Manifestations ‘The incubation period ranges from 1 to 26 days (median, 6-8 days). Orofacialmucosal lesions: They are the most common manifestations of HSV. cele pecans Let SNR te MG couse of acute ‘* Most common affected site is buccal mucosa ‘sporadic viral encephalitis (MC + Most i lesions are gingivo stomatitis and pharyngitis. ‘site temporal lobe) frequent primary sin pharyngit . thalanpert te) + Most frequent recurrent lesion is herpes labialis (painful vesicles near lips) Scanned with CamScannertevlew of Mebilogy ead Innogy ru) Nervous system + Encephalitis: HSV is the MC cause of acute sporadic viral encephalitis (MC site temporal lobe), HSV-1 causes > 95% of cases. © Children get primary infection: HSV is acquired exogenously and invades CNS via the olfactory bulb © Adults get recurrent infections due to reactivation of HSV in trigeminal nerve. + Meningitis: FISV can cause recurrent lymphocytic meningitiscalled as Mollaret’s meningitis + Other manifestations: © Autonomous nervous system involvement (sacral region) © Transverse myelitis © Guillain-Barré syndrome © Peripheral nervous system involvement (e.g, Bell's palsy) ‘Cutaneous lesions: HSV usually infects through abraded skin and causes various lesions. “Herpetic whitlow: Lesions present on the fingers of dentists and hospital personnel. Febrile blisters “Herpes gladiatorum: Mucocutaneous lesions present on the body of wrestlers Eczema herpeticum: Caused by HSV-1 in patients with chronic eczema. Similar lesions are also produced by vaccinia virus infection; both conditions together are designated as Kaposi's varicelliform eruptions. + Erythema multiforme: HSV is the most common to be associated, ‘Ocular lesions: HSV-1 is more common than HSV-2 to infect eyes. + Severe conjunctivitis isthe most common manifestations + Recurrent lesions develop in to dendritic ulcers of cornea or vesicles on the eyelids, + Corneal blindnes Genital lesions: HSV-2 is more common than HSV-1 to cause primary as well as recurrent genital lesions. * Genital lesions are described as bilateral, painful multiple, tiny vesicular ulcers + This may be associated with fever and inguinal lymphadenopathy. Visceral and disseminated herpes + isk factors: Immunocompromised patients underlying, malnutrition or AIDS, pregnancy. * Common manifestations include: Pneumonitis,tracheobronchitis and hepatitis. Neonatal Herpes: HSV is one of the common causes of congenital infections, along with the other TORCH agents. + Transmission: Can also occur in utero or after birth; but MC being during birth + Risk of developing neonatal herpes is maximum (10 times more) ifthe mother recently ‘acquires the virus (primary infection). ‘+ HSV-2 is more common to cause neonatal herpes (75% of total cases) than HSV-1 Have a higher tendency to develop visceral infections. Laboratory Diagnosis ‘+ Cytopathology: Tzanck smear preparation by Wright's or Giemsa stain: © Detects inclusion bodies (Lipschultz body) and formation of multinucleated giant cells, ballooning of infected cells © Itcannot differentiate between HSV-1, HSV-2, and VZV © Sensitivity of staining is low (< 30% for mucosal swabs). ‘Virus isolation: Remains the most definitive tool for HSV diagnosis © Conventional cell lines: Detects diffuse rounding and ballooning of cell lines. ‘+ Viral antigen detection: in specimen by direct IF. It is sensitive, specific and can differentiate HSV-1 from HSV-2. + HSV DNA detection by PCR the most sensitive test and can differentiate HSV-1 and HSV-2. + Antibody detection by ELISA or other formats © Mostavailable tests usually detect IgG or total antibodies, hence cannot differentiate recent and past infections. © Serologic assays based on the type-specific antigens can differentiate between HSV-1 and HSV-2_ Scanned with CamScannerHerpesviruses and Other DNA Viruses | ‘Treatment + Acyclovir is the drug of choice. It acts by inhibiting viral DNA polymerase * — Foscarnet is the DOC for acyclovir resistance cases. AZ ile ee TeES VZV produces vesicular rashes on the skin and mucous membranes in two forms: + Chickenpox: Diffuse bilateral vesicular rashes, occur following primary infection, | VZV produces two types of usually affecting children. infections: = Zoster or Shingles: Occur following reactivation of latent VZV in the ophthalmic branch |* Chicken pox: Diffuse bilateral of trigeminal ganglia (which is also the site of latency of VZV). It occurs mainly in adult | glowing primey infection in life. Vesicular rashes are unilateral and segmental. children, Zoster or Shingles: Occur in ‘adults following reactivation of Chickenpox latent VZV. Vesicular rashes are unilateral and segmental. Clinical Manifestations ‘+ Incubation period is about 10-21 days (2-3 weeks). ‘+ Typical description of chickenpox rashes © Vesicular, bilateral, diffuse and centripetal (start on the face and trunk, spread rap- idly to involve flexor surfaces) Complications of chickenpox: © Rashes appear in multiple crops, fever appears with each crop of rashes +" MC infectious complication: © Chickenpox is a disease of childhood. ‘Secondary bacterial infection ; ; MC extracutaneous © When occurs in adults, it is more severe with bullous and hemorthagic rash. er Shicalors CNS FWENeT Ent Most serious complication is: Complications Varicella pneumonia Complications are more common in adults and in immunocompromised individuals. ee aaa + MC infectious complication is: Secondary bacterial infection of the skin. * MC extracutaneous complication: CNS involvement (cerebellar ataxia, encephalitis and aseptic meningitis): Usually occurs in children. + Most serious complication is: Varicella pneumonia, develops commonly in pregnant women. + Reye's syndrome: Fatty degeneration of liver following salicylate (aspirin) intake. Chickenpox in pregnancy affects both mother and the fetus. + Mothers are at high-risk of developing varicella pneumonia Semple + Fetal or congenital varicella syndrome: VZV is highly teratogenic. ieee eee © Risk is maximum when mother acquires a primary infection during pregnancy. ‘worst outcome © Late first trimester/early second trimester: Congenital malformation in fetusis more | + Infected at 6-12 weeks- frequent, characterized by cicatricial skin lesions, limb hypoplasia and microcephaly. max! eer upn ‘with finn, * Infection near delivery fe pipe eve © Ifmother gets infection > 5 days before delivery: Then baby is mostly asymptomatic | and brain involvement. due to protective maternal Ab © Ifmother gets infection before 5 days to after 2 days of delivery: Maternal Ab would not have produced in such a short time. This leads to dissemination of virus in the baby to cause neonatal varicella (a severe form of chickenpox). Caer MMR and 2 Pox Epidemiology (Mumps, Measles, Rubella, Chickenpox is a highly contagious disease. Chickenpox and Smallpox): * Period of infectivity: 2 days before the onset of rash to 5 days after thereafter, until the | 7 vesicles are crusted. ‘One attack gives lifelong immunity Humans are: only host Reservoir: Humans are the only known reservoir hosts. ign secondary tick rate Source of infection: Patients are the only source, there are no carriers. Ones tesbei Naaaked Secondary attack rate is about 70-90%. probably get life long immunity. Scanned with CamScannerReview of Microbiology and Immunology Zoster ophthalmicu Unilateral painful crops of skin rashes surrounding the eye. VZIG (Varicella zoster immunoglobulin): Given within 96 hrs of exposure Given to Neonates born to chickenpox mother: If the ‘onset of chickenpox in the mother is between < 5 days before delivery til 48 hrs after delivery Congenital CMV Infection: CMV is probably the MC intrauterine infection Affects near 1% of infants born. 5% of the infected fetus develops disease. Zoster or Shingles Zoster usually occurs due to reactivation of latent VZV in old age (> 60 year age), in {immunity or rarely in healthy adults. + Rashes: There are unilateral and segmental, confined to the area of skin supplied by the affected nerves. + Complications © Post-herpetic neuralgia (pain at local site): MC complication in elderly patients. © Zoster ophthalmicus: Unilateral painful crops of skin rashes surrounding the eye. © Ramsay Hunt syndrome develops when geniculate ganglion of facial nerve is in- volved. It is characterized by tetrad of facial nerve palsy plus vesicle on tympanic membrane, external auditory meatus and the tongue. Vaccine * Live attenuated vaccine using Oka strain of VZV is available. + Itis given to children after 1 year of age; 2 doses, first dose is given at 12-15 months and second dose at 4-6 yrs Treatment * Acyclovir is the drug of choice. It can prevent the complications of chickenpox and can also halt the progression of zoster in adults, but cannot prevent post-herpetic neuralgia. * —-VZIG (Varicella zoster immunoglobulin) © Itis recommended for postexposure prophylaxis. It is given within 96 hrs (prefer- ably within 72 hrs) of exposure. © It is also indicated for neonates born to mothers suffering from chickenpox if the onset of chickenpox in the mother is between < 5 days before delivery till 48 hrs after delivery. VZIG not indicated if the mother has zoster. CYTOMEGALOVIRUS (CMV) CMV is the largest virus in Herpesviridae fam enlargement of infected host cells. + Host specificity: CMV are strictly species-specific. + Cell type specificity: CMV infects kidney and salivary glands. + Cell-to-cell spread: CMV is almost always closely associated with the cells and spread primarily cell-to-cell, so that very little virus may be cell-free. It is so named because it causes massive Clinical Manifestations Congenital CMV Infection + CMV is probably the MC intrauterine infection associated with congenital defects, affecting near 1% of infants born, + Cytomegalic inclusion disease develops in about 5% of the infected fetus. The remaining, arealthough asymptomatic at birth, 5-25% of them may develop significant psychomotor, hearing, ocular, or dental defects within 2 years, + Congenital defects include: © MC defects are petechiae, hepatosplenomegaly, and jaundice. © Less common: Microcephaly, cerebral calcifications, IUGR, and prematurity. + Risk is maximum if the infection occurs in early pregnancy and if the mother is primarily infected during pregnancy. Perinatal CMV Infection + Transmission to newborn occurs during: (i) Delivery, (ji) Postnatal—through infected breast milk/secretion of mother. Scanned with CamScannerHerpesviruses and Other DNA Viruses + Mostly asymptomatic, but shed virus in urine up to several years. * Few infants, especially premature babies develop interstitial pneumonitis. immunocompetent Adults + Mononucleosis like syndrome develops in healthy adults following blood transfusion. Aner Epstein Barr Vius (EBV) CMV (20-50%) wt emus CMY 20-50%) HHV-6, Toxoplasma, Ehrlichia, HIV + Atypical lymphocytosis seen, ‘Atypical lymphocytosis | Seen saan + Heterophile antibodies (Paul Clinical symptoms Fever, myalgia, rashes Similar presentation, except that Piariet tee) i Negeere Hepatosplenomegaly exudative pharyngitis, cervical Exudative pharyngitis, lymphadenopathy are absent Cervical lymphadenopathy ile antibodies _| Elevated (Paul-Bunnell test) Negative Specific antibodies Antibodies to specific EBV Antibodies to CMV or other agents may antigens are elevated be vated. In the Immunocompromised Host CMV produces severe infection in immunosuppressed individuals; due to reactivation of latent CMV viruses. + In untreated AIDS patients with CD4 T-cell count < 50/j1-CMV may cause ‘Chorioretinitis (MC presentation), gastroenteritis and dementia. + Organ transplant recipients: CMV is probably the MC viral infection in transplant recipients. © CMV infection occurs usually between 1 fo 4 months following transplantation. © Bilateral interstitial pneumonia in bone marrow transplant recipients. CMV is the MC viral infection in transplant recipients: * Bilateral interstitial pneum in BM transplants, + Febrile leukopenia in solid ‘organ transplants + Obliterative bronchiolitis in lung transplants + Graft atherosclerosis in heart transplants Rejection of renal allografts. Epidemiology + Transmission: In contrast to HSV, CMV transmission requires close contact © Oral and respiratory contact is the predominant mode © Others-Transplacental, blood transfusion (risk is 0.1-10%) and sexual + Reservoir: Humans are the only known host for CMV. + Prevalence: In under developed nations, 90% of people being seropositive in contrast to 40-70% in developed nations, Laboratory Diagnosis + Detection of inclusion bodies in urine: CMV produces both perinuclear cytoplasmic and intranuclear inclusions (describe as Owl's eye appearance) + Virus Isolation: CMV can be isolated from throat washings and urine. © Human fibroblasts are the most ideal cell lines, growth occurs in 2-3 weeks. © Shell vial technique: Used to detect growth in 4-5 days. 3 : MV Isolation: * Antibody detection: ‘Specimen: Washi = nd © IgM antibodies are indicative of active infection. ut ea © Four fold rise of IgG indicates recurrent infection. Human fibroblasts © Antibodies are often undetectable in immunocompromised patients. cr oe eye appearance in + Antigen detection: CMV-specific pp65 antigens. It is highly specific and reliable method + PCR detects specific CMV DNA in blood or body fluids such as CSF. Treatment CMY does not respond to acyclovir. + Ganciclovir is the DOC for cytomegalic inclusion disease or retinitis or transplant infections. + Others: Valganciclovir (given orally), foscarnet (DOC in ganciclovir-resistant cases), cidofovir and CMV Ig. Scanned with CamScannerOncogenesis in EBV is due to: LUMP-1 (latent membrane protein-1) Viral EBNA-2. EBV associated malignancies: Burkitt's lymphoma Nasopharyngeal Carcinoma Hodgkin's lymphoma. NHL (Non-Hodgkin's lymphoma). EPSTEIN-BARR VIRU. Pathogenesis EBV is transmitted by oropharyngeal contact through infected salivary secretions + Binds to EBV receptors: Complement receptors (CD21 or CR2) on B-cell and pharyngeal epithelial cells. + Primary infection occurs in the oropharynx. EBV replicates in epithelial cells or B-lymphocytes of the pharynx and salivary glands, + Inside B-cells, EBV directly enters into latent phase. + Pathogenesis in children, developing infectious mononucleosis: © Infected B-cells become immortalized by the virus and synthesize large number of variety of immunoglobulins (polyclonal), many of those are autoantibodies © In response to this, the bystander CD8 T-lymphocytes are stimulated and appear atypical. + Pathogenesis in people developing EBV induced cancers (Mechanism of oncogenesis): EBV can induce malignant transformation of infected B-cells and epithelial cells by expressing latent EBV antigens such as LMP and EBNA. © LMP-1 (latent membrane protein-1) is the most important viral oncogene. © Viral EBNA-2 (EBV nuclear antigen-2) activates host cell cyclin-D, thus promotes cell proliferation. Clinical Manifestations Infectious Mononucleosis Itis also called as kissing disease (salivary contact) or glandular disease * Age-Young adults of developed countries are usually affected. * Its characterized by: © Headache, fever, malaise and Exudative pharyngitis © Cervical lymphadenopathy and Hepatosplenomegaly © Rashes following ampicillin therapy © Atypical lymphocytosis (CD8 T-cells) © Autoantibodies reactive to sheep RBC antigens (detected by Paul-Bunnell test). EBV Associated Malignancies EBY is associated with several malignancies: + Burkitt's lymphoma (tumor of the jaw seen in children and young adults): EBV is associated with 90% of African and 20% of non-African cases of Burkitt's lymphoma. © Most of the cases have pre-existing mutation [t(8;14)] that in turn activates the growth promoting MYC oncogene © Falciparum malaria may impair host CMI and stimulates the EBV-infected B-cells + Nasopharyngeal Carcinoma: Seen among Chinese having h/o intake of salted fish (nitrosamine) and herbal snuff (phorbol ester) + Hodgkin’s lymphoma (especially the mixed-cellularity type). + NHL (Non-Hodgkin's lymphoma): All central nervous system non-Hodgkin's lymphomas and 50% of systemic non-Hodgkin's lymphomas are EBV positive. Other Conditions Associated with EBV + Lymphoproliferative disorder such as Duncan syndrome, an X-linked recessive disease affecting young boys. + Hairy cell leukoplakia: Wart-like growth of epithelial cells of the tongue developed in some HIV-infected patients and transplant recipients + Chronic fatigue syndrome Scanned with CamScannerHerp: Laboratory Diagnosis Heterophile Antibody Detection by Paul-Bunnell Test * — Itisaheterophile agglutination test that uses sheep RBCs to detect heterophile antibodies in patient's serum * Differential absorption test and Monospot test are done for confirmation. EBV Specific Antibody Detection * Antibody to viral capsid antigen (VCA): © IgM type: It indicates current infection. © IgG type: It is a marker of past infection and indicates immunity. * Antibodies to early antigen also indicate current viral infection © EA-D antibody (antibody to early antigen that occurs in diffuse pattern in nucleus and cytoplasm of the infected cells): It is elevated in acute infection and Burkitt's lym- phoma © EA-R antibody, antibody to early antigen restricted to the cytoplasm: It is elevated in nasopharyngeal carcinoma + Antibodies to EBNA (EBV nuclear antigen) reveal past infection, but four fold rise of titer suggest current infection. Treatment * Acyclovir is useful in the treatment of oral hairy leukoplakia, but not effective for infectious mononucleosis and other malignancies. * Antibody to CD20 (rituximab) has been effective in some cases. HUMAN HERPESVIRUS-6 HHV-6 infects the T-cells by binding to CD46 receptor. It has two variants 6A and 6B. + Sixth disease: In children, HHV-6 (usually the 6B variant) causes sixth disease, also called as exanthema subitum or roseola infantum. * Inolder age groups, HHV-6 has been associated with mononucleosis-like syndrome. HUMAN HERPESVIRUS-8 HHV-8 is also called as Kaposi’s sarcoma-associated herpesvirus (KSHV) + Epidemiology oral co Inhigh pxevalencearea-HHV.8 is endemic in Africa where it is trancmitted by Scanned with CamScannerIt is nonenveloped DNA virus, space vehicle shaped Disease produced by adenovirus Adenovirus serotype associated Hemorrhagic cystitis ‘Adenovirus type 11 and 21 (boys) Infant diarrhe ‘Adenovirus serotype 40, 41 Ocular Infections Epidemic keratoconjunctivitis ‘Adenovirus type 8,19, 37 (Shepard eye, industrial worker) Pharyngoconjunctival fever or ‘Swimming pool conjunctivitis (follicular) ‘Adenovirus type 3,7,14 (tends to occur in outbreaks, at children’s summer camps) Respiratory Diseases Upper respiratory tract infection Serotypes 1, 2,3 and 5 Pneumonia Serotypes 3, 7, and 21 ‘Acute respiratory disease syndrome In miltary recruits, associated with type 4 and 7 Transplant recipients Serotypes 34 and 35. 1 risk to develop pneumonia, hepatitis, nephritis, colitis, encephalitis, and hemorrhagic cystitis Scanned with CamScannerViral Exanthems and Other Cutaneous Viral Infections CHAPTER 56 —— CHAPTER PREVIEW —— = Herpesvirus infections '¢ Herpes Simplex Virus Infections ‘© Varicella-Zoster Virus Infections "= Parvovirus Infections ‘= Human Papilloma Virus Infections = Pox\irus Infections ‘An exanthem is an eruption or rash on the skin, that may bbe associated with fever or other systemic symptoms. Majority of exanthems have an infectious etiology; most, ‘commonly by viruses. Exanthems may also be seen due to drug reactions. ‘The viruses that can cause exanthematous and other types of skin lesions include (Table 56.1): Herpesviruses: Herpes simplex virus, varicella-zoster virus, rarely Epstein-Barr virus (secondary to ampicillin therapy) and HHV-6 and HHV-7 infection DNAviruses other than herpesviruses such as: smallpox virus, parvovirus and human papilloma viruses (HPV) RNA viruses such as: Measles, Rubella and Coxsackie viruses. Exanthematous rashes are also a common feature of viral hemorrhagic fever, discussed in Chapter 34. eens [Viruses Viralexanthems/other skin lesions Herpesviruses Herpes simplex vius Vesicular lesions Varicella-zoster virus Chickenpox and zoster Epstein-Barr virus Following ampicillin therapy Human Roseola infantum (exanthem subitum or herpesvirusé __ sith disease) ‘Other DNA viruses Powviuses ‘smallpox Molluscum contagiosum* Parvovirus Erythema infectiosum fith disease) Papular-purpuric gloves and socks syndrome” Human papilloma Warts: Common warts flat warts plantar virus (HPV) ‘wats, anogenital warts (condyioma scuminatum) RNA viruses, Measles virus Rashes, Kops spots bella virus Rashes Coxsackie viruses Hand-foot mouth disease Agents of viral Dengue, Ebolaand others (Chapter 34) hemorrhagic fever “These are not exanthematous lesions HERPESVIRUS INFECTIONS GENERAL PROPERTIES Herpesviridae comprises of a group of viruses that possess a unique property of establishing latent or persistent infections in their hosts and later on undergoing periodic reactivation. Morphology Herpesviruses are large (150-200 nm size), spherical in shape with icosahedral symmetry. Nucleocapsid: They possess. linear dsDNA, surrounded bya capsid comprising of capsomeres (Fig. 56.1) + Envelope: The nucleocapsid is surrounded by a lipid envelope into which glycoprotein spikes are inserted; which help in viral entry by binding to the specific host, cell receptors % Tegument: Between the capsid and envelope, there is anamorphous, sometimes asymmetric structure present, called tegument Envelope Lipid Glycoprotein spikes Tegument Linear ds ONA Icosahedral capsid Fig. 56.1: Herpes simplex virus (schematic diagram). Scanned with CamScannerCo erry ed rere ery See Cr ee a ma neler Site oflatency | Genus Alpha Short (12-18 hours) Neurons Simplexvirus Human herpesvirus 1 Herpes simplex virus type 1 Colytic ‘Human herpesvirus 2 Herpes simplex virus type 2 Varicellovius Human herpesvirus 3. Varicella-zoster virus Beta Long (224 hours) Glands, Cytomegalovirus HumanherpesvirusS Cytomegalovirus Cytomegalic: kidneys Long (>24 hours) Lymphoid Roseolovirus Human herpesvirus 6 Human herpesvirus 6 Lymphoproliferative tissues (Tells) Human herpesvirus 7 Human herpesvirus 7 Gamma Variable Lymphoid Lymphocryptovirus Human herpesvirus 4 Epstein-Barr virus Lymmehoprotterativa)| 1 (tscues © cols) (aiacioowes Human herpesvirus 8 Kaposi's sarcoma- + Replication of herpesviruses takes place in the host cell nucleus and is similar to replication of any other dsDNA virus as described in Chapter 4. The only difference is that the linear dsDNA of herpesviruses becomes circular inside the host cell and then replicates by rolling circle mechanism. Classification Family Herpesviridae comprises of three subfamilies (a, i and y)—classified based on the site of latency, duration of ‘growth cycle and type of cytopathology they produce (Table 56.2). * Each subfamily in turn has one or more genera and each genus consists ofa few species + For general use, the common names are still popular, which are also followed in this textbook % There are about 100 herpesviruses infecting different animals, out of which only eight are human herpesviruses which infect exclusively man (Table 56.2). HERPES SIMPLEX VIRUS INFECTIONS Herpes simplex viruses belong to a-subfamily of Herpes- viridae, % They are extremely widespread and exhibit a broad host range; can infect many types of cells and different animals. However, the human herpesviruses infect exclusively man © They replicate fast (12-18 hours cycle), spread fast and are cytolytic + They can cause a spectrum of diseases, involving skin, mucosa and various organs 4 They undergo latency in nerve cel ‘causing recurrent lesions. Herpes simplex viruses (HSV) are of two distinct types: HSV-1 and HSV-2. They differ from each other in many aspects (Table 56.3). reactivate later Pathogenesis Primary Infection Transmission occurs through abraded skin or mucosa from any site, but more commonly by: CE (area ‘Common modes of Direct contact with ‘Sexual mode or transmission ‘mucosa or abraded skin vertical mode Latencyin ‘Trigeminal ganglia Sacral ganglia ‘Age affected Young children Young adults Common ‘© Oralfacial mucosal» Genital lesions manifestations lesions © Skinlesions— ‘* Encephalitis and below the waist ‘meningitis '* Neonatal © Ocularlesions herpes * Skin lesions—above the waist Neurovirulence Less More Drugresistance Less More [Antigenichomology HSV-1 and 2 show >80% antigenic homology DNA homology _HSV-1 and 2 show >50% homology in the ‘genomic sequence = HSV-1: Oropharyngeal contact with infected saliva or direct skin contact = HSV-2: Sexual contact or rarely vertical mode (from mother to fetus). + Site of infection: HSV replicates at the local site of infection and produces lesions anywhere, but more ‘commonly in: = HSV-1 lesions are confined to areas above the waist (most common site—around mouth) = HSV-2 produces lesions below the waist (most common site—genital area) % Spread via nerve: Virus then invades the local nerve ‘endings and is transported by retrograde axonal flow to, the dorsal root ganglia, where it replicates further, and then undergoes latency + Primary HSV infections are usually mild; in fact, most are asymptomatic 4 Howeverin immunocompromised hosts, viremia occurs that leads to widespread organ involvement and systemic manifestations. Scanned with CamScannerSECTION 7 Skin, Soft Tissue and Musculoskeletal System Infections Latent Infection HSV has a tendency to undergo latency in neurons: = HSV-1: undergoes latency in trigeminal ganglia = HSV-2: undergoes latency in sacral ganglia. + HSV does not replicate in latent stage and also cannot be isolated during latency. Recurrent Infections Reactivation of the latent virus can occur following various provocative stimuli, such as fever, axonal inju physical or emotional stress, and exposure to ultraviolet light. + Viathe axonal spread, virus goes back o the peripheral site and further replicates in skin or mucosa producing secondary lesions 4 Recurrent infections are less extensive and less severe because of presence of pre-existing host immunity that limits the local viral replication 4 Recurrent infections are usually asymptomatic; but the virus continues to shed in the secretions. Clinical Manifestations Both HSV-1 and 2 have been isolated from nearly all mucocutaneous sites and viscera; however, in general, oral-facial infections are common with HSV-1, whereas HSV-2 frequently causes genital infectionsand intrauterine infections. The incubation period ranges from 1 to 26 days (median, 6-8 days). Oral-facial Mucosal Lesions Oral-facial mucosal lesions are the most common manifestation of HSV infections (Figs 56.2A and B). 4 Most common affected site is buccal mucosa 4 Most frequent primary lesions are gingivostomatitis and pharyngitis 4 Most frequent recurrent lesion is herpes la vesicles near lips) (Fig. 56.2A) + Other lesions produced are—ulcerative stomatitis, tonsilltis and vesicular lesions on the eyelids (Fig. 56.2B) 4 Many cases are asymptomatic but can predispose to secondary bacterial infection. ialis (painful Figs 56.2A and B: A. Vesicular lesions on lips and tongue due to HV-1infection;B.Periocular vesicular lesions due to HSV-1 infection. Source: Public Health image Library, A. IDF 12616 (Robert E Sumpter, B. IDF {6492 (Or KL Hermanni/Centers for Disease Control and Prevention (COO), ‘Atlanta (with permission) Cutaneous Lesions HSV usually infects through abraded skin and causes various cutaneous lesions. Herpetic whitlow: Lesions present on the fingers of dentists and hospital personnel + Febrile blisters (herpes febrilis): Fever due to any other ‘cause can provocate HSV to cause recurrent blisters Herpes gladiatorum: Mucocutaneous lesions present on the body of wrestlers + Skin lesions are often severe on underlying eczema or burns which permit extensive local viral replication and spread + Eczema herpeticum: Caused by HSV-1 in patients with chronic eczema. Similar lesions are also produced by vaccinia virus or coxsackievirus A16 infect these conditions together are designated as Kaposi's varicelliform eruptions Erythema multiforme: HSV is commonly associated with this condition. Herpes antigens have been detected in the immune complexes found in serum or skin biopsies. Other infective Syndromes of HSV CNS infections: HSV causes various neurological manifestations such as encephalitis, meningitis, Bell's palsy (due to facial nerve involvement) etc. (Chapters 73.and 74) % Ocular manifestations: HSV causes various ocular manifestations such as keratoconjunctivitis, corneal ulcer and blindness. Detail is discussed in Chapter 78 Genital lesions: HSV-2 is more common than HSV-1 to produce genital lesions; described as bilateral, painful, multiple, tiny vesicular ulcers (Chapter 77) Visceral and disseminated herpes: HSV viremia results in disseminated infection; involving multiple organs = Risk factors: Immunocompromised patients, underlying malnutrition or AIDS, pregnant women and transplant recipients are at a hi disseminated infection = Common manifestations include: Pneumonitis, tracheobronchitis and hepatitis. ® Neonatal herpes: Transmission is more common, during birth than in utero. Neonates are almost always symptomatic and present with either local lesions or disseminated infection or CNS infections (Chapter 79) Epidemiology Herpes simplex viruses are worldwide in distribution. No animal reservoirs or vectors are involved with the human viruses. HSV-1 and2 differ in their epidemiological pattern. Epidemiological Pattern of HSV-1 + Transmission: HSV-1 infection is more common and is transmitted by contact with infected secretions (saliva) Scanned with CamScannerCHAPTER S6 © Viral Exanthems and Other Cutaneous Viral Infections + Primary infection occurs early in life and is either asymptomatic or remains confined to oropharyngeal disease 4 Age: Children are commonly affected 4 Adults: Antibodies develop in 70-90% of adults, but they fail to eliminate the virus from the body. Most adults become carriers throughout the life, occasionally get transient recurrent attacks. Epidemiological Pattern of HSV-2 4 HSV-2s transmitted by sexual or vertical routes 4 Primary infection occursin adult life. Antibodies develop ‘only in 20% of people particularly among black women than men and whites HSV-2tends to recur more often than HSV-1, irrespective of the site of infection. Cama HSV infections a Cytopathology (Tzanck preparation) by Wright's or Giemsa stain-detects inclusion bodies (Lipschultz body) and formation ‘of multinucleated giant cells Virus isolation by: > Conventional cell lines—used to demonstrate diffuse rounding and ballooning of cll lines > Shell via culture—detects antigens in celine by I. Viral antigen detection in specimen by direct IF HSV DNA detection by PCR and real-time PCR (detecting alycoprotein B and UL 30 genes) a Antibody detection by ELISA or other formats-detecting antibodies to glycoprotein G. Laboratory Diagnosis ‘The sensitivity ofall the methods to diagnose HSV infection depends on the type of specimen, as well as the type of, infection. The sensitivity is more for vesicular lesions and primary infection than for ulcerative lesions and recurrent infections. Cytopathology Scrapings obtained from the base of the lesion can be stained with Wright's or Giemsa (Tzanck preparation), or Papanicolaou stain. Sensitivity of staining is low (<30% for mucosal swabs). It cannot differentiate between HSV-1, HSV-2, and varicella-zoster virus; as all of them produce similar but characteristic cytopathological changes such as: + Production of Cowdry type A intranuclear inclusion bodies (Lipschultz body) Formation of multinucleated giant cells with faceted nuclei and ground glass chromatin (Tzanck cells) 56.34) + Ballooning of infected cells, margination of chromatin, Virus Isolation It remains the most definitive tool for HSV diagnosis. McCoy cell lines are preferred for isolation of HSV. Viral growth can be detected in 2-4 days by: ae %e Fig Sean Bi Tech aro i Sng a Iutunudlested ance Tenckcl nthe center tton Sowing Brindret tr HS /2 abo detection. Source: A. Public Health Image Library, IDF 14428/Centers for Disease Control and Prevention (CDC), Atlanta 8. Euroimmun (with permission + Characteristic cytopathic effect: Diffuse rounding and ballooning of the infected cells + Viral antigen detection by neutralization test or immunofluorescence staining with specific antiserum + Shell vial technique can be followed to decrease the detection time to <24 hours. Viral Antigen Detection by Immunofluorescence Viral antigen detection (targeting cell surface glycoprotein antigens) by direct IF is also a sensitive and specific assay Itcan differentiate HSV-1 from HSV-2. HSV DNA Detection % Polymerase chain reaction (PCR) is the most sensitive test for detecting HSV infections and can be used to differentiate between HSV-1 and HSV-2 + Real-time PCR has been developed targeting genes such as glycoprotein B and UL 30; which are more sensitive; can quantitate the viral load in specimens (prognostic ‘ker of HSV encephalitis) and also can differentiate between HSV-1 and -2 # ‘The BioFire FilmArray is an automated nested mulitplex PCR. Its Meningitis/Encephalitis (ME) panel can detect simultaneously 14 microbial pathogens causing CNS infections, including HSV-1 and HSV-2. Antibody Detection Antibodies appear in 4-7 days after the infection and peak in 2-4 weeks. IgM appears first and is replaced by IgG, which persists for life. % Mostavailable tests usually detect IgG or total antibodies, hence cannot differentiate between recent and past infections. Seroconversion or a rise in titer is more meaningful + Serologic assays (e.g, ELISA) based on the type-specific antigens such asglycoprotein G antigens (gG1 and gG2) can differentiate between HSV-1 and HSV-2. Western blotis moreaccurate, with 98% sensitivity and specific Both ELISA and indirect IF formats are available (Fig 56.38). Scanned with CamScannerHSV infections Several specific antiviral drugs are effective for HSV infections. ‘Acyclovir is the drug of choice. It acts by inhibiting viral ONA polymerase. © For mucocutaneous infections: Acyclovir, famciclovir and valacyclovir have been the mainstay of treatment @ Ocular infection: Topical idoxuridine, trifluorothymidine, topical vidarabine, and cidofovir are used 2 For HSV encephalitis and neonatal herpes, acyclovir is the treatment of choice. ‘Acyclovir resistance has been reported among few HSV strains which have altered substrate specificity for phosphorylating acyclovir. Resistance is more common in HSV-2 and among immunocompromised patients. Foscarnet is the drug of choice to treat such cases. Prevention General measures can be taken such as: 4% Use of condom to prevent genital herpes & Neonatalherpescan be prevented by prior administration of acyclovir to mothers during third trimester of pregnancy or delivery by elective cesarean section No vaccine is currently licensed. Several vaccine trials are going on, such as recombinant HSV-2 glycoprotein Infection control measures: Patients with mucocutaneous herpes in hospitals, should be kept on contact precautions until lesions are dry and crusted (Chapter 21). VARICELLA-ZOSTER VIRUS INFECTIONS Varicella-zoster virus (VZV) produces vesicular eruptions (rashes) on the skin and mucous membranes in the form of two clinical entities: SECTION 7 © Skin, Soft Tissue and Musculoskeletal System Infections 1. Chickenpox: It is characterized by generalized diffuse bilateral vesicular rashes which occur following primary infection, usually affecting children (Fig. 56.4A) ‘Zoster or shingles: It occurs following reactivation of latent VZV, present in the trigeminal ganglia that occurs mainly in adult life. Vesicular rashes are unilateral and segmental (confined to the skin innervated by a single sensory ganglion) (Figs 56.4B and C). Chickenpox thogenesis VZV enters through the upper respiratory mucosa or the conjunctiva by aerosol (most common) and contact transmission. From the local site, itspills over to blood and then is carried through the infected mononuclear cells to target sites such as: + Skin (produces rashes) + Respiratory tract (shed in respiratory secretions) # Neurons (undergoes latency). Clinic + Incubation period is about 10-21 days (2-3 weeks) ® Rashes are the main manifestation of chickenpox = Rashes are vesicular (Fig. 56.4A) = Centripetal in distribution: Usually start on the face and trunk, spread rapidly to involve flexor surfaces; sparing distal part of the limbs = Bilateral and diffuse in distribution = Rashes appear in multiple crops: Lesions in various stages of evolution, such as maculopapules, vesicles, pustules, and scabs can be found in one area at the same time = Fever appears with each crop of rashes. % Chickenpoxis a disease of childhood fanifestations Figs 56.48 to C: A. Rashes of Chickenpox; B and C. Segmental distribution of rashes of Zoster. ‘Source: A. Pubic Heath image Library 1D¥/2882/J0 Mila Centers for Disease Control and Prevention (CDQ), Alanta (wth permission 8. CW Leung, ‘Department of Pediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong with permission) C. Recommendations ofthe ‘Advisory Committee on Immunization Practices [ACI MMWR Morb Mortal Wey Rep 2006:571RR-5:1 with permission). Scanned with CamScannerCHAPTER 56 @ Viral Exanthems and Other Cutaneous Viral Infections A When occurs in adults, it is more severe with bullous and hemorrhagic rashes leaving behind pitted scars on skin after recovery. ‘Complications Complications are more common in adults and in immunocompromised individuals. Most common infectious complication bacterial infections of the skin % Most common extracutaneous complication is: CNS involvement (cerebellar ataxia, encephalitis and aseptic meningitis), usually occurs in children + Most serious complication is: Varicella pneumonia, which develops more commonly in adults (up to 20% of cases) than in children and is particularly severe in pregnant women, ® Reye's syndrome can occur secondary to VZV infection. Itis characterized by fatty degeneration of liver following salicylate (aspirin) intake + Other complications are: Myocarditis, nephritis, comeal lesion and arthritis ® Chickenpox in pregnancy: Chickenpox in pregnancy canaffect both mother and the fetus. = Mothers are at high-risk of developing varicella pneumonia = Fetus is at higher risk of developing congenital vari- cella syndrome (in early pregnancy); characterized by cicatricial skin lesions and limb hypoplasia (Chap- ter 79, for detail. secondary Epidemiology Chickenpox is a highly contagious disease. + Itis primarily a disease of the temperate regions; occurs throughout the year with prevalence of 13-16/1,000 people per year 4 Age: Common in children between 1 to 14 years of age + Period of infectivity: Child is infectious from 2 days before the onset of rash to 5 days thereafter, until the vesicles are crusted + One attack gives lifelong immunity Reservoirs Humans are the only known reservoir host Source of infection: Patients are the only source, there are no carriers + Secondary attack rate is about 70-90%. Zoster or Shingles or Zona Zoster usually occurs due to reactivation of latent VZV in old age (>60 years of age), in immunocompromised individuals or occasionally in healthy adults. + Itusually starts with severe pain in the area of skin or mucosa supplied by one or more groups of sensory nerves and ganglia + Rashes: They are unilateral and segmental, confined to the area of skin supplied by the affected nerves (Figs 56.4B and C) Most common nerve involved is ophthalmic branch of trigeminal nerve. Head, neck and trunk are the most common affected sites. Complications of Zoster Post-herpetic neuralgia (pain at the local site lasting for months): Itis the most common complication in elderly patients © Zoster ophthalmicus: Unil rashes surrounding the eye + Ramsay Hunt syndrome develops when geniculate ganglion of facial nerve is involved. Itis characterized by triad of ipsilateral facial paralysis, ear pain, and vesicles on the face, tympanic membrane and external auditory meatus + Visceral disease, especially pneumonia can occur which is the most common cause of death (<1%) in zoster patients ® Recurrent or chronic zoster is common with HIV-infected patients. Laboratory Diagnosis (VZV) Laboratory diagnosis of VZV infection is as follows: + Specimen collection: Common specimens include vesicular lesions, scabs and maculopapular lesions Cytopathology: Giemsa staining of the scrapings from the ulcer base (Tzanck smear) reveals cytopathological changes similar to that of HSV infection, such as formation of multinucleated giant cells Virus isolation: Virus isolation in various cell lines can also produce HSV-like cytopathic effects such as diffuse rounding and ballooning of infected cells, + VZN-specific methods: ‘= Specific antigen detection by direct immunofluores- cence staining = Specific IgM and IgG antibody detection by ELISA = PCR detecting VZV-specific genes = The BioFire Meningitis/Encephalitis (ME) Panel tests simultaneously 14 microbial pathogens causing CNS infections including VZV. Gxt: \V2V infections ‘Acyclovir, famciclovir or valacyclovir are the agents of choice. It ‘can prevent the complications of chickenpox and can also halt the progression of zoster in adults, but cannot prevent post- herpetic neuralgia. iteral painful crops of skin Vaccine Live attenuated vaccine using Okastrain of VZV isavailable. + Itis given to children after 1 year of age; 2 doses, first dose is given at 12-15 months and second at 4-6 years + In seronegative adults; 2 doses given at 1-month gap + As this vaccine is not being given as a part of national immunization schedule, the countrywide vaccine coverage is inadequate leading to frequent outbreaks Scanned with CamScannerSECTION7 @ Skin, Soft Tissue and Musculoskeletal System Infections + Transmission of the vaccine virus can occasionally cause mild rashes in the recipient * Protectivity: The vaccine is >80% effective in preventing chickenpox in children but less so in adults (70%). However, it is 95% effective in preventing severe disease. VZIG (Varicella-zoster Immunoglobulin) + Itisuseful for post-exposure prophylaxis; given within ‘96 hours (preferably within 72 hours) of exposure. AS adults are at higher risk of varicella-related deaths, VZIG is recommended for adults, especially those who are at greater risk for complications—immunocompromised persons such as HIV, pregnancy, etc. It is also indicated for neonates born to mothers suffering from chickenpox if the onset of chickenpox in mother is between <5 days before delivery till 48 hours after delivery. VZIG isnot indicated for the neonate ifthe mother has zoster. Infection Control Measures Patients infected with VZV should be kept in isolation. Airborne precautions (e.g. negative air-flow rooms) plus contact precautions must be followed until lesions are dry and crusted (Chapter 21). For localized zoster in an immunocompetent host, contact precaution alone can be followed. OTHER HERPESVIRUS INFECTIONS Other herpesviruses include: @ Epstein-Barr virus: EBV causes infectious ‘mononucleosis (Chapter 68) and various malignancies (Chapter 80). Itcan produce rashes following ampicillin therapy + Cytomegalovirus: CMY causes congenital infection (Chapter 79); also produces various infections in transplant recipients Human herpesvirus 6: t infects the T cells by binding to (CD46 receptor. It has two variants 6A and 6B = Transmission is through infected oral secretions © Sixth disease: In children, HHV-6 (usually the 68 variant) causes sixth disease, also called as exanthem subitum or roseola infantum. It is characterized by high grade fever and skin rashes = Inolder age groups, HHV-6 has been associated with mononucleosis-like syndrome. ® Human herpesvirus 7: HHV-7 also shows tropism for T cells, transmitted by oral secretions, mainly in children, © It shares 30-50% DNA homology with HHV-6 = Ithas been associated with fever, seizures, respi- ratory or gastrointestinal symptoms, and pityriasis rosea © Human herpesvirus 8: It causes a malignancy called Kaposi sarcoma in HIV-infected individuals (Chapter 80). Cin Laas ke NS aD Nee ee PARVOVIRUS INFECTIONS Morphology Parvoviruses are the simplest animal viruses infecting humans, responsible fora common childhood exanthema called as erythema infectiosum (fifth disease). % ‘Theyare the smallest viruses (18-26 nm size) Non-enveloped with icosahedral symmetry % ‘Theyare the only DNA virusesto possess single-stranded DNA + Parvovirus B19 is the most common parvovirus, pathogenic to man + ‘They depend upon the host cell enzymes for replication. Pathogenesis Parvovirus B19 exclusively infects humans. % ‘Transmission: By the respiratory route (most common), followed by blood transfusion and transplacental route + Infects precursors of RBCs: It has a special tropism for erythroid progenitor cells present in the adult bone ‘marrowand fetal liver as it binds to blood group P antigen as receptors; which are present on the RBC surface This results in destruction of RBCs and inhibition of erythropotesis. ical Manifestations Erythema infectiosum (or fifth disease): In children, it produces rashes on the face with characteristic slapped cheek appearance (Fig. 56.5)-Adult women present with symmetrical polyarthropathy which usually involves the hand joints and knee ‘Transient aplastic crisis: It can occur in infected patients with underlying hemolytic anemia, resulting in severe acute anemia Fig. 56.5: Fifth disease or rashes with slapped cheek appearance. Source: Whipedia/Andrew Ker (with permissio Scanned with CamScannerCHAPTER 56 @ Viral Exanthems and Other Cutaneous Viral Infections Pure red cell aplasia: It can occur in those with underlying immunosuppression due to persistent B19 infections, resulting in chronic anemia Non-immune hydrops fetalis can occur in fetus, which results in fatal anemia and fetal death. Transplacental transmission occurs in 30% of cases and maximum risk isin the second trimester Papular-purpuric gloves and socks syndrome: It presents as rapidly progressive, painful, pruritic, and symmetric swelling and erythema of the distal hands and feet, usually in the spring and summer; which may bbe confused with acute meningococcemia. Laboratory Diagno: Molecular methods: The most sensitive assay for diagnosis is PCR, which detects viral DNA (e.g. genes coding for VP1 and VP2) from serum, tissue or respiratory secretions. Real time PCR is used for quantification of viral load in blood, during acute infections % Antibody detection: ELISA has been available detecting, antibodies against VP1 and VP2 antigens. IgM appears carly, indicates recent infection and remains elevated for 2-3 months Antigen detection: Immunohistochemistryhas been used to detect viral antigens in fetal tissues and bone marrow. (Treatment Parvovirus infections No antiviral drug is available Symptomatic treatment s given 2 Immunoglobulins containing neutralizing antibodies to human parvovirus are available commercially. HUMAN PAPILLOMAVIRUS INFECTIONS Human papillomavirus (HPV) is a DNA virus, belongs Papillomaviridae family. It has selective tropism for epithelium of skin and mucous membranes. It has >100 serotypes, which produce an array of infections ranging from ‘benign warts, to malignantneoplasia of cervix (Chapter 80).. Benign warts: They are small, hard, rough growth on the skin (Fig. 56.6). They are of following types: Common skin warts (verruca vulgaris) and flat warts (verruca plana) are common in children (seen with serotypes 2, 4, 27, 57) ¢ Plantar warts (verruca plantaris)-benign lesion, widely prevalent among adolescents (seen with serotype 1) ® Anogenital warts (condyloma acuminatum): It is a sexually transmitted infection, seen among adults and is associated with HPV serotypes 6 and 11 (Chapter 77), POXVIRUS INFECTIONS Morphology Poxviruses are the largest (400 nm in length x 230 nm in. diameter) among all the viruses, large enough to be seen, under light microscope. Fig. 56.6: Plantar warts Source: Wikipedia (with permission Most complex viruses; their structure does not fit into either icosahedral or helical symmetry + Brick-shaped or ellipsoid Envelope: Externally, there is an envelope, made up of two lipoprotein membranes (outer and inner) with ridges arising from the outer membrane. The envelope encloses a core and two structures of unknown function called lateral bodies (Figs 56.7A and B) Core or the nucleocapsid is biconcave dumbbell shaped + Possess single linear dsDNA. Itisthe only DNA virus that replicates in the cytoplasm. ‘The following are the poxviruses of human importance. % Variola: It was the causative agent of smallpox, the first disease to be eradicated from the world Vaccinia: It was used as a vaccine for smallpox ‘® Molluscum contagiosum virus: It causes warty lesions called as molluscum contagiosum. Smallpox Smallpox was the first infectious disease to be eradicated from the world. It was characterized by highly contagious severe exanthema (rashes). The agents of smallpox were variola major and variola minor. Figs 56.7A and B: A. Smallpox virus (schematic diagram); B. Smallpox virus (electron micrograph). Source: 8.108 1849 D Fred Murphy, Syvia Whitheld/Centers for Disease onto! and Prevention (CDC) Alanta (th permission) Scanned with CamScannerSECTION7 @ Skin, Soft Tissue and Musculoskeletal System Infections Smallpox Time Line % Last natural case of variola major was seen in a Bangladeshi woman in Assam in May 1975, Last natural case of variola minor was seen in Merca, Somalia, 26th October 1977 * Eradication was declared by WHO nearly after three years of the last case, i.e. on 8" May 1980 Laboratory spread: There was a small outbreak in Birmingham (1978), due to accidental spread of the virus from the virus laboratory, following which stocks from ‘most laboratories have been destroyed Maintenance: Currently, only two laboratories hold stocks of smallpox virus = CDC (Centers for Disease Control and Prevention) Atlanta (USA) = Center for Research on Koltsova (Russi % Agent of bioterrorism: As vaccination was stopped following eradication, people borne after 1980 are not immunized. Hence, smallpox virus can be a pote! agent of bioterrorism. firology and Biotechnology, Reasons that Made Eradication Successful @ Variola was an exclusively human pathogen, no animal reservoir ‘Source: Patients were the only source, there were no carriers, ase detection was easy-due to characteristic appearance of rashes (Table 56.4) ‘Subclinical cases were not transmitting the disease Global smallpox eradication program was launched in 1967 by WHO (World Health Organization). With a strong international cooperation and intense effort; disease was. wiped out nearly after 10 years Highly effective live vaccinia vaccine > Freeze dried form was used (stability) > Multiple puncture technique was followed to administer the vaccine by using a bifurcated needle, which was found to be simple, effective and economical. Clinical Manifestations ‘The portal of entry of the virus was via the mucous mem- branes of the upper respiratory tract (aerosol transmis- sion). Pee nallpox and chicken Enis eee Incubation period: Incubation peri 12 days (7-17 days) 15 days (10-21 days) Site of rash:Palm, soleand Site of rash: Axila and flexor, extensor surface surface Rash: Deep seated and appear Rash: Superficial and insingle stage, evolution is__pleomorphic (appear in crops) slow, centrifugal distribution evolution is rapid, dew drop rashes, centripetal distribution Fever subsides with Fever rises with each crop of rash appearance of rsh % After an incubation period of 12 days (7-17 days), the patient developed the rashes Description of rashes: Smallpox rashes were unique in appearance and could easily be differentiated from that of chickenpox (Table 56.4) = Rashes were deep seated and all rashes in an area appeared in one stage, evolution was slow (Fig. 56.8) = Centrifugal distribution-palm and sole and extensor surface were affected first = Fever subsided with appearance of rash. Laboratory Diagnosis Direct detection in scrapings from rashes = Intracytoplasmic inclusion bodies (Paschen bodies) = Electron microscopy: Brick-shaped appearance with biconcave DNA core. Egginoculation: Characteristic pock formation is seen on the chorioallantoic membrane (CAM) ofa chick embryo. Ge satpox Cases used to be treated in the past wit @ Vaccinia immunoglobulins @ Antiviral drugs such as methisazone, cidofovir or tecovirimat. Vaccination % Live vaccinia vaccine was highly effective. = Itwas given asa single dose, at 1-2 years of age = Asun-attenuated live virus was used, adverse reactions were common; such as mild vaccinia-induced rashes. % Cowpox vaccine discovered by Edward Jenner (the father of vaccination) was in use before vaccinia vaccine was available Variolation was the first attempt of providing artificial immunity against smallpox. It was in use even before cowpox vaccine was available (17th-18th century). Healthy people were inoculated with the skin scraping of a smallpox patient. Fig. 56.8: Smallpox rashes over the face. ‘Source: Public Heath Image Library, ID¥ 3/Centrs for Disease Control ‘and Prevention (COC), Allanta/Chery! Tyron (with permission. Scanned with CamScannerCHAPTER S6 @ Viral Exanthems and Other Cutaneous Viral Infections Vaccinia ‘Vaccinia virus cross-reacts with variola and the antibodies produced against vaccinia are protective for variola, The antigenic cross reactivity was so much that vaccinia was able to eradicate variola globally. However, vaccinia differs from variola in many ways: Itisnon-pathogenic to humans or produces milder skin lesions 4 Produces an inclusion body called Guarnieri body (variola produces Paschen body) 4 OnCAM, vaccinia virus produces larger and hemorrhagic and necrotic pock lesions than variola. Molluscum Contagiosum Molluscum contagiosum virus is an obligate human poxvirus that produces characteristic skin lesions. Clinical Manifestations + Lesions: It produces dome-shaped, pink pearly wart- like lesions (2-5 mm size), umbilicated, with a dimple at the center (Fig. 56.94). Lesions are found singly or in clusters, anywhere on the body excepton the palms and soles. Genital lesions are seen in adults Transmission: = Children are commonly affected, acquire infection by direct and indirect contact e.g, by barbers, common use of towels, swimming pools) = Rarely sexual transmission has been reported in young adults. % Self-limiting: Lesions disappear in 3-4 months, There are no systemic complications In HIV-infected patients: Disease is more generalized, severe and persistent. Laboratory Diagnosis Molluscum bodies are the intracytoplasmic eosinophilic inclusions seen in skin scrapings stained with histo- pathological stains (Fig. 56.98) % Electron microscopy and PCR can be used for confirma- tion + Not cultivable: It cannotbe propagated in tissue culture, embryonated egg or in animals. (CEN __Motuscumcontagionum Surgical removal ofthe lesions by ablation (by cryotherapy or laser therapy) is the mainstay of treatment. Cidofovir has shown tw have some efficacy. As this virus does not cross-react with any other poxvruses, smallpox vaccine is not protective. Other Poxviruses of Human Importance They are zoonotic, mainly infect various animals. Human infection is rare. Monkeypox: Can produce vesicular rash similar to smallpox but milder. Infection can be prevented by smallpox vaccination Figs 56.98 and B: A. Molluscum contagiosum lesions on skin; . Histopathology of skin showing molluscum bodies, Source: A.CDC/.Speting MO, Walter Reed Army Medical Center 8. Public Health Image Library, ID 850/Center for Disease Control and Prevention (COC), Atarea/Dr Edwin P Ewing, (wit permission. + Orf virus: Produce localized skin lesions, called as contagious pustular dermatitis or mouth sore + Pseudocowpox (Paravaccinia): Can rarely infect milk handlers to produce nodular skin lesions called milker's nodule + Cowpox and butffalopox: Can produce pox-like lesions illness. and mild syster RNA VIRUSES CAUSING UNS A Tet MEASLES Measles is an acute, highly contagious childhood disease, characterized by fever and respiratory symptoms, followed by typical maculopapular rash (see Fig. 56.10B). The ‘causative agent, measles virus is a RNA virus, belongs to Paramyxoviridae family (Chapter 66). Pathogenesis 4 ‘Transmission: Measles is transmitted via the respiratory route either by— = Droplets inhalation over short distances (common) = Small-particle aerosols that remain suspended especially in schools, hospitals, and enclosed public places in the air for longer period (less common). 4 Spread: The virusmultipliestocally intherespiratory tract; then spreads to the regional lymph nodes -» enters into the bloodstream through infected monocytes (primary viremia) —> further multiplies in reticuloendothelial system > spills over to blood (secondary viremia) —> disseminates to various sites 4 Target sites: The virus is predominantly seeded in the epithelial surfaces of the body, including the skin, respiratory tract, and conjunctiva. Scanned with CamScannerFigs 56.10A to C: A. Kop! SECTION 7 © Skin, Soft Tissue and Musculoskeletal System Infections spot in buccal mucosa (measles) (arrow showing); B. Measles rashes (on face); ‘C. Multinucleated giant cell of measles infected cell lines (arrow showing) Clinical Manifestations Incubation period is about 10 days which may be shorter in infants and longer (up to3 weeks) in adults. Disease can be divided into three stages. 1. Prodromal Stage This stage lasts for 4 days (i.e. from 10% to 14% day of infection) and is characterized by manifestations such as: % Fever is the first manifestation, occurs on day 1 (Le. on 10" day of infection) Koplik’s spots are pathognomonic of measles, appear after two days following fever (ie, on 12" day of infection) and are characterized by: = White to bluish spot surrounded by an erythema = Appear first on buccal mucosa near second lower molars (Fig. 56.10) = Rapidly spread to involve the entire buccal mucosa and then fade with the onset of rash. + Non-specific symptoms may be present such as cough, ccoryza, nasal discharge, redness ofeye, diarrheaor vomiting. 2. Eruptive Stage Maculopapular dusky red rashes appear after 4 days of fever (i. on 14" day of infection). + Rashes typically appear first behind the ears —> then spread to face, arm, trunk and legs -> then fade in the same order after 4 days of onset (Fig. 56.10B) + Rashes are typically absent in HIV infected people. Fever (10" day) -> Koplik’s spot (12" day) -> rash (14% day) 3. Post-measles Stage Itis characterized by weight loss and weakness. There may be failure to recover and gradual deterioration into chronic illness. Complications Children of <5 years, adults of >20 years, pregnant women, and immunocompromised hosts are at higher risk of complications. Source: A Public Health Image Library ID# 611; 8. I 17980; . 1D 859/Centers for Disease Control and Prevention (CDC), Atlanta (wth permis) Secondary Bacterial Infections Following measles, there is profound immune suppression, and fall of cell-mediated immunity which in turn predisposes to various secondary bacterial infections. % Otitis media and bronchopneumonia are most common + Recurrence of fever or failure of fever to subside with the rash 4 Worsening of underlying tuberculo: negative Mantoux test. with a false Complications Due to Measles Virus Itself + Giant-cell pneumonitis (Hecht’s pneumonia) in immu- nocompromised children, and in HIV infected people + Acute laryngotracheobronchitis (croup) + Diarrhea, leads to malnutrition including vitamin A deficiency. Central Nervous System Complications CNS complications are rare, but most severe (Chapter 74). + Subacute sclerosing panencephalitis (SSPE) is the most important CNS complication + Others include post-measles encephalomyelitis and ‘measles inclusion body encephalitis. Crome Measles 2 Specimen: Nasopharyngeal swab Antigen detection: By using anti-nucleoprotein antibodies & Virus isolation: By inoculation of specimen into monkey or human kidney cell line, produces CPE as multinucleated giant ‘cells (Warthin-Finkeldey cells) Antibody detection in serum: Against nucleoprotein antigen by ELISA 1 Reverse-transcription PCR: detects viral RNA. m9 Laboratory Diagnosis Specimens Nasopharyngeal swab, conjunctival swab, blood, respiratory secretions, and urine are the ideal specimens. Synthetic swabs are recommended. Scanned with CamScannerCHAPTER 56 © Viral Exanthems and Other Cutaneous Viral Infections Antigen Detection Measles antigens in the infected cells can be detected directly by using anti-nucleoprotein antibodies (direct immunofluorescence test). Virus Isolation % Cell lines: Monkey or human kidney cells are optimal cell lines used for isolation of measles virus Cytopathic effect may be observed after 7-10 days of inoculation into cell lines characterized by- multinucleated giant cells (Warthin-Finkeldey cells) containing both intranuclear and intracytoplasmic inclusion bodies (see Fig. 56.10C) Shell vial culture is recommended for early detection within 2-3 days. Antibody Detection + Detection of measles-specific IgM antibody in serum or oral fluid or four-fold rise of IgG antibody titer between acute and convalescent-phase sera is taken as significant + Demonstration of raised titers of anti-measles antibody in the CSF is diagnostic of SSPE % ELISA is the most recommended test that uses recombinant measles nucleoprotein (NP) antigen. Reverse-transcription PCR RT-PCRis available targeting measles specific RNA such as N gene(nucleoprotein) in clinical specimen. + Itis extremely sensitive and specific + It may also permit characterization of measles virus ‘genotypes for molecular epidemiologic studies RNA can be detected in specimens up to 10-14 days post rashes, in contrast to virus isolation, which often becomes negative alter 3 days of rash. ‘Measles genotypes There are 8 clades of measles which are further grouped into 23 recognized genotypes (WHO) Genotype D8 followed by B3 and D4 are the commonly reported globally as well as from India. Ct Measles @ There is no specific antiviral therapy available for measles Treatment is symptomatic and consists of general supportive measures Vitamin A has been effective in reducing the morbidity and ‘mortality due to measles. Prevention General Preventive Measures Airborne precaution such as isolation in negative pressure room, use of PPEs such as N95 respirator, etc. must be followed while handling measles cases (Chapter 21 for detail) ‘Measles Vaccine Live attenuated vaccine is available for measles. + Strains: The following vaccine strains are used currently = Schwartz strain (currently serves as the standard in much of the world) = Edmonston-Zagreb strain = Moraten strain. % Vaccine is prepared in chick embryo cell line % Reconstitution: Vaccine is available in lyophilized form and it has to be reconstituted with distilled water and then should be used within 4 hours Vaccine is thermolabile, hence, it mustbe stored at -20°C One dose (0.5 mL) containing more than 1000 infective viral units is administered subcutaneously Combined vaccines: Measles vaccine is available in combined form with rubella (MR vaccine), with mumps and rubella vaccine (MMR vaccine) and with varicella (MMR-V vaccine) Indication: Under national immunization schedule of India, measles-rubella (MR) vaccine is given at 9 completed months to 12 months along with vitamin A supplements and second dose of MR vaccine at 16-24 ‘months Contraindications for MMR vaccine are: Severe life-threatening allergic reaction to MMR vaccine, advanced immune deficiency state (e.g.,transplant, chemotherapy, advanced HIV), pregnancy, active tuberculosis, or has received another live vaccine within the past 30 days Side effects include: = Mild measles like illness may develop in 15-20% of vaccines. There is no spread of the vaccine virus in the community = Toxic shock syndrome (due to contamination of vial with S aureus toxins). Contacts: Susceptible contacts over 9-12 months may be protected against measles ifthe measles vaccine is given within 3 days of exposure. ‘This is because incubation period of measles induced by the vaccine strain is about 7 days, compared to 10 days for the naturally occurring measles = Measles immunoglobulin (Ig) can also be given within 3 days, at a WHO recommended dose of 0.25 mg/kg of body weight = However, both vaccine and Ig should not be given together. At least 8-12 weeks of gap must be maintained. Epidemiology Measles is endemic throughout the world with epidemics which recur regularly every 2-3 years, typically in late winter and early spring, 4 Source: Cases are the only source of infection. Carriers are not known to occur. In-apparent or subclinical infections are rare Scanned with CamScannerSECTION 7 © Skin, Soft Tissue and Musculoskeletal System Infections + Reservoir: Humans are the only reservoir of infection. ‘There is no animal reservoir + Infective material: Virusis shedin the secretions of nose, throat and respiratory tract of cases of measles, especially uring the prodromal stage and early stage of rash + Period of communicability: Patients are infectious from four days before to four daysafter the onset of rash. Patients are highly contagious, isolation is recommended from the onset of prodromal stage until third day of rash + Secondary attack rate is very high (90%) # Age: Measles is a childhood disease = Children (6 months to 3 years) are the most susceptible group in developing countries = Older children (>5 years) are commonly affected in developed countries or in vaccinated population. + Immunity: No age is immune if there is no previous immunity = Thereis single serotype hence one attack (vaccine or infection) gives lifelong immunity = Infants are protected up to 6 months due to pre- existing maternal antibodies. + Epidemic of measles occurs if proportion of susceptible children exceeds 40%. Though disease burden has much decreased after the vaccine is made available, measles is stil a leading cause of death of young children in many developing countries World: The measles cases have dramatically reduced in recent days due to widespread vaccination = In 2018, there were 3,59,921 confirmed cases of measles worldwide (with 1.4 lakh deaths); compared to >40 lakh cases in 1980) = Congo reported the maximum cases in 2018, followed by Ukraine and Pakistan. + India: The burden of measles is substantially reduced ‘due to widespread vaccination. In 2018, around 19,474 ‘cases were reported from India; compared to >1 lakh cases in 1980. ‘Measles elimination ‘Measles is amenable to eradication. With the efficient and ‘widespread immunization program, itis possible to eradicate ‘measles from the world. WHO has introduced ‘The Strategic Plan for achieving and ‘maintaining Measles and Rubella elimination in WHO South- East Asia Region: 2020-2024! The following objectives are set toachieve this target: 295% coverage with two doses of MR vaccine 9. Develop and sustain a case-based surveillance system Develop and maintain an accredited measles and rubella laboratory network . Strengthen support and linkages to achieve the above three strategic objectives. ‘Measles is said to be eliminated if the confirmed cases are <1 per million population. The American region and some Of the Western Pacific Region (Australia, Hong Kong, Japan, Korea, New Zealand, SriLanka, etc) have recently achieved the measles elimination status. RUBELLA Rubella virus produces a childhood exanthema similar to that of measles. Therefore, rubella is also known as German measles. However, unlike measles, itis highly teratogenic; ‘can cause congenital rubella syndrome. Rubella belongs to Togaviridae family, and is the only ‘member under genus Rubivirus It contains ssRNA, surrounded by a capsid (C) protein and an envelope Its envelope contains a lipid layer from which two types of spike-like glycoproteins (E1 and E2) are projected ‘There is only one serotype and humans are its only known reservoirs Clinical forms: Rubella may present in two clinical forms—postnatal infection and congenital infection. Postnatal Rubella Postnatal rubella may occur during neonatal age, childhood, and adult life. Transmission Rubella virus spreads from person-to-person by respiratory droplets via upper respiratory mucosa. Spread Rubella virus replicates locally in the nasopharynx, and then, spreads tothe lymph nodes. Subsequently, viremia develops after 7-9 days, and lasts until 14th day by which time both antibody and rashes appear almost simultaneously suggesting an immunologic basis for the appearance of rash. Clinical Manifestations Incubation period is about 14 days (range, 12-23 days) Subclinical infection may be seen in 20-50% of cases Rashes are often the first manifestations in children, but in older children and adults, 1 to 5-day prodrome often precedes the rash, which includes low-grade fever, malaise, and upper respiratory symptoms Rashes are generalized and maculopapular in nature, start on the face, extend to trunk and extremities, and disappear in 3 days (Fig, 56.11) Lymphadenopathy (occipital and postauricular) is the most striking feature Forchheimer spots may be seen in some cases. They are pin-head sized petechiae; develop on the soft palate and ually start with the onset of rash. Complications Arthralgia and arthritis are common in adults, particularly in women. Thrombocytopenia and encephalitis are rarely encountered. Laboratory Diagnosis + Isolation of virus: Nasopharyngeal or throat swabs taken, 6 days before and after the onset of rash Scanned with CamScannerCHAPTER 56 © Viral Exanthems and Other Cutaneous Viral Infections 56 Figs 56.11 and B: A. Child with rubella rash; B. Cataract seen in ‘congenital rubella infection (arrows showing). ‘Source: Public Health Image Library, A.ID# 101468. ID#4264iCerters for ‘Disease Control and Prevention (CDC) Atlanta (wth permision). = Ideal cell ines: Monkey or rabbit origin cell lines may beused = Itcan also be identified more rapidly in cell lines by shell vial technique. % Serology (Antibody detection): = ELISAis the preferred method for rubella diagnosis. It detects both IgM and IgG separately. Various antigens employed are whole virus lysate or recombinant E1/ E2antigens = Results need to be confirmed by IgG avidity test to differentiate active infection from the past infection orvaccination. Molecular test: RT-PCR is available for detecting rubella specific RNA (nucleoprotein N gene) in clinical specimens. Congenital Rubella Syndrome ‘The most serious consequence of rubella virus infection is congenital rubella syndrome. Rubella is highly teratogenic; affects ear (deafness), eyes (cataract, Fig. 56.11B), and heart (patent ductus arteriosus). The severity is maximum in first trimester. Detail is discussed in Chapter 79. Epidemiology % Source: The cases are the only source of infection. There isno known carrier state * Duration of protection: Once infected, the person acquires lifelong immunity. In India, still 40% females of reproductive age group are susceptible to rubella infection + Period of communicability of rubella is about 1 week before to 1 weekafter the appearance of rash # Transmission occurs via—airborne droplet, transplacental and rarely via contact, and sexual modes Occurrence: Rubella occurs worldwide and through- ‘out the year with a peakin the spring. Epidemics occur every 6-8 years, with explosive pandemics every 20-25, years * The largest rubella epidemic (postnatal) occurred globally in 1962-1965. However; with increasing vaccine use, the epidemics are encountered less nowadays 4 World: In 2018, 26,006 confirmed rubella cases were reported globally. Nigeria followed by China accounted, for maximum cases % India: In 2018, India reported 2,328 number of rubella ‘cases. There was an outbreak of rubella reported from. Rajasthan in 2014 4 Genotype: Based on EI protein coding region, Rubella has been typed into 13 genotypes; four of which are commonly circulating in world: 1E, 1G, 1), and 2B. Genotype 2B is the predominant type in the World and also from Indi Ci: Rubella Rubella is a mild, self-limited illness and no specific treatment is available. Prevention General Preventive Measures Airborne precaution must be followed while handling rubella cases (refer Chapter 21 for detail). Rubella Vaccine RA 27/3 is a live attenuated vaccine for rubella, prepared from human diploid fibroblast cell line. % It is available singly or in combination with vaccines of mumps and measles (MMR vaccine) + Schedule: Single dose (0.5 mL.) of vaccine is administered subcutaneously + Following vaccination, seroconversion occurs in 90% of recipients and immunity persists for 14-16 years or probably lifelong, + Indication: In India, rubella vaccine is indicated to all women of reproductive age (first priority group) followed by all children (1-14 years). Under national immunization schedule, rubella vaccine is given along with measles (MR vaccine) at 9-12 months of age and second dose at 16-24 months in selected states * Precautions: Vaccine is contraindicated in pregnancy = Asit is teratogenic, pregnancy should be avoided at least for 4 weeks (28 days) following vaccination = However, if a woman conceives <4 weeks following vaccination: wait and watch policy should be followed. No immediate termination of pregnancy is required = Infants below 1 year should not be vaccinated due to possible interference from persisting maternal antibody. HAND-FOOT-AND-MOUTH (HFM) DISEASE HFM disease usually affects children; is characterized by ulcerations on oral and pharyngeal mucosa and vesicular rasheson the palms and soles, which heal without crusting (Figs 56.12A to C), Fever and sore throat with flu like symptoms are the other manifestations. Scanned with CamScannerSECTION 7 Skin, Soft Tissue and Musculoskeletal System Infections Agents Figs 56.128 to C: Vesicular eruptions in Hand foot-and-mouth (HFM) disease: A. Hand; B. Foot; C. Mouth, Source: A and B, Centers for Disease Control and Prevention (with permission HEM disease is mainly caused by Coxsackievi- ruses, rarely by other enteroviruses = Coxsackievirus A16 is the most common cause = Coxsackievirus AG can cause HFMD with more severe manifestation = Enterovirus71 also has been associated with cases in East and Southeast Asia. iC Wikipedia, Mr Midgley (with permission) % Transmission: The virus can spread to others through an infected person’s nose and throat secretions, such as saliva, sputum, or nasal mucus, fluid from blisters or scabs and also feces. Transmission occurs through, contact (direct or indirect) and droplets. $$ [[acrsp auestions J}. Write essay on: 1. A 7-year-old boy had developed multiple painful vesicles over the lips and buccal mucosa. His parents revealed that two children of his school had a similar presentation few days back. Scrapings taken from the lesion demonstrated presence of multinucleated nt cel (Tzanck cell, a. What is the most probable diagnosis? b. List the other agents causing this type of infection. ‘& _Howisthisinfection diagnosedin thelaboratory? Write short notes on: 1. A child. presents with vesicular rashes, which appeared frst on the face and trunk, spread rapidly to involve flexor surfaces; sparing distal part of the limbs. Rashes are bilateral and diffuse in distribution, appear in multiple crops. Fever appears with each ‘crop of rashes. What is the clinical diagnosis? Discuss ‘about the prevention of this disease. 2. A child presents with rashes, starts behind the ears {and then spread over body. On examination, bluish ‘white spots were seen in buccal mucosa. What is the clinical diagnosis. Discuss about the prevention of this disease. ‘Multiple Choice Questions (MCQs): 1. All of the following are clinical manifestations of Parvovirus B19 infection, except: a. Erythemainfectiosum Answers te 2a 3b Ac Sa a b. Transient aplastic crisis © Condyloma acuminata d._Hydrops fetalis ‘The correct sequence of manifestation seen in measles is: a. Fever» Koplik’s spot —» rash 'b. Koplik’s spot > fever rash d. Rash» Koplik’s spot ~> fever ‘Subacute sclerosing panencephalitis (SSPE) is a ‘complication following which viral infection? a. Mumps b. Measles Rubella di. Influenza Which virus-vaccine strain combination is not correct? a. Mumps—lery-Lynn strain b. Measles—Edmonston-Zagreb strain © Rubella—Schwarz strain 4. Chickenpox—Oka strain Following rubella vaccination, pregnancy should be avoided for at least how many months? a. Tmonth b. 2months © 3months 6 months Scanned with CamScannerHERPES SIMPLEX VIRUS 1. A 25 year female came with multiple painful tiny vesicular ulcers over vulva and vaginal walls. On examination there is painful enlarged lymph nodes. The causative organism might be? (JIPMER May 2016) a. Cgranulomatis 'b. Chlamydia trachomatis c. H.ducreyi d. HSV-2 2. The most common cause of sporadic viral encephali is: (AIMS 2004) a. Japanese B encephalitis b. Herpes simplex encephalitis c. HVencephalitis d. Rubella encephalitis 3. True about Herpes virus: (PGI Dec 2003) a. HSV encephalopathy is treated with acyclovir b. Oropharyngeal involvement is common in HSV:1 cc. Recurrent genital involvement is seen in HSV:2 d. Recurrence is rare in HSV:1 4. Regarding HSV: 2 infection: (PGI June 2002) a. Primary infection is usually wide spread b. Recurrent attacks are due to reactivation of latent infection c. Encephalitis: HSV:2 is a common cause d. Newborn may acquire infection via the birth canal at the time of labor e. Treatment is with acyclovir VARICELLA ZOSTER VIRUS 5. Newborn is presented with chorioretinitis, hypoplasia of limbs and scaring of hands. Most probable diagnosis is? a. Herpes b. Rubella c CMV d. Fetal varicella syndrome 6. A patient presented with a vesicle on skin. Microscopy of Tzank smear showed giant cells. Causative agent is: a. Vaccinia virus (AIIMS May 2015) b. Varicella zoster Mycobacterium d. Molluscum contagiosum 7. Indication for varicella immunoglobulin is: (IPMER Nov 2014) a. A pregnant woman nonimmune to Varicella Zoster, exposed to a child with chickenpox 12 days ago 10. 1. 12. 13. 14. b. A pregnant woman nonimmune to Varicella Zoster, exposed to mother with shingles 2 days ago c. A pregnant woman with no history of chickenpox develops shingles d. Pregnant woman previously treated with varicella immunoglobulin 10 days ago, but re-exposed to a case of chickenpox. Shingles are seen in: a. IMN b. Herpes zoster ©. Chickenpox d. Smallpox (NEET Pattern Based) Congenital varicella infection causes all except: a. Microcephaly (NEET Pattern Based) b. Limb hypoplasia c. Cortical atrophy d. Cataract A baby is delivered with scarring of the skin and deformed limbs. Which of the following intrauterine infection can be held responsible? (AIIMS May 2011) a. CMV b. Treponema pallidum c. Varicella d. Rubella A mother delivers a baby three days after developing chickenpox. Which of the following is true? (AIIMS May 2011) No risk to both mother and baby Baby has a risk of congenital Varicella infection Give antiviral treatment to mother Give no treatment to mother and give antiviral treatment to baby ‘Treatment of varicella in immunocompetent host is: a. Acyclovir (DNB June 2010) b. Acyclovir and vaccination ¢. Prevention of complications d. Immunoglobulin Varicella zoster remains latent a. Lymphocytes b. Monocytes ¢. Trigeminal ganglion Plasma cells Infectivity of chickenpox last for: (AI 2002, UP 2002, MP 2001) Till the last scab falls off 6 days after onset of rash 3 days after onset of rash Till the fever subsides Bose (Al 2010) aoe Scanned with CamScanner15. Which of the viral disease is associated with reactivation? (Recent MCQ 2013) a. Pleurodynia b. Shingles c. Infectious mononucleosis d. Viral arthritis 16. A patient is suffering from painful vesicular eruption at T-4 dermatome. The cause (AIMS May 2014) a. EBV infection b. Herpes zoster CMV infection d. Herpes simplex Co acoder Ve TTS 17. What is the most common infection of the retina for a person living with HIV... (Recent Question 2015) a. CMV retinitis b. VZV causing progressive outer retinal necrosis c. Syphilitic retinitis 18. Owl's eye appearance inclusions are seen a. Herpes simplex virus infections (APPG 2015) b. Cytomegalovirus infections ¢. Epstein-Barr virus infection d. Adenovirus infection 19. CMV infection immediate diagnosis by: a. Direct DNA estimation (AIMS May 2013) b. Antigen detection c. Isolation of the virus d. ELISA for serum antibody 20. A 40-year-old man underwent kidney transplantation. ‘Two months after transplantation, he developed fever and feature suggestive of bilateral diffuse interstitial pneumonitis. Which of the following is most likely etiologic agent: (AIIMS 2003, 2002) a. Herpes simplex virus b. Cytomegalovirus cc. Epstein-Barr virus d. Varicella Zoster virus 21. A person with renal transplant developed infection of graft within 2 months. Most probable cause of infection is? (AIMS May 2014) a. Polyoma BK virus b. CMV c. Hepatits C a. A |. Herpes simples virus neonate has hepatosplenomegaly. His urine was stained with Giemsa stain which revealed owl's eye appearance inclusions. Which will be the most probable cause? (two pictures given in exam: (AIMS May 2014) a. CMV b. HIV cc. Rubella Herpesviruses and Other DNA Viruses EPSTEIN-BARR VIRUS 23. Which of the following is a receptor for EBV? (Recent Question 2015) CRI cR2 cR3 cR4 (24. EBV receptors is: (TNPG 2015) a. CD21 b. cD9 «. CD10 d. CDs 25. Lymphocytosis with atypical lymphocytes are seen in infection with: (NEET Pattern Based) a. HSV b. HBV c. EBV d. RSV 26. How Epstein-Barr Virus causes autoimmunity? a. Molecular mimicry (AI 2012) b. Exposure of sequestered antigens c. Antigenic cross reactivity d. Polyclonal B-cell activation 27. EBV causes all EXCEPT: (DNB Dec 2009, a. Nasopharyngeal carcinoma PGI June 2003, Al 2002) b. Burkitt's lymphoma c. Verrucous lymphoma d. Hodgkin's lymphoma 28. Paul-Bunnel test is done for? a. HBV (NEET Pattern Based, DNB Dec 2010) b. EBV «. CMV d. HIV 29. Oral hairy leukoplakia is associated with: a. Cytomegalovirus (DNB June 2010) b. Human immunodeficiency virus c. EBV d. HPV 30. EBV causes all except: (JIPMER 2010, Al 2006, PGI Dec 2006, PGI June 2002, AI 2004, AIIMS Nov 2004) Kaposi sarcoma Infectious monocytosis Burkit's lymphoma Duncan's disease 31. True about infectious mononucleosis: (PGI Jume 2008) Associated with heterophile antibodies Monocytosis Associated with cold agglutinin Associated with CMV infection Self limited disease Boge poop pang Scanned with CamScanner