Orthopoxvirus

Classification

General Characteristics and Epidemiology

Basic features of orthopoxviruses

• Largest and most complex viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology
• Taxonomy:
  • Family: Poxviridae
  • Genus: Orthopoxvirus
• DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology:
  • Double-stranded
  • Linear
• Structure:
  • Nucleosome (instead of a capsid Capsid The outer protein protective shell of a virus, which protects the viral nucleic acid. Capsids are composed of repeating units (capsomers or capsomeres) of capsid proteins which when assembled together form either an icosahedral or helical shape. Virology)
  • Proteolipid envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology
  • Oval or brick-shaped

Clinically relevant species

Notable orthopoxviruses that infect humans include:

• Variola virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology (smallpox)
• Monkeypox virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
• Vaccinia virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology (used in the smallpox vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination)
• Cowpox virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology

Epidemiology

• Orthopoxvirus infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are rare events.
• Smallpox:
  • The last case of naturally occurring smallpox was in the 1970s.
  • Considered eradicated in 1980
  • Mortality Mortality All deaths reported in a given population. Measures of Health Status had been as high as 25%–30%.
• Monkeypox:
  • Sporadic Sporadic Selective IgA Deficiency epidemics Epidemics Sudden outbreaks of a disease in a country or region not previously recognized in that area, or a rapid increase in the number of new cases of a previous existing endemic disease. Epidemics can also refer to outbreaks of disease in animal or plant populations. Influenza Viruses/Influenza have occurred in Africa.
  • As of August 2022, a global outbreak has resulted in thousands of infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (including in the U.S.).
  • Mortality Mortality All deaths reported in a given population. Measures of Health Status can be as high as 17%.
    • Dependent on local health resources and an individual’s underlying health status
    • More recently, the case-fatality ratio is ~ 3%–6%.
    • Fatalities during the 2022 outbreak have been rare.
• Cowpox:
  • < 150 cases reported
  • Most cases occur in individuals < 18 years of age.

Pathogenesis

Transmission

Host risk factors

More severe disease tends to occur in:

• Immunosuppressed patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Certain skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions conditions (e.g., eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema))

Viral replication cycle

• Unlike many other viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology:
  • Viral replication is cytoplasmic.
  • No cell receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors or specific protein is targeted by the virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology to gain entry into the cell.
• Entry into a host cell is mediated by endocytosis Endocytosis Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. The Cell: Cell Membrane → viral core is released into the cytoplasm
• Intermediate genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure are expressed → DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
• Progeny virions are assembled → mature virions are released from the cell upon cellular lysis

Pathophysiology

• Smallpox:
  • Inhaled secretions and virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology → entry into the respiratory tract
  • Viral replication → spread to regional lymphatic tissue → replication → viremia Viremia The presence of viruses in the blood. Erythema Infectiosum
  • Dissemination to lymphoid organs Lymphoid organs A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs → secondary viremia Secondary viremia Mumps Virus/Mumps → symptoms
  • Virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology localizes in dermal blood vessels → endothelial swelling Swelling Inflammation
  • Infection of epidermal cells → cutaneous manifestations
• Vaccinia: virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology replicates at the site of inoculation → localized cutaneous manifestations

Clinical Presentation

The following table summarizes notable clinical diseases caused by orthopoxviruses:

Diagnosis and Management

Diagnosis

The diagnosis can be supported with the following testing:

• PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) for viral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure from lesion specimens ( oropharynx Oropharynx The middle portion of the pharynx that lies posterior to the mouth, inferior to the soft palate, and superior to the base of the tongue and epiglottis. It has a digestive function as food passes from the mouth into the oropharynx before entering esophagus. Pharynx: Anatomy, conjunctiva Conjunctiva The mucous membrane that covers the posterior surface of the eyelids and the anterior pericorneal surface of the eyeball. Eye: Anatomy, urine, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions)
• Serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus (not specific for individual viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology)
• Viral culture Viral culture West Nile Virus
• Electron microscopy of lesion specimens

Management

• There is no known treatment for these diseases.
• Management is supportive.
• Potential antiviral Antiviral Antivirals for Hepatitis B treatments:
  • Tecovirimat
    • FDA-approved for the treatment of smallpox infection
    • Effectiveness is unknown
  • Brincidofovir
    • Has in vitro activity against orthopoxviruses
    • No clinical data in humans

Prevention

The smallpox vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination is not only responsible for the eradication of smallpox but also appears to:

• Confer protection against some other orthopoxviruses, such as monkeypox
• Blunt the clinical course of smallpox if given after exposure

Differential Diagnosis

• Chickenpox Chickenpox A highly contagious infectious disease caused by the varicella-zoster virus. It usually affects children, is spread by direct contact or respiratory route via droplet nuclei, and is characterized by the appearance on the skin and mucous membranes of successive crops of typical pruritic vesicular lesions that are easily broken and become scabbed. Chickenpox is relatively benign in children, but may be complicated by pneumonia and encephalitis in adults. Varicella-Zoster Virus/Chickenpox: primary infection Primary infection Herpes Simplex Virus 1 and 2 caused by the varicella–zoster virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology. The typical clinical presentation includes prodromal symptoms, an oral enanthem Enanthem Varicella-Zoster Virus/Chickenpox, and a generalized, intensely pruritic vesicular rash Rash Rocky Mountain Spotted Fever. These lesions appear in crops and will be in varying stages of evolution. The diagnosis is primarily clinical. Management is supportive, though antiviral Antiviral Antivirals for Hepatitis B therapy can be used in certain patient populations. 
• Molluscum contagiosum Molluscum contagiosum Molluscum contagiosum is a viral infection limited to the epidermis and is common in children below 5 years of age. Lesions appear as grouped, flesh-colored, dome-shaped papules with central umbilication. Molluscum Contagiosum (MC): viral infection limited to the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions. Molluscum contagiosum Molluscum contagiosum Molluscum contagiosum is a viral infection limited to the epidermis and is common in children below 5 years of age. Lesions appear as grouped, flesh-colored, dome-shaped papules with central umbilication. Molluscum Contagiosum is mainly seen in children < 5 years of age. Lesions are grouped, flesh-colored, dome-shaped papules with central umbilication. The disease is mild in immunocompetent patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship and self-resolves within months. Diagnosis is usually clinical. This infection is highly transmissible, and patient education is key in management. Cryotherapy Cryotherapy A form of therapy consisting in the local or general use of cold. The selective destruction of tissue by extreme cold or freezing is cryosurgery. Chondrosarcoma with liquid nitrogen Liquid Nitrogen Molluscum Contagiosum is the 1st-line therapy in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who require it.
• Hand, foot, and mouth disease Hand, foot, and mouth disease A mild, highly infectious viral disease of children, characterized by vesicular lesions in the mouth and on the hands and feet. It is caused by coxsackieviruses A. Coxsackievirus: mild, self-limited disease caused by coxsackie group A virus Coxsackie group A virus Coxsackievirus. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, mouth pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis. An oral enanthem Enanthem Varicella-Zoster Virus/Chickenpox may occur. Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions can be macular, papular, or vesicular and often include the palms, soles, and buttocks. Diagnosis is usually clinical. Management is supportive.
• Bacillary angiomatosis Bacillary Angiomatosis A reactive vascular proliferation that is characterized by the multiple tumor-like lesions in skin, bone, brain, and other organs. Bacillary angiomatosis is caused by infection with gram-negative Bartonella bacilli (such as Bartonella henselae), and is often seen in AIDS patients and other immunocompromised hosts. AIDS-defining Conditions: condition seen in HIV HIV Anti-HIV Drugs/ AIDs AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship that results in angiomatous skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions due to Bartonella Bartonella Bartonella is a genus of gram-negative bacteria in the family Bartonellaceae. As a facultative intracellular parasite, Bartonella can infect healthy people as well as act as an opportunistic pathogen. Bartonella species are transmitted by vectors such as ticks, fleas, sandflies, and mosquitoes. B. henselae is the most common of the 3 species known to cause human disease. Bartonella infection. The skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions are usually protuberant, red papules or nodules that are friable. Painful osteolytic bone lesions Bone Lesions Multiple Myeloma can also occur. Diagnosis can be made with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, cultures, and PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR). Management includes antibiotics and antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs for HIV HIV Anti-HIV Drugs.