Under modern classification, Poxviruses and their family, Poxviridae, are a genomically linked lineage of large, complex, dual stranded DNA viruses that replicate and assemble entirely in the cytoplasm, completely independent of their host’s nucleus. Historically this family is infamous for the variola virus (VARV), which was responsible for smallpox, a disease touted to hold causal mortality of more humans than all other infectious etiologies put together.
Of 28 known genera, 4 have shown to infect humans, Orthopoxviridae, Parapoxviridae, Yatapoxviridae, and Molluscipoxviridae. Only 2 are species-specific to humans; however, the orthopox, variola (VARV), and the only known molluscipox, Molluscum contagiosum (MCV); the latter of which is even more super-specific, permissive down to only a single human cell lineage (human basal keratinocyte).
Structurally all the Poxviridae are massive, maintaining a brick-shaped proteolipid envelope further packed with even more “mature virion” inside; each one sporting their very own fusion-ready envelope - infectious in their own right. (albeit with a differing route). Here the DNA is housed in a protein core, surrounded with its assortment of preppy transcriptional machinery, even including a viral variant of DNA-RNA polymerase.
Poxviruses are unique in that no specific cellular receptor or protein is targeted or utilized for entry into its host. Cell entry seems to be a complex and multifactorial process involving ubiquitous elements in mammalian cell surfaces such as glycosaminoglycans (GAGs) or components of the extracellular matrix to fuse. No less than eleven different proteins take part in the elaborate process. As such, simply gaining entry is not definitive – the process being promiscuous and unselective in any mammalian cell. Rather than just sporting the right surface protein, what deems the cell as viable or “permissive” to the virus is dependent on how the host itself reacts to the wanton invasion. In the appropriate susceptible host, defense mechanisms, including INF-gamma release and apoptosis will be inhibited; instead, those very cellular responses elicit the tropic markers for core unloading, advancing the multiple mRNA transcription sequences, assembly, and its inevitable propagation. This incursive and reflective dance between the two involves everything from cell cycle control (mitogen arrest), differentiation, signaling, and cellular immunomodulation.
Smallpox is widely regarded as one of the most destructive diseases since antiquity, and because of its distinctive symptoms and rash, it was recognized and documented by almost every culture in the old world. As a poxvirus, it was incredibly stable, hardy, and contagious, with an infectivity rate in non-vaccinated persons exceeding 85 percent. Respiratory droplets were presumed the main mode of dissemination, but viable infectious virion survive for years in the scabs of victims, and general hardiness allowed for fomitic spread.
Early attempts at antigenic immunogenicity were recognized and employed since the fourth century in China and India with inoculation of milder variants (variola minor etc.), but it was not until the isolation of variola vaccinia (cowpox) by Edward Jenner in 1786 did an established “vaccine” come into the picture. The strong antigenic stimulus of vaccinia, lack of non-human reservoirs, and slow mutation rate led to its official extinction in 1980.
Molluscum contagiosum is a common dermatological disease in children with genital lesions generally considered sexually transmitted in adults. In immunocompromised individuals, It can present with a very extensive debilitating, dermatological disease.
Other poxviruses have established some level of host-range in humans, such as monkeypox and orf virus, with demonstrated human to human spread, but others are largely considered zoological diseases, with low infectivity and isolated occurrence.
Molluscum contagiosum has not been shown to propagate in any sustainable manner outside of the basal keratinocyte, in vitro or otherwise, as such the disease is unlikely to spread beyond dermatological manifestations.
Variola, on the other hand, is much more indiscriminate and following a 2-week incubation phase, established disseminated disease. Entering via the respiratory tract or mucosal lining, variola would start multiplying in the reticuloendothelial system before moving on into lymph nodes.
Clinically it starts with a prodromal phase lasting anywhere from 2 to 4 days. This involved severe headaches, backache, fever, arthralgia as well as other basic constitutional symptoms. Concluding eventually with a somewhat distinctive eruptive small red vesicular lesion inside and all over the oral cavity, including the tongue, oropharynx, palate mucosal membranes called “enanthema.”
The patient was supposedly infectious at this very point.
In less than 24 hours - the classic dimpled vesicular rash would begin to erupt – the “exanthema,” first in the face and extremities, this rash progressed more centrally to the trunk through the course of the illness. Somewhat uncommon for viral exanthems, they involved the palmar and plantar surfaces, and these would last the longest.
Not much is known about the systemic path to mortality (i.e., prognostic factors) – at least not to the equivalent degree of other extant viral syndrome or infections. Death was attributed to “toxemia” in relevant vs. modern literature). What is known, however, is that immunomodulation and dysfunction were key; prokaryotic superinfections led to extensive morbidity, including pustular conversion of lesions, keratitis, pneumonia, and of course, sepsis.
Primary involvement with variola wouldn’t lend itself to be ignored; however, arthritis in children (metaphyseal fibroblast failure) and viral encephalitis were all well-known sequelae.
Because of their overt size, Poxviridae were some of the first viruses visualized under microscopy. Large cytoplasmic inclusions called Guarneri and Paschen bodies are visible on infected squamous and visceral cells respectively, in molluscum they are even larger inclusions called Henderson-Patterson bodies.
Thorough patient evaluation is indispensable with special care given to vaccination, exposure, travel, and occupational histories, Red flags are when the patient has been in contact with the virus either for scientific or military research or disclosed any proximity to known zoonotic sources (bushmeat, hunting, etc.).
A complete physical exam is vital; however, as many poxvirus lesions, especially those of molluscum, are almost pathognomonic (dome and crater) in appearance. Assessing hyperpyrexia, lymphadenopathy, and oral and ocular exams could also show plausible evidence in determining a full clinical picture, specifically looking for evidence of pneumonitis.
Variola could be suspected when an acute onset of fever is followed by a breakout of uniform vesicles or pustules all at the same stage of development, with no palm or sole sparing. These umbilicated vesicles are characteristic of the disease. If suspicion is strong, immediate isolation/quarantine to a negative pressure room and prophylactic vaccination of the patient and contact tracing should not be delayed. Health officials should be contacted.
With proper precautions and steps, ruling out smallpox should be the priority. Skin biopsy can also rule in poxvirus by the presence of visible virus nucleation sites called Guarneri bodies in the cytoplasm of the host cell, but- along with the antibody testing is not specific for variola versus other poxviruses. However, if suspected, infections can be diagnosed with PCR as well, note that a viral culture (chorioallantois medium) is the gold standard, this diagnosis should be confirmed in a safety level 4 laboratory.
Serological testing is often unnecessary for molluscum contagiosum infections; however, as it is often diagnosed clinically. In genital manifestations, especially in children, further workup should include a sexually transmitted infection (STI) panel.
First-generation vaccines were vaccinia derived from calf-lymph. The next generation was cultured in kidney epithelial cells (Vero cells) from an African green monkey. Vaccination or the further attenuated vaccine - Modified Vaccinia Ankara (MVA) within 3 days of exposure is believed to drastically reduce or halt the progression of the disease, and if given within 7 days may also modify disease progression.
Tecovirimat is the only approved therapeutic drug to treat orthopoxvirus infection and has shown promising activity against every Orthopoxviridae (including variola) - impeding viral progression in vitro as well as in several animal models with their respective poxviruses. It has shown to be well tolerated and very specific to the orthopoxvirus clade. It is a potent inhibitor of p37, a highly conserved and unique protein required for formation and egress of the poxvirus extracellular virion envelope, an essential component for poxvirus spread.
Because poxviruses use a viral variant of DNA dependent RNA polymerase, cidofovir (an anti-viral inhibitor of the aforementioned) and its oral prodrug - brincidofovir have been discussed as viable treatments. Although nephrotoxic and might require a baseline and following kidney function, it has shown efficacy in at least one animal model to reduce mortality in a dose-dependent fashion.
Because smallpox has mortality linked to hemorrhagic and hemodynamic instability, septicemic superinfection, and cardiogenic shock, regular interval vitals, blood counts, and coagulation profiles should be taken.
Molluscum contagiosum infections are often self-limited and spontaneously resolving in all but immunocompromised hosts, Management is limited to reassurance, topical podophyllotoxin, imiquimod, cryotherapy, and curettage, instilling habits to avoid autoinoculation.
Monkeypox resembles smallpox clinically with similar lesions and timeline but often presents with lymphadenopathy, caution is advisable as human/human spread has been confirmed but on an order of magnitude less then variola.
Severe cases of chickenpox should also be ruled out, especially if the vesicular rash spares the palms and soles and demonstrates variability in size and development. Although secondary syphilitic rashes also involve the palms and soles, they would not convert or evolve as rapidly.
Drug-induced and hypersensitivity exanthemas such as toxic epidermal necrolysis should be ruled as well with a proper history.
Vaccinations from First-generation vaccines have rare but serious reactions. 1254 per million reported complications with children under 5 years whom, held the most serious adverse events. There was a nationwide case fatality rate of 1 per 1 million primary vaccinations.
Cidofovir is notoriously nephrotoxic, although brincidofovir shows a much more acceptable side effect profile.
The “ordinary variant” of smallpox; was actually the best-case scenario and held a case fatality rate of 30 percent.
Younger, unluckier patients, however, might develop a malignant variant, also known as flatpox, with unique maculoid as opposed to vesicular lesions, these are soft and velvety to the touch. And the prodromic symptoms are particularly harsh with sustained hyperpyrexia.
Older or pregnant patients could develop a hemorrhagic variant, also known as hemorrhagic smallpox - Here development of sudden and acute thrombocytopenia could be reminiscent of many other hemorrhagic viral syndromes; but compounded by depleted coagulation factors, fluid third spacing, bleeding, and hypotension. Liver and concomitant bone marrow failure advance the hemodynamic instability quite synergistically.
Either variant was almost universally fatal, holding what could be considered predominantly grim outcomes.
No other Poxviridae infection in humans comes even close to attaining such morbid prognosis. With much milder disease seen in vaccinia, cowpox, monkeypox, other orthopox, and Parapoxviridae, case fatality rates rarely exceed 5 to 10 percent.
Survivors often have debilitating scarring from healed lesions, especially those that underwent superinfection. Ocular complications like keratitis, corneal ulceration, and eventual blindness are described, as well as a distinctive cause of blindness pneumonia, respiratory failure, cyanosis, bacteremia, sepsis, and hemodynamic shock.
Vaccinia and variola truly were dark chapters of human history; however, the threat posed by Poxviridae as a “species” is still very extant. Because variola ran so rampant, and for so long through human populations, it likely ceded other Poxviridae from really gaining any real foothold on humans as a species (even if only antigenically). This predatorial monopoly no longer exists, and the extinction of variola has left a large niche rife for the taking.
Especially in the wake of the recent COVID-19 pandemic, funding, and development towards understanding zoonotic viral host-switches, their virulence, patterns, and transmissibility must increase -with special scrutiny given to Poxviridae. Current knowledge is grossly insufficient, and in this past year, this fact has been proven dramatically.
Finally, when the possibility of manufactured bioterrorism was realized in the dusk of the 20th century, smallpox was the obvious consideration. Although the inventory of the U.S. strategic defense stockpile is classified, it is generally assumed that enough vaccinia vaccines were produced en-masse to treat the entirety of the territorial U.S. population.
Either in a biological attack or host-switch pandemic, centralized and swift action is paramount. Failures seen with the coronavirus pandemic in early contact tracing, selective quarantining, and post-contact investigations, is not an option. While media and societal courtesy have been fairly successful amid the COVID pandemic for inducing social distancing, with variola, this progression might happen via Darwinian mechanics instead.
|||McFadden G, Poxvirus tropism. Nature reviews. Microbiology. 2005 Mar [PubMed PMID: 15738948]|
|||Haller SL,Peng C,McFadden G,Rothenburg S, Poxviruses and the evolution of host range and virulence. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2014 Jan [PubMed PMID: 24161410]|
|||Moss B, Membrane fusion during poxvirus entry. Seminars in cell & developmental biology. 2016 Dec [PubMed PMID: 27423915]|
|||[PubMed PMID: 28786952]|
|||Moss B, Poxvirus cell entry: how many proteins does it take? Viruses. 2012 May [PubMed PMID: 22754644]|
|||Henderson DA, Smallpox: clinical and epidemiologic features. Medicine and health, Rhode Island. 2002 Mar [PubMed PMID: 11917745]|
|||Thèves C,Biagini P,Crubézy E, The rediscovery of smallpox. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2014 Mar [PubMed PMID: 24438205]|
|||[PubMed PMID: 27726788]|
|||Guharoy R,Panzik R,Noviasky JA,Krenzelok EP,Blair DC, Smallpox: clinical features, prevention, and management. The Annals of pharmacotherapy. 2004 Mar [PubMed PMID: 14755066]|
|||Breman JG,Henderson DA, Diagnosis and management of smallpox. The New England journal of medicine. 2002 Apr 25 [PubMed PMID: 11923491]|
|||Buddingh GJ, A STUDY OF GENERALIZED VACCINIA IN THE CHICK EMBRYO. The Journal of experimental medicine. 1936 Jan 31 [PubMed PMID: 19870469]|
|||[PubMed PMID: 31991671]|
|||Henderson DA,Inglesby TV,Bartlett JG,Ascher MS,Eitzen E,Jahrling PB,Hauer J,Layton M,McDade J,Osterholm MT,O'Toole T,Parker G,Perl T,Russell PK,Tonat K, Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 1999 Jun 9 [PubMed PMID: 10367824]|
|||Grosenbach DW,Honeychurch K,Rose EA,Chinsangaram J,Frimm A,Maiti B,Lovejoy C,Meara I,Long P,Hruby DE, Oral Tecovirimat for the Treatment of Smallpox. The New England journal of medicine. 2018 Jul 5 [PubMed PMID: 29972742]|
|||Foster SA,Parker S,Lanier R, The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak. Viruses. 2017 Oct 30 [PubMed PMID: 29773767]|
|||[PubMed PMID: 24740746]|
|||Gualdi G,Pascalucci C,Panarese F,Prignano F,Giuliani F,Verga E,Amerio P,Verdolini R, Molluscum contagiosum in paediatric patients: to treat or not to treat? Could a personalised Imiquimod regimen be the answer to the dilemma? The Journal of dermatological treatment. 2020 Apr 29 [PubMed PMID: 32347136]|
|||Delaune D,Iseni F, Drug Development against Smallpox: Present and Future. Antimicrobial agents and chemotherapy. 2020 Mar 24 [PubMed PMID: 31932370]|
|||Henderson DA, Stocks of variola virus. American journal of public health. 1987 Feb [PubMed PMID: 3026189]|