Diagnosis: Smallpox?

During a smallpox epidemic, the initial chill, followed by fever, headache, vomiting, and the severe pain in the back, are symptoms which should put the attending physician on his guard. Mistakes arise in the initial stage owing to the presence of scarlatinal or measly rashes which may be extremely deceptive. The scarlatinal rash has not always the intensity of the true rash of this disease. The measly rash cannot always be distinguished from true measles, instances of which may be mistaken for the initial smallpox rash.” -Sir William Osler

If you were to go back throughout recorded history and look at the evidence for smallpox, you would come to realize that many of the cases associated with this disease can be traced back to interchanging names for the same set of symptoms related to eruptions of the skin. The names varied based on the geographic location as well as the time in history that the terminology was used. In some cases, the diseases were all referred to as “the poxes.” The more severe symptoms were referred as the Great Pox while the less severe were known as the Lesser Pox. Europeans used differing names to distinguish disease severity such as la grosse verole and la petite verole. Germans used the name blattern to refer to both syphilis and smallpox synonymously. The Italian name for measles was morbilli yet it was also applied to scarlatina, rubella, and smallpox. Even the name chickenpox was just a term used to describe less severe, or “chicken,” cases of smallpox. This is why it is difficult, if not impossible, for clinicians to differentially diagnose smallpox from these other “separate” diseases as they are all varying stages of the same detoxification process.

This first source breaks down this confusion by looking at the history of both smallpox and measles. You will see the many names used interchangeably to describe these different stages of the same process as well as the challenges with separating them as distinct diseases:

Smallpox and measles: historical aspects and clinical differentiation

“The difficulty was in differentiating smallpox and measles in their early phases, which had important public health implications. The prodromal rash of smallpox sometimes resembled measles.”

Smallpox

“Both smallpox and measles were highly contagious and had in common rash and fever. Even though the Persian physician Rhazes Ar-Raz Abmiz was the first person to clinically distinguish smallpox from measles in 900 AD, European physicians continued to confuse the illnesses until relatively recent times [2]. In 1751, Thomas Sydenham clearly differentiated measles from smallpox [3]. Even Sir William Osler, the master clinician of the modern era, emphasized the difficulty in differentiating early measles from smallpox [4].”

“As many ancient pestilences were referred to as the plague, so was the case with poxes. The Great Pox referred to syphilis, and the Lesser Pox may have referred to rubella, chickenpox, and smallpox. The Europeans used distinctive terms to differentiate syphilis from smallpox. La grosse verole was a term used to describe syphilis, whereas smallpox was referred to as la petite verole. In other countries, the word for pox was applied to different diseases  during different times. In German, syphilis was initially referred to as blattern during the 16th and 17th centuries, but blattern later was applied to smallpox during the 18th century.”

Measles

“In the ancient world, measles and smallpox existed together. Measles, also known as morbilli, is the diminutive Italian term derived from morbillo. The term morbilli was used to differentiate the ‘‘small plague’’ of measles from the ‘‘great plague,’’ referred to as Il Morbo. For centuries, scarlatina, rubella, measles, and smallpox were undifferentiated febrile diseases with rashes. The terminology for measles is confusing, as is the clinical differentiation between measles and chickenpox. Scarlet fever was termed morbilli confluentes. Measles in German is masern; in French measles is rougeole; and the synonym for measles in English is rubeola [14].”

“Smallpox is no longer a common infectious disease, and differentiation from chickenpox is less critical from a public health standpoint than in the smallpox era. With the potential for the use of smallpox as an agent for bioterrorism, however, clinicians need to reacquaint themselves with the cardinal clinical findings of smallpox. Should smallpox reemerge, clinicians will face the same diagnostic dilemmas in differentiating smallpox from measles in its early stages. A presumptive diagnosis of measles or smallpox in its early stages is of critical importance to the individual and has important public health implications. Clinicians without previous experience should rely on careful clinical descriptions made by astute and discerning physicians, who by careful observations were able to sort out the key features between smallpox and measles, permitting clinical differentiation.”

doi: 10.1016/S0891-5520(03)00091-6.

Good thing The Weather Channel is here to keep us all straight on these “differences.”

As can be seen, the “poxes” were all considered varying stages of the same disease. It wasn’t until physicians looked for minute differences that the symptoms began to be separated as distinct diseases. I wrote about this practice of breaking down the stages in this article about the attempts by William Heberden to clinically separate smallpox from chickenpox in 1767. Regarding the separation of smallpox and measles, Muslim physician Al-Razi is given credit as the first person to distinguish between the two. While I am unable to find passages from his book, a section from a review provides a nice summary as to the differences Al-Razi noticed necessitating the split:

“The most common signs of both smallpox and measles were continuous fever, nose itching, allergy in the body, redness of the cheeks and eyes, sore throat, chest pain, breathing difficulties, cough, hoarseness, headache and sometimes syncope. It was not necessary for all these symptoms and signs to appear together, some might be absent. On the other hand, regarding the specific signs, he said that back pain was more severe in smallpox, while it might be slight or absent in measles. Distress, syncope and anxiety were more prominent in measles.”

https://www.google.com/url?sa=t&source=web&rct=j&url=https://www.qscience.com/content/journals/10.5339/qmj.2000.2.7%3Fcrawler%3Dtrue%26mimetype%3Dapplication/pdf&ved=2ahUKEwiZrpfDoYb4AhWRZDABHS-4Dfc4HhAWegQICRAB&usg=AOvVaw2sYRI7XGqIwE-z5Xf5WC7T

In other words, according to Al-Razi, the major differences necessitating the separation of one disease into two was that back pain was more severe with smallpox while distress, anxiety, and syncope were more prominent in measles. Beyond these slight variations in severity of certain symptoms, both smallpox and measles shared every single symptom of disease between them. Maybe this is why it is stated that every other physician of the time considered them one and the same:

“Many historians such as Justaph Lobon, Sigrid Honka, Dughlas and others considered Al-Razi to be the first in the history of medicine to differentiate between these two diseases. He described each disease separately and in detail, unlike all the Greek and Arab physicians before him, who considered the two diseases as one.

As can be seen, even these minute differences were not enough for differentiation as the symptoms often were not specific and overlapped between the “separated” diseases. This is why the diagnosis of smallpox has commonly been mistaken for other ailments such as measles as well as chickenpox:

Chickenpox or Smallpox: The Use of the Febrile Prodrome as a Distinguishing Characteristic 

“Before its eradication, smallpox was confused with chickenpox more frequently than with any other illness [1]. The similarities between the diseases and the importance of making the correct diagnosis led an infectious disease expert to declare that there was “no more important diagnosis in clinical medicine than the differentiation of these two diseases.”

https://academic.oup.com/cid/article/39/12/1810/323131

Which is which?

And also why chickenpox is confused with monkeypox which itself is confused with smallpox:

Human monkeypox: confusion with chickenpox

“The question arose as to the possibility that clinical diagnostic errors cause some cases of monkeypox to be misdiagnosed as other eruptive diseases. This paper presents the results of a study assessing the extent of and reasons for these clinical diagnostic errors in areas where health staff as well as the general public are aware of human monkeypox. In Zaire in the period 1981-1986, 977 persons with skin eruption not clinically diagnosed as human monkeypox were laboratory tested. 3.3% of human monkeypox cases were found among 730 patients diagnosed as cases of chickenpox, 7.3% among cases diagnosed as “atypical chickenpox” and 6.1% among cases with skin rash for which clinical diagnosis could not be established. The diagnostic difficulties were mainly based on clinical features characteristic of chickenpox: regional pleomorphism (in 46% of misdiagnosed cases), indefinite body-distribution of skin eruptions (49%), and centripetal distribution of skin lesions (17%). Lymph-node enlargement was observed in 76% of misdiagnosed patients. In the absence of smallpox, the main clinical diagnostic problem is the differentiation of human monkeypox from chickenpox.”

https://pubmed.ncbi.nlm.nih.gov/2907258/

Clinical Diagnosis?

This raises the question of whether or not smallpox can even be diagnosed clinically based on symptoms alone as the intermingling of shared disease symptoms and presentation made the differential diagnosis of smallpox from the other related skin eruption diseases difficult. This difficulty was outlined in the first chapter of the 1988 WHO classic Smallpox and its Eradication which provided a comprehensive list of the many different diseases that smallpox was confused with at the time of diagnosis. Along with the acknowledgement to the near impossibility of diagnosing smallpox clinically as well as the numerous mistaken diagnoses throughout the centuries, it is also metioned that laboratory methods are needed in order to confirm a diagnosis. In other words, a case of smallpox could not be diagnosed based on symptom presentation alone:

CHAPTER 1: THE CLINICAL FEATURES OF SMALLPOX

Human monkeypox

“Although a rare disease, human monkeypox ranks first among the diseases that might be confused with smallpox, because differential diagnosis was impossible on clinical grounds alone, although gross lymphadenopathy was found in most cases of monkeypox and not in smallpox (see Chapter 29) . In the field, diagnosis depended on the occurrence  of a disease indistinguishable from ordinary-type smallpox in the appropriate epidemiological situation: a particular geographical area (western and central Africa), no endemic smallpox, and the appropriate environmental surroundings (a small village in a tropical rain forest). Laboratory confirmation was essential, either by recovery of the virus from lesion material or retrospectively by appropriate serological tests.

Chickenpox

“This disease of world-wide occurrence was the single most important infection to be considered in the differential diagnosis and was particularly important in three circumstances: in countries in which variola minor was endemic, in vaccinated individuals, and in situations in which chickenpox occurred rather frequently in adults, often as a severe disease, as in several parts of India. For example, in post-eradication searches in India in 1976, 63% of the “suspected smallpox” cases were in fact cases of chickenpox (Jezek et al ., 1978e).”

“Difficulties arose with severe chickenpox in adults (White, 1978), a disease found especially in some parts of India (Kerala,Tamil Nadu (formerly Madras State), and West Bengal). Indeed, some severe cases of chickenpox in adults were associated with such an extensive rash, including lesions on the palms and soles, that it was impossible to be certain at any stage of the disease as to whether it was chickenpox or smallpox. During the eradication programme, all such cases were regarded as smallpox and appropriate control measures were undertaken. Sometimes the lesions in this type of chickenpox were haemorrhagic, and it was in these cases that the rate of development of the rash and its distribution were important diagnostic features.”

Tanapox

“This poxvirus disease occurs as a zoonosis in parts of Kenya and Zaire, and probably elsewhere in Africa (see Chapter 29) . The lesions are usually single, and few in number if they are multiple. They are nodular rather than pustular and evolve much more slowly than the lesions of smallpox . However, when first seen, such lesions could be confused with those of mild smallpox in a vaccinated subject.

Measles

In the first 2 days of the rash, before vesicles developed, the most likely cause of confusion was measles (Plate 1 .29A), and this difficulty could persist for several more days in flat-type smallpox, although the severity of this disease was much greater than that of measles . The  presence of Koplik’s spots was, of course, diagnostic of measles, and in any case the difficulty disappeared as the rash evolved. Historically, measles did not present a problem in countries with endemic smallpox, but in non-endemic countries an early case of smallpox was sometimes diagnosed as measles, with possibly serious consequences in terms of secondary cases. On the other hand, in countries in which smallpox was endemic, physicians were often prone to diagnose all outbreaks of rash associated with deaths as smallpox and to report them as such to the health authorities. Some of these outbreaks later proved to be due to measles.

Syphilis

Earlier writers, e .g ., Councilman (1907) and Ricketts (1908), paid considerable attention to syphilitic rashes as presenting a problem in differential diagnosis. With the advent of penicillin and the consequent reduction in the incidence of syphilis especially of secondary syphilis-in the developed countries, the disease has ceased even to be mentioned by writers, such as Christie (1980), dealing with the general domain of infectious diseases. However, in African countries and India secondary syphilis remained a disease to be considered in the differential diagnosis of smallpox, up to the time of eradication.

Erythema multiforme

“This disease (Plate 1.29C) could cause difficulties at any stage of the rash; the distribution of lesions is sometimes very like that of smallpox. In both diseases the patient could be quite ill and have a profuse vesicular eruption particularly affecting the extremities.”

“In severe cases there could be confusion with flat-type smallpox, since the vesicles were occasionally soft, superficial and flat, individually resembling those of flat-type smallpox. They sometimes coalesced and produced large bullae, also seen in some cases of severe smallpox.”

Lesions due to vaccination

Generalized vaccinia, described in Chapter 7 (see Plate 7.7), rarely caused confusion; the history of vaccination and the nature and
distribution of the rash differed substantially from what was found in smallpox. However, problems of precise diagnosis sometimes arose in smallpox contacts who had been vaccinated during what turned out to be the incubation period of smallpox. They usually showed a positive take at the vaccination site and often a modified rash, which could have been caused by variola or vaccinia virus. Operationally, all such cases were regarded as smallpox from the point of view of management. Precise diagnosis could be made by the culture of virus from several of the vesicles or pustules.

Drug eruptions

Although less important in countries in which smallpox was still endemic, drug eruptions (Plate 1 .30A and B) were an important diagnostic problem in countries in which smallpox had been eradicated years before and doctors rarely considered the possibility of the disease. Many instances exist in which the rash of an imported case of smallpox, and sometimes the rashes of second generation cases deriving from it, were diagnosed as drug rashes, since the sick patients had customarily been treated with some kind of drug for the pre-eruptive fever. The diagnosis usually became quite clear with the passage of time and the evolution of the rash, but vaccine-modified smallpox could continue to mislead the physician if he had never considered smallpox as a possible diagnosis.

In endemic countries in recent years, since a wide variety of drugs have become available, cases of smallpox and drug eruption sometimes occurred coincidently. Rao (1972) described a case in which the drug rash completely obscured that due to smallpox and the diagnosis was only made when variola virus was recovered from some “seeds” extracted from the palms of the hands.

Rashes due to other causes

There are few diseases characterized by a rash that did not at some time suggest a diagnosis of smallpox, occasionally with dramatic effect in non-endemic countries. Acne, scabies and insect bites may be mentioned as examples. Coxsackievirus infections could pose a problem (Mukherjee et al ., 1976), and in countries in which both diseases were endemic, dengue haemorrhagic fever and other arbovirus infections associated with a rash were sometimes initially diagnosed as smallpox.”

LABORATORY CONFIRMATION OF
SMALLPOX DIAGNOSIS

“Laboratory methods played a crucial role in the global smallpox eradication programme; indeed, eradication could not have been confidently certified to have been achieved without their use. A detailed historical description of the laboratory methods used for the diagnosis of smallpox is presented in Chapter 2 and an account of the development of laboratory support for the Intensified Smallpox Eradication Programme is given in Chapter 10.

As well as being of critical importance in the global smallpox eradication programme, laboratory methods were also useful for the confirmation of clinical diagnoses. Indeed, although laboratory workers could make mistakes, the recovery of variola virus from a skin lesion was usually regarded as conclusive evidence that a particular patient was or had been suffering from smallpox. Such confirmation was rarely sought in endemic countries when smallpox was a common disease. Any doubtful case was always regarded as smallpox; containment and vaccination procedures operated independently of and were initiated before laboratory confirmation. However, laboratory confirmation or refutation of suspected smallpox was a valuable procedure in non-endemic countries and in smallpox-free regions of the endemic countries as eradication approached.

If an electron microscope was available, the examination of material from vesicles, pustules or scabs, examined by the negative staining technique, could give a rapid presumptive diagnosis of poxvirus, or sometimes herpesvirus, infection. Definitive diagnosis depended on the isolation of the causative virus on the chorioallantoic membrane of the developing chick embryo and its further characterization, if necessary, by biological tests. Usually the character of the pocks produced on the chorioallantoic membrane was distinctive enough for the diagnosis of variola, vaccinia, monkeypox or herpesvirus infection to be made (see Chapter 2).”

https://biotech.law.lsu.edu/blaw/bt/smallpox/who/red-book/index.htm

If there was any doubt about the confusion with other diseases and the impossibility of diagnosing smallpox clinically based on symptoms alone, the information contained within the WHO’S 1988 sci-fi classic was later confirmed by the CDC. Here is the CDC’s own official list of common conditions which can be confused with smallpox as well as the problems associated with clinical diagnosis and the need for laboratory confirmation:

Common Conditions That Might Be Confused with Smallpox

Varicella (primary infection with varicella-zoster virus)

  • Most common in children <10 years
  • Children usually do not have a viral prodrome

Disseminated herpes zoster

  • Immunocompromised or elderly persons
  • Rash looks like varicella, usually begins in dermatomal distribution

Impetigo (Streptococcus pyogenes, Staphylococcus aureus)

  • Honey-colored crusted plaques with bullae are classic but may begin as vesicles
  • Regional, not disseminated rash
  • Patients generally not ill

Drug eruptions

  • Exposure to medications
  • Rash often generalized

Contact dermatitis

  • Itching
  • Contact with possible allergens
  • Rash often localized in a pattern suggesting external contact

Erythema multiforme minor

  • Target, “bull’s eye,” or iris lesion
  • Often follows recurrent herpes simplex virus infections
  • May involve hands and feet (including palms and soles)

Erythema multiforme major (Stevens-Johnson syndrome)

  • Major form involves mucous membranes and conjunctivae
  • There may be target lesions or vesicles

Enteroviruses infection, especially Hand, Foot, and Mouth Disease

  • Summer and fall
  • Fever and mild pharyngitis 1 to 2 days before rash onset
  • Lesions initially maculopapular but evolve into whitish-grey, tender, flat, and often oval vesicles
  • Peripheral distribution (hands, feet, mouth, or disseminated)

Disseminated herpes simplex

  • Lesions indistinguishable from varicella
  • Immunocompromised host

Scabies; insect bite (including fleas)

  • Itching is a major symptom
  • Patient is not febrile and is otherwise well

Molluscum contagiosum

  • May disseminate in immunosuppressed persons
  • Can occur anywhere on the body
  • Presents as small, raised, and usually white, pink, or flesh-colored lesions with a dimple or pit in the center

Monkeypox

Also consider monkeypox in the differential diagnosis. The main difference between monkeypox and smallpox is that monkeypox causes swelling in the lymph nodes (lymphadenopathy) while smallpox does not. Swelling of the lymph nodes may be generalized (involving many different locations on the body) or localized to several areas (e.g., neck and armpit). Ask the patient questions about recent contact with any exotic or ill animals, as well as travel history to countries in Central or West Africa, where monkeypox is endemic.

Laboratory Confirmation

For patients with a high risk of having smallpox, the state health department will contact CDC to conduct laboratory testing to confirm or rule out smallpox. In the absence of known smallpox disease, the predictive value of a positive smallpox test diagnosis is low, so only cases that meet the clinical definition of the disease should be tested.

Laboratory Case Definition

Laboratory diagnostic testing for variola virus will occur in a CDC Laboratory Response Network (LRN) laboratory using LRN-approved PCR tests and protocols for variola virus. Initial positive results require confirmatory testing at CDC.

The laboratory criteria for diagnosis are:

  • Polymerase chain reaction (PCR) identification of variola DNA in a clinical specimen, OR
  • Isolation of smallpox (variola) virus from a clinical specimen (WHO Smallpox Reference Laboratory or laboratory with appropriate reference capabilities) with variola PCR confirmation.

Note: Generic orthopoxvirus PCR and negative stain electron microscopy (EM) identification of a poxvirus in a clinical specimen are suggestive of an orthopoxvirus infection but not diagnostic for smallpox.

https://www.cdc.gov/smallpox/clinicians/diagnosis-evaluation.html

Laboratory Diagnosis?

There is quite a bit of agreement between both the WHO and the CDC regarding the impossibility of diagnosing smallpox clinically due to the confusion with numerous other conditions and diseases. The best a clinical diagnosis can do is provide a “suspected” label. In order for a smallpox diagnosis to be confirmed, it must be done so by means of laboratory testing. However, can smallpox even be diagnosed by way of these methods?

Not if we are to believe the information provided by the CDC. While the CDC, like the WHO, stated that clinical diagnosis needed to be confirmed by laboratory methods, it supplied various caveats that paint this confirmation as an impossibility. According to the CDC, in the absence of known smallpox disease, the predictive value of a positive smallpox test diagnosis is low. I outlined this PCR prevalence problem previously.  As smallpox can not be diagnosed clinically, PCR testing is required to confirm any suspected cases. However, PCR results are not “valid” when disease prevalence is low and therefore can not be used to confirm clinical diagnosis. Even with this admittance, the CDC then listed both PCR verification and isolation in culture as the criteria for laboratory diagnosis. They even state that the culture needs to be confirmed by way of PCR. However, once again, it must be stated that they admit that PCR can not be used for confirmation when disease prevalence is low as this results in nothing but false-positives (granted, all PCR positives are false-positives). In other words, PCR can not be used to confirm the cases of smallpox in order to determine the level of disease prevalence needed in order to determine the accuracy of the PCR results. Thus, specific PCR detection is impossible for smallpox. Even if the CDC wanted to use generic PCR designed for all “orthopoxviruses” along with negative stain electron microscopy (EM) identification of a “poxvirus” in a clinical specimen, they admitted that these results would only be suggestive of an “orthopoxvirus” infection and not diagnostic for smallpox. This means that not only can there not be confirmation of smallpox by way of clinical diagnosis, there can also not be confirmation based on laboratory diagnosis either.

The reason for the inability to confirm the diagnosis of smallpox has to do with the lack of any paper showing the purification and isolation of any particles assumed to be the variola “virus.” I have looked for quite some time for any such paper making this claim and it is nowhere to be found. All that is ever claimed is the growth of the invisible “virus” by way of different culture techniques. However, in order to know what conditions are necessary in order to grow any “virus,” the “virus” in question must be shown to physically exist first by means of purification and isolation. Without such direct verification, any result from any indirect laboratory test is essentially useless and utterly meaningless as the tests can not be validated nor calibrated to the actual “viral” particles.

For more clarity on this laboratory diagnosis prblem, we now return to highlights from the second chapter of Smallpox and its Eradication, the WHO’s 1988 fictional retelling of the history of smallpox. In this chapter, you will see:

  1. That most of the evidence for smallpox and other “orthopoxviruses” as well as the structure and chemical make-up came only from the study of vaccinia “virus”
  2. The most useful laboratory test for distinguishing between species of “orthopoxvirus” is the appearance of pocks on the CA membrane which is heavily influenced by culture conditions and temperature thus negating any “viral” effect
  3. In spite of the fact that variola “virus” is limited in which hosts it can infect, its contradictory nature apprently allows it to grow and produce a cytopathic effect in cultured cells derived from many species
  4. Its contradictory nature also allows it to produce a cytopathogenic effect that does not have anything to do with “virus” growth due to its low cytopathogenicity and instead infected cells are pushed together by the growing non-infected cells around them
  5. Light microscopy and electron microscopy could not be used to distinguish between variola, vaccinia and monkeypox “viruses,” which are morphologically indistinguishable
  6. All of the indirect laboratory methods can not distinguish between “orthopoxviruses”
  7. The most comprehensive analysis of 4 laboratory methods (EM, gel precipitation, CA membrane, tissue cultivation in Vero cells) showed inconsistent and contradictory results

CHAPTER 2: VARIOLA VIRUS AND OTHER ORTHOPOXVIRUSES

Variola virus 

“This virus, which caused human smallpox, has a restricted host range in laboratory animals. Early reports of its transfer to animals are dificult to interpret, but monkeys were used quite early (Zuelzer, 1874) and extensively (e.g., Brinckerhoff & Tyzzer, 1906). Variola virus was subsequently grown in the rabbit cornea and a test developed to differentiate it from chickenpox virus (Paul, 1915). Later it was grown in chick embryos (Torres & Teixeira, 1935), and North et al. (1944) and Downie & Dumbell (1947b) showed that the pocks produced by variola virus on the chorioallantoic membrane were suficiently distinctive to allow its differentiation from vaccinia and cowpox viruses. A detailed account of the virology of variola virus is presented later in this chapter.

Vaccinia virus

Though a different species of Orthopoxvirus from Jenner’s “variolae vaccinae”, vaccinia virus is the agent that has been most widely used for vaccination. Baxby (1 977c, 1981) has summarized speculations about its origins (see Chapter 7). Many strains are supposed to have been derived from variola virus (Wokatsch, 1972; see Chapter 11). However, when experiments were carried out under conditions which precluded the possibility of cross-infection with vaccinia virus, “transformation” of variola virus into vaccinia virus could not be demonstrated (Herrlich et al.,1963).

There are many strains of vaccinia virus with different biological properties, although all have many features in common, such as their wide host range, rapid growth on the chorioallantoic membrane and distinctive genome maps. Since vaccinia virus has a broad host range and has been very widely used for many decades, accidental infections of domestic animals were not uncommon when human vaccination was practised on a large scale (see Table 2.7). Sometimes serial transmission occurs naturally in such animals (cows, buffaloes, rabbits).

In the history of smallpox eradication, vaccinia virus is second only to variola virus in its importance. It is also the “model” orthopoxvirus, with which the vast majority of laboratory investigations of viruses of this genus have been performed. Aspects of its virology are further discussed later in this chapter and its use in the prevention of smallpox is described at length in Chapters 6, 7 and 11.”

CHARACTERISTICS SHARED BY ALL SPECIES OF ORTHOPOXVIRUS

“Having shown the way in which early studies of the morphology of poxvirus particles led to a classification of the family and the designation of the genus Orthopoxvirus, it is necessary now to outline current views on the structure and chemistry of these viruses. The vast majority of such studies were carried out with vaccinia virus, but they apply, with minor variations, to all orthopoxviruses.”

Appearance of Orthopoxvirus Pocks on the Chorioallantoic Membrane

“The most useful laboratory test for distinguishing between species of Orthopoxvirus is the appearance of pocks on the CA membrane. Unlike plaques in cultured cells, which result
from the direct interaction between cells and virus, a third component enters into the appearance of pocks-namely, leukocytes and erythrocytes delivered to the site via the bloodstream. Basically, a pock is a greyish-white focus, varying in diameter from 0.4 mm to 4 mm, according to virus species. It is produced by a combination of hyperplasia of the ectodermal layer of the CA membrane and the infiltration of cells into the mesodermal layer. Sometimes, as with variola virus, the surface of the pock is glossy white, owing to pronounced hyperplasia of the ectoderm; sometimes, as with monkeypox virus, the superficial layer ulcerates and there is a superficial haemorrhage into the crater. The pocks of cowpox virus are bright red, because very little leukocytic infiltration occurs and there are capillary haemorrhages into the pock.

Expression of the “characteristic” pock phenotype is influenced by the concentration of pocks and the temperature of incubation. Expression of the “red” pock phenotype is enhanced when the pocks are semiconfluent or confluent. Also, at higher temperatures pocks tend to be greyish-white and non-ulcerated, whereas at lower temperatures some species (but not variola virus) produce pocks with an ulcerated, haemorrhagic centre. For example, at 37° C camelpox virus produces small pocks very similar to those of variola virus (Mayr et al., 1972), but at 35° C it produces pocks with a haemorrhagic centre (Marennikova et al., 1973). Likewise, at 37° C monkeypox virus produces white pocks very like those of variola virus (Magnus et al., 1959), whereas at 35° C the pocks are ulcerated and haemorrhagic (Marennikova et al., 1971).”

Monkeypox incubated at 35°C while all others were at 36°C?

Growth in Cultured Cells

“In contrast to its limited host range in laboratory animals, variola virus will grow and produce a cytopathic effect in cultured cells derived from many species (Hahon, 1958; Pirsch et al., 1963). However, it grows best in cells from humans and other primates in which it produces characteristic “hyperplastic” foci. In fact, this appearance (Plate 2.13) is not due to proliferation of the infected cells, but to their aggregation. Because of the low cytopathogenicity of variola virus, infected cells remain in the monolayer and are pushed together by the growing non-infected cells around them (On0 & Kato, 1968). Kitamura (1968) described an assay of variola virus based on counting the hyperplastic foci that develop in HeLa and FL cells (Plate 2.13); in primate cells (Vero and JINET) these foci progress to form small plaques
(Tsuchiya & Tagaya, 1970). Variola virus will replicate and produce a cytopathic effect in continuous-line pig embryo kidney cells (Marennikova et al., 1971), a test which has been used to differentiate it from monkeypox virus. However, Veda & Dumbell (unpublished observations, 1974) found that different strains of monkeypox virus varied in their capacity to grow and produce a cytopathic effect in pig embryo kidney cells; some hardly grew at all, others
grew moderately well, but none grew as well as variola or vaccinia viruses.”

“Like the examination of stained smears, electron microscopy could not be used to distinguish between variola, vaccinia and monkeypox viruses, which are morphologically indistinguishable, but it was of great value in confirming or possibly excluding poxvirus infection and in distinguishing between poxvirus infection and chickenpox.”

Similar plaques between smallpox, monkeypox, and cowpox? Who’da thunk? 🤔

Other serological tests for viral antigen were sometimes used but never became widely popular. Kitamura et al. (1977a) suggested that direct immunofluorescence could be used for rapid diagnosis in the field, but they and other workers (Tarantola et al., 1981) recorded a number of false positive results, a major disadvantage as the achievement of eradication approached.

All the methods described so far had the limitation that, if positive, they did not distinguish between different orthopoxviruses. This drawback was of little significance when smallpox was a common disease, but it became increasingly important as eradication proceeded, particularly after human monkeypox was recognized in 1970.”

“The most comprehensive analysis of the laboratory diagnosis of smallpox was reported by Nakano (1973), who kindly updated the figures in 1982 to show the situation at that time (Table 2.10). The material under study had been shipped to the Centers for Disease Control, Atlanta, USA, from Africa, South America and Asia and had usually been in transit for between 2 and 4 weeks, and occasionally longer, often at high ambient temperatures. Four methods were used: electron microscopy, gel precipitation, and cultivation on the CA membrane and in Vero cells. By March 1981 a total of 6919 specimens had been examined, many of them from suspected chickenpox cases during precertification testing in Ethiopia and Somalia. Of the 981 positive specimens, 940 were identified as variola virus and 41 as human monkeypox virus.

Electron microscopy had the advantage of being much the most rapid method of making a presumptive diagnosis, which was a very important requirement, especially in non-endemic countries. In scabs or material that had been some time in transit, it was also the most sensitive, although fields might have to be searched for as long as 30 minutes before a specimen was declared negative. The longer period of search undoubtedly accounted for the greater percentage of successes recorded by Nakano with stored specimens, compared with the experience of Noble et al. (1970). Inoculation on the CA membrane had the great advantage of allowing differentiation between the 4 orthopoxviruses that can infect man (variola, monkeypox, cowpox and vaccinia viruses). It was also the most sensitive with fresh specimens of vesicular fluid, since one infectious particle was potentially capable of producing a pock. Positive results were obtained on the CA membrane with 14 specimens that were negative by electron microscopy, whereas 97 specimens were positive by electron microscopy but negative by CA membrane inoculation. However, Nakano (1 979) found that the susceptibility of the CA membrane, although usually quite satisfactory, was sometimes unacceptably low, as judged by control inoculation in cultured cells. For this reason he found it useful to make inoculations on cultured cells, especially with critical specimens in which recovery of the responsible virus was very desirable (e.g., in suspected human monkeypox). Out of 186 specimens that were tested by all 4 methods, 182 were positive by electron microscopy, 135 by tissue culture inoculation and 117 by CA membrane inoculation-i.e., 18 specimens were positive by tissue culture but negative on the CA membrane. Growth in pig embryo kidney cells was sometimes used to differentiate between variola and monkeypox viruses. Nakano confirmed the finding of Noble et al. (1970) that gel precipitation was the least sensitive technique and that it was often negative in lesion material that had been exposed to ambient temperatures for several days.”

Click to access 9241561106_chp2.pdf

In Summary:

  • There was much difficulty in differentiating smallpox and measles in their early phases due to the similar appearance of the rashes
  • Even though the Persian physician Rhazes Ar-Raz Abmiz was the first person to clinically distinguish smallpox from measles in 900 AD, European physicians continued to confuse the illnesses until relatively recent times
  • Sir William Osler, the master clinician of the modern era, emphasized the difficulty in differentiating early measles from smallpox
  • The Great Pox referred to syphilis, and the Lesser Pox may have referred to rubella, chickenpox, and smallpox
  • La grosse verole was a term used to describe syphilis, whereas smallpox was referred to as la petite verole
  • In other countries, the word for pox was applied to different diseases during different times
  • In German, syphilis was initially referred to as blattern during the 16th and 17th centuries, but blattern later was applied to smallpox during the 18th century
  • The term morbilli was used to differentiate the ‘‘small plague’’ of measles from the ‘‘great plague,’’ referred to as Il Morbo
  • For centuries, scarlatina, rubella, measles, and smallpox were undifferentiated febrile diseases with rashes
  • The terminology for measles is confusing, as is the clinical differentiation between measles and chickenpox
  • Scarlet fever was termed morbilli confluentes
  • Measles in German is masern; in French measles is rougeole; and the synonym for measles in English is rubeola
  • As smallpox is no longer a common infectious disease, differentiation from chickenpox is less critical
  • In other words, since smallpox is claimed not to exist, they do not have to worry about any chickenpox cases that look exactly like smallpox
  • Should smallpox reemerge, clinicians will face the same diagnostic dilemmas in differentiating smallpox from measles in its early stages
  • According to Al-Razi, the first physician to separate smallpox and measles in 900 AD, the most common signs of both smallpox and measles were:
    1. Continuous fever
    2. Nose itching
    3. Allergy in the body
    4. Redness of the cheeks and eyes
    5. Sore throat
    6. Chest pain
    7. Breathing difficulties
    8. Cough
    9. Hoarseness
    10. Headache
    11. Syncope
  • On the other hand, regarding the specific signs, he said that back pain was more severe in smallpox, while it might be slight or absent in measles and that distress, syncope and anxiety were more prominent in measles
  • In other words, they shared every symptom of disease and the only difference was in regards to the severity of a few of the shared symptoms
  • Al-Razi was unlike all the Greek and Arab physicians before him, who considered the two diseases as one
  • Smallpox was confused with chickenpox more frequently than with any other illness
  • The similarities between the diseases and the importance of making the correct diagnosis led an infectious disease expert to declare that there was “no more important diagnosis in clinical medicine than the differentiation of these two diseases.”
  • The question arose as to the possibility that clinical diagnostic errors could cause some cases of monkeypox to be misdiagnosed as other eruptive diseases
  • In Zaire in the period 1981-1986, 977 persons with skin eruption not clinically diagnosed as human monkeypox were laboratory tested
    1. 3.3% of human monkeypox cases were found among 730 patients diagnosed as cases of chickenpox
    2. 7.3% among cases diagnosed as “atypical chickenpox”
    3. 6.1% among cases with skin rash for which clinical diagnosis could not be established
  • The diagnostic difficulties were mainly based on clinical features characteristic of chickenpox:
    1. Regional pleomorphism (in 46% of misdiagnosed cases)
    2. Indefinite body-distribution of skin eruptions (49%)
    3. Centripetal distribution of skin lesions (17%)
  • In the absence of smallpox, the main clinical diagnostic problem is the differentiation of human monkeypox from chickenpox
  • Diseases commonly mistaken with smallpox:
    1. Monkeypox
      • Human monkeypox ranks first among the diseases that might be confused with smallpox, because differential diagnosis was impossible on clinical grounds alone
      • In the field, diagnosis depended on the occurrence of a disease indistinguishable from ordinary-type smallpox in the appropriate epidemiological situation
    2. Chickenpox
      • In post-eradication searches in India in 1976, 63% of the “suspected smallpox” cases were in fact cases of chickenpox
      • Some severe cases of chickenpox in adults were associated with such an extensive rash, including lesions on the palms and soles, that it was impossible to be certain at any stage of the disease as to whether it was chickenpox or smallpox
      • During the eradication programme, all such cases were regarded as smallpox and appropriate control measures were undertaken
    3. Tanapox
      • Lesions could be confused with those of mild smallpox in a vaccinated subject
    4. Measles
      • In the first 2 days of the rash, before vesicles developed, the most likely cause of confusion was measles, and this difficulty could persist for several more days in flat-type smallpox
      • Historically, measles did not present a problem in countries with endemic smallpox, but in non-endemic countries an early case of smallpox was sometimes diagnosed as measles, with possibly serious consequences in terms of secondary cases
      • On the other hand, in countries in which smallpox was endemic, physicians were often prone to diagnose all outbreaks of rash associated with deaths as smallpox and to report them as such to the health authorities
      • Some of these outbreaks later proved to be due to measles
    5. Syphilis
      • Earlier writers, e .g ., Councilman (1907) and Ricketts (1908), paid considerable attention to syphilitic rashes as presenting a problem in differential diagnosis
      • In African countries and India secondary syphilis remained a disease to be considered in the differential diagnosis of smallpox, up to the time of eradication
    6. Erythema multiforme
      • This disease could cause difficulties at any stage of the rash; the distribution of lesions is sometimes very like that of smallpox
      • In both diseases the patient could be quite ill and have a profuse vesicular eruption particularly affecting the extremities
      • In severe cases there could be confusion with flat-type smallpox, since the vesicles were occasionally soft, superficial and flat, individually resembling those of flat-type smallpox
      • They sometimes coalesced and produced large bullae, also seen in some cases of severe smallpox
    7. Lesions due to vaccination
      • Problems of precise diagnosis sometimes arose in smallpox contacts who had been vaccinated during what turned out to be the incubation period of smallpox
      • They usually showed a positive take at the vaccination site and often a modified rash, which could have been caused by variola or vaccinia “virus”
      • All such cases were regarded as smallpox from the point of view of management
    8. Drug eruptions
      • Drug eruptions were an important diagnostic problem in countries in which smallpox had been eradicated years before and doctors rarely considered the possibility of the disease
      • Many instances exist in which the rash of an imported case of smallpox, and sometimes the rashes of second generation cases deriving from it, were diagnosed as drug rashes
      • Vaccine-modified smallpox could continue to mislead the physician if he had never considered smallpox as a possible diagnosis
      • In endemic countries where a wide variety of drugs have become available, cases of smallpox and drug eruption sometimes occurred coincidently
    9. Rashes due to other causes
      • There are few diseases characterized by a rash that did not at some time suggest a diagnosis of smallpox
      • Acne, scabies and insect bites may be mentioned as examples
      • Coxsackievirus infections could pose a problem
      • Dengue haemorrhagic fever and other arbovirus infections associated with a rash were sometimes initially diagnosed as smallpox
  • Laboratory methods played a crucial role in the global smallpox eradication programme as eradication could not have been confidently certified to have been achieved without their use
  • In other words, there was no way, based on clinical diagnosis, to declare smallpox eradicated as it was regularly confused with numerous conditions/diseases
  • Laboratory methods were also useful for the confirmation of clinical diagnoses
  • Laboratory workers could make mistakes, however, the recovery of variola “virus” from a skin lesion was usually regarded as conclusive evidence that a particular patient was or had been suffering from smallpox
  • Such confirmation was rarely sought in endemic countries when smallpox was a common disease and any doubtful case was always regarded as smallpox
  • Laboratory confirmation or refutation of suspected smallpox was a valuable procedure in non-endemic countries and in smallpox-free regions of the endemic countries as eradication approached
  • If an electron microscope was available, the examination of material from vesicles, pustules or scabs, examined by the negative staining technique, could give a rapid presumptive diagnosis of poxvirus, or sometimes herpesvirus, infection (i.e. the type of particle observed could only be considered presumptive, not definitive)
  • Definitive diagnosis depended on the isolation of the causative “virus” on the chorioallantoic membrane of the developing chick embryo and its further characterization, if necessary, by biological tests
  • Usually the character of the pocks produced on the chorioallantoic membrane was distinctive enough for the diagnosis of variola, vaccinia, monkeypox or herpesvirus infection to be made (i.e. the pocks were not always distinctive enough to differentiate the “viruses”)
  • The CDC’s own list of diseases commonly confused with smallpox included many of the same as those listed by the WHO as well as:
    1. Disseminated herpes zoster (shingles)
    2. Impetigo (Streptococcus pyogenes, Staphylococcus aureus)
    3. Contact dermatitis
    4. Enteroviruses infection, especially Hand, Foot, and Mouth Disease
    5. Disseminated herpes simplex (herpes)
    6. Molluscum contagiosum
  • In the absence of known smallpox disease, the predictive value of a positive smallpox test diagnosis is low, so only cases that meet the clinical definition of the disease should be tested
  • Initial positive results require confirmatory testing at CDC
  • The laboratory criteria for diagnosis are:
    1. Polymerase chain reaction (PCR) identification of variola DNA in a clinical specimen, OR
    2. Isolation of smallpox (variola) “virus” from a clinical specimen (WHO Smallpox Reference Laboratory or laboratory with appropriate reference capabilities) with variola PCR confirmation
  • Generic orthopoxvirus PCR and negative stain electron microscopy (EM) identification of a poxvirus in a clinical specimen are suggestive of an “orthopoxvirus” infection but not diagnostic for smallpox
  • Variola “virus” was grown in the rabbit cornea and a test was developed to differentiate it from chickenpox “virus” (Paul, 1915)
  • Later it was grown in chick embryos (Torres & Teixeira, 1935), and North et al. (1944) and Downie & Dumbell (1947b) showed that the pocks produced by variola “virus” on the chorioallantoic membrane were suficiently distinctive to allow its differentiation from vaccinia and cowpox “viruses”
  • Though a different species of “orthopoxvirus” from Jenner’s “variolae vaccinae”, vaccinia “virus” is the agent that has been most widely used for smallpox vaccination
  • Many strains are supposed to have been derived from variola “virus” yet when experiments were carried out under conditions which precluded the possibility of cross-infection with vaccinia “virus,” “transformation” of variola “virus” into vaccinia “virus” could not be demonstrated
  • There are many strains of vaccinia “virus” with different biological properties
  • In the history of smallpox eradication, vaccinia “virus” is second only to variola “virus” in its importance
  • It is also the “model orthopoxvirus,” with which the vast majority of laboratory investigations of “viruses” of this genus have been performed
  • The vast majority of studies on the structure and chemistry of pox “viruses” were carried out with vaccinia “virus,” but they claim to apply, with minor variations, to all “orthopoxviruses”
  • In other words, the structure and chemical make-up of the pox “viruses” were derived from vaccinia “virus” and not by the study of the other “viruses” themselves as it was assumed that the results from vaccinia apply to them all
  • The most useful laboratory test for distinguishing between species of “orthopoxvirus” is the appearance of pocks on the CA membrane
  • Expression of the “characteristic” pock phenotype is influenced by the concentration of pocks and the temperature of incubation
  • At higher temperatures pocks tend to be greyish-white and non-ulcerated, whereas at lower temperatures some species (but not variola “virus”) produce pocks with an ulcerated, haemorrhagic centre
  • At 37° C camelpox “virus” produces small pocks very similar to those of variola “virus” but at 35° C it produces pocks with a haemorrhagic centre
  • At 37° C monkeypox “virus” produces white pocks very like those of variola “virus” whereas at 35° C the pocks are ulcerated and haemorrhagic
  • In other words, the pock formations are directly influenced by the culture conditions and tempature and have nothing to do with any “virus”
  • In contrast to its limited host range in laboratory animals, variola “virus” is said to grow and produce a cytopathic effect in cultured cells derived from many species (i.e. it can’t infect the animals but it can somehow “grow” on their cells)
  • It’s CPE in human and primate cells is not due to proliferation of the infected cells, but to their aggregation because of the low cytopathogenicity of variola “virus”
  • In other words, the CPE is said not to be due to the growth of “virus”
  • It is said that variola “virus” will replicate and produce a cytopathic effect in continuous-line pig embryo kidney cells, a test which has been used to differentiate it from monkeypox “virus”
  • However, Veda & Dumbell found that different strains of monkeypox “virus” varied in their capacity to grow and produce a cytopathic effect in pig embryo kidney cells; some hardly grew at all, others grew moderately well (i.e. the CPE was not specific to smallpox thus it could not be used to distinguish between smallpox and monkeypox)
  • Like the examination of stained smears, electron microscopy could not be used to distinguish between variola, vaccinia and monkeypox “viruses,” which are morphologically indistinguishable
  • Serological tests for “viral” antigen were sometimes used but never became widely popular
  • Kitamura et al. suggested that direct immunofluorescence could be used for rapid diagnosis in the field, but they and other workers recorded a number of false positive results
  • All the methods described had the limitation that, if positive, they did not distinguish between different “orthopoxviruses”
  • The most comprehensive analysis of the laboratory diagnosis of smallpox was reported by Nakano (1973), who updated the figures in 1982
  • Four methods were used:
    1. Electron microscopy
    2. Gel precipitation
    3. Cultivation on the CA membrane
    4. Cultivation in Vero cells
  • By March 1981 a total of 6919 specimens had been examined, many of them from suspected chickenpox cases during precertification testing in Ethiopia and Somalia
  • Of the 981 positive specimens, 940 were identified as variola “virus” and 41 as human monkeypox “virus”
  • Electron microscopy had the advantage of being much the most rapid method of making a presumptive diagnosis although fields might have to be searched for as long as 30 minutes before a specimen was declared negative (they would not need to search for the “virus” if the sample was purified and isolated)
  • Positive results were obtained on the CA membrane with 14 specimens that were negative by electron microscopy, whereas 97 specimens were positive by electron microscopy but negative by CA membrane inoculation
  • Nakano (1 979) found that the susceptibility of the CA membrane, although usually quite satisfactory, was sometimes unacceptably low, as judged by control inoculation in cultured cells
  • Out of 186 specimens that were tested by all 4 methods:
    1. 182 were positive by electron microscopy
    2. 135 by tissue culture inoculation
    3. 117 by CA membrane inoculation-i.e., 18 specimens were positive by tissue culture but negative on the CA membrane
    4. Growth in pig embryo kidney cells was sometimes used to differentiate between variola and monkeypox “viruses”
  • Nakano confirmed the finding of Noble et al. (1970) that gel precipitation was the least sensitive technique
  • In other words, all of these indirect laboratory diagnostic tests gave inconsistent and contradictory results

In the past, all diseases involving eruptions of the skin were considered the same disease. This can be seen by the numerous descriptions and labels used interchangeably in order to describe these similar sets of symptoms over the centuries. The separation of the ailments into separate diseases based on minute and often overlapping differences is mainly a modern invention. This can be seen with smallpox which was distinguished from related diseases such as measles, chickenpox, shingles, scarlett fever, monkeypox, etc. Even with these separations, clinicians had a difficult and challenging time diagnosing these diseases based on just symptoms alone. There are numerous examples of clinical misdiagnosis between smallpox and its relatives. Thus, as laboratory methods became available, it became imperative to confirm any clinical diagnosis using these new methods. However, the older tests were unable to distinguish one “orthopoxvirus” from another and the newer tests such as PCR can not be used as a confirmation as they rely on the determination of disease prevalence to be high in order for the results to be valid. Prevalence can only be determined by clinical diagnosis, and clinical diagnosis, as noted by the WHO and CDC, requires laboratory confirmation. See the problem here?

This racket of labeling the same symptoms as different diseases can be seen throughout history as noted with the smallpox example but also regarding syphilis and AIDS, polio and acute flaccid myelitis, as well as “Covid-19” and allergies, the common cold, the flu, and pneumonia. This breakup of the symptoms into new diseases provides ample opportunity for the medical mafia to sell us both on the disease and the supposed pharmaceutical cure. It can be used to convince us on the idea of vaccination as a successful intervention leading to the eradication of the older disease which was actually phased out in favor of the identical symptom set which has been rebranded, repackaged, and relabelled. It is far past time we learn from history and break free of this symptomological pharmaceutical business model in order to have a future free from its toxic influence.

36 comments

  1. Impressive work, as usual! I’m curious—have you looked into leprosy so far? And, are you familiar with the ‘Cult of the Medics’ series that David Whitehead has been producing? Thank you for your work, so appreciated!

    Liked by 1 person

    1. Thank you for the kind words and continued support! 🙂 Sadly, I have not delved into leprosy yet. It is definitely on my “To do” list. I also am not familiar with the “Cult of the Medics” series but based on the title, it sounds right up my alley! 😉 I will have to look it up.

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  2. Great post Mike thanks. Good for us to get ahead of the game on this ‘class’ of skin disease.

    The temperature differentials is that the higher temps (36,37C, or 98, 99F) correlate with white pustules because these skin temperatures correspond with those of internal temps during (lymphatic) fevers over 100F. The white being white blood cells, which are for isolating and removing fat-soluble toxins. This is the dynamic associated with ‘smallpox.’ Fat soluble toxins are the ones we isolate and store in fatty tissues such as the fatty layers of our skin. Not being water soluble that cannot be filtered out by osmosis into the bloodstream and taken to the filtering organs. The reason that smallpox is highly correlated with famine is that during famine the body needs to call on all remaining fat reserves, leaving the heretofore preserved fat-soluble toxins unearthed and reactive.

    The red, ulcerated, hemorrhagic sores would be the intelligent method for dealing with water-soluble toxins that, by the osmotic force, get sucked back into the capillaries and sent to the ‘filter’ system. When there’s too much toxicity crossing the capillary membranes it hurts them and that damage causes distributed contusions and apoptosis that look to the eye as sores. Presumably the toxicity can be endogenous (distributed epithelial apoptosis due to acute nutrient deficiencies) or exogenous (water-soluble chemicals).

    This topic relates to the Jeff Green topic an Clarifire’s subsequent, accurate reflections. Jeff Green’s non-sequitur ‘viruses as enzymes’ theory is presumably based on the class of enzymes known as monooxygenases. Their job is to act as solvents of fat-soluble toxins. Structurally these enzymes are referred to as microsomes (small exosomes) which is presumably the (inadequate) grounds for him associating them with exosomes/viruses. But he’s a young buck, 31yrs old or something like that, which is also reflected in his metaphysical writings. He’s obviously very bright though and would do well to come round here and contribute to these investigations.

    Monooxygenases seem to be intriguing tools. I believe they are credited with being manufactured by the mitochondrial symbionts within each of our cells. This makes perfect sense because mitochondria are basically a primitive prokaryotic cell evolved to nest within a eukaryotic cell. As single-celled organisms they had to have sufficient fat storage facilities because they did not have the fat-storage adaptation of multicellular organisms that was tissue differentiations such as adipose tissues, so they had adiposal -type fatty droplets within their cytoplasm, which in turn created the need for monooxygenases.

    These monooxygenase enzymes are a key part of the apoptotis function and the reactive oxygen species (ROS) function that Zach Bush specializes in. These enzymes are heavy duty solvents that deal with fat-soluble toxins but they cause oxidative stress and cell death because there’s no such thing as a free lunch.

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    1. Thanks! Yes, this monkeypox/smallpox business has taken up my attention at the moment as it seems people are falling for the hype once again so best to get ahead of it. I’m hoping to jump back into other areas soon. 🙂

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    2. Feverish, small white-pox speaks to Tom Cowan’s teaching that we are gel-based hydrostatic creatures and that fevers loosen our gels such that the (fat-soluble) toxins can be freed for detoxification. In multicellular eukaryotes like us that must mean that our adipose cells release their toxins from their loosened fat droplets, the mitochondrion makes monooxygenase microsomes, which are protein-strand enzymes (chemical compound solvents) packaged in a lipid membranes so as to protect the cell from the solvent, and both the microsomes and the toxin(s) exit the cell. That’s right, the intelligent bartender tells them to “take it outside,” into the interstitial ‘back alley.’
      In the alley, among the garbage and the gas exchange and everything else, the lipid membranes around the enzymes dissolve by some mechanism and the solvent solves the toxin by breaking it down, in a best-case scenario into a water-soluble toxin that can directly enter the bloodstream for processing, but otherwise it is solved into constituents that the white blood cells can then handle and transport into the capillaries and on to the larger bloodstreams. Looks like vigilant(e) justice to me.

      In the event that famine is causing mitochondrial dysfunction, or the toxicity is otherwise overwhelming, the fever and the white blood cells will show up but the enzymatic function is inadequate, and the unearthed, reactive toxins will cause an increased production of white blood cells in order to isolate the toxins in ‘pus’ that solidifies in scabs and fall-from the body as a result of its intelligent backup plan.

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    3. Useful to know the difference between detox of fat soluble and water soluble toxins. A small key that can fill in just enough detail to solve quite a few symptomological puzzles, I suspect.

      As to whether virology is at the core of the problem, well not quite. “Viral” symptoms being healing is at the core, and virology is one false lead based on the idea that symptoms are bad (in fact they’re a bad sign but not a bad thing, like fire trucks surrounding a house – the old analogy stands).

      Yeadon is in error to think refutation of evidence for “viruses” isn’t sufficient to dismiss virology, but if what his real point is is that we would do better to identify the cause, well, he should phrase it better.

      Truly understanding the body’s approach to self-cleaning, including any sympathetic timing aspects of that for tribal coordination, takes a lot of work, but it is still valuable to shut down the world’s No. 1 false lead so that investigation toward reap understanding can begin.

      Now of course the real root causes of “all of this” are deeper societal and civilizational ones, involving religion, nutrition, civilizational “C” and “V” factors elaborated in Jim Penman’s Biohistory, and yes, large tribe sizes beyond Dunbar’s number being the ultimate elephant in the room. It depends on where you want to focus and how radical a critique of society and civilization one is prepared to commit to. Even telling people to fast during a flu could rip apart civilization to a degree, for reasons that won’t be clear without a lot of thinking about the fabric of society, but as far as individual health there is no question that it’s the right answer.

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      1. Yeah Yeadon certainly could have expressed it better. I was reading between the lines of that back and forth. Same goes for Massey’s expression. They were both physically and therefore emotionally unprepared for such a situation, so they’re bargaining with a non-negotiable situation from different subcultures. What else is new? It pays to have been willing to see all this collapse-management theater ahead of time. And worked towards self-reliance and gotten healthy in the process. Cause and Effect wherein the actions speak louder than the words because the words come out of the actions.

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  3. I suggest moving the last two paragraphs (i.e. your conclusion) to the very top of this article, making them the first two paragraphs. This would then provide the context and purpose of this article, as is fitting for an introduction.

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  4. You are taking all the pox fun away from the virologists Mike. What are they to do if this is all just detox of either water- or fat-based toxins?

    Liked by 1 person

  5. Labeling the same symptoms as different diseases…. allows for the development and administration of a whole bunch of “vaccines” and “treatments.” But surely that’s a coincidence, these people would never play like that with our health. 🙂 Thanks for keeping up the hard-hitting investigative work, Mike!!

    Meanwhile, an exchange between Dr Mike Yeadon and Christine Massey, Yeadon insists on tagging her position as “no virus” vs “no proof a virus does not exists,” thus castigates her (in a friendly way) for positing a negative which of course cannot be proven, and asserts “the absence of evidence is not the same as evidence of absence.” Real scientific there.
    https://www.fluoridefreepeel.ca/my-open-exchange-with-michael-yeadon-may-8-2022/
    My “open exchange” with Michael Yeadon, Christine Massey, May 28, 2022.

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    1. I read these emails and again I find that Yeadon really has a good point. After all “virus” /”no virus” they’re both assumptions and theories. The fact is that you catch a cold in winter time and some of your close people they catch also.

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      1. Christine Massey, Mike, i, and others are NOT saying “no virus,” you seem to be missing that just like Yeadon. We are saying “there is no scientific proof for a virus.” The entire “pandemic” is based upon the notion that there is a scientific proof for a virus, and thus it is based upon false premises.

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      2. The notion that “no virus” is an assumption/theory is simply wrong. That is not how science works. A theory is an attempt to explain something in our world. If tests of that theory do not support it then that theory is modified and subjected to more tests. If the theory proves untenable then it is rejected. As such, “no viruses” is NOT a theory. It is then END RESULT of real and significant efforts that have led to the conclusion that the theory of the existence of viruses is unsupportable. In other words, the theory of viruses is rejected and has been demonstrated to be false.

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      3. Jeffrey, that’s just not true. The ‘pandemic’ is *ultimately* based upon the notion that there’s an abnormally high spread of an abnormally broad-based symptomology. In that context it doesn’t *functionally* matter whether it’s because of viruses or exosomes or conscious resonance or the ongoing mass extinction, because, hey, that’s the multicultural prison planet reality we live in, and the wardens are always going to have control of the intercom system and find excuses to put the inmates on lockdown as necessary.

        Yeadon’s point is fair. Virology isn’t the *root* issue. But he’s also not addressing the root issue in his campaigning against the current global curtailment of human rights for the non-elite. He root issue is the permanent curtailment of human rights by civilization itself, for which there is no political campaigning. As such, the tower of babel is founded on politics which is nothing more than ‘tribalism’ unmoored from Reason.

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      4. I disagree. Virology is the root issue. As long as the belief in “viruses” stands, they will continue to use it to justify their drugs, vaccines, lockdowns, quarantines, masks, surveillance, etc. They will repeat this cycle with every new “virus” just as we are now seeing them do with monkeypox.

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      5. The problem is assuming we can “catch” something. People do go through detoxification in the winter and sometimes people go through these detoxes at similar times. This, however, does not prove an invisible particle was transmitted between people.

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      6. Mike my point regarding virology not being the root issue was that virology is not to blame for the depopulation agenda. IMO the nuclear power industry is to blame for the depopulation agenda, because in a hard resource collapse such as this civilization is structurally facing, the social dynamics of the population collapse must be as orderly as possible until the global nuclear power industry is decommissioned or the elites’ lives themselves will surely be at grave risk by the grid-power dependent spent fuel pools exploding because they are not getting electricity to the turbines that power the water circulation system. The elites know this perfectly well of course, that the nuclear power age is a Pandora’s Box for them, too. So in their mind they are implementing a beneficial ‘stealth’ weakening and possible ‘slow-release’ culling by vaxxxing into a fake plandemic, and a carefully orchestrated and calibrated famine- and depression-causing fake NATO-RUSSIA ‘war’ (hard economic decoupling). Those are the overlapping rounds 1 and 2 of the Degrowth Agenda. Both of these ’rounds’ are just feathering mechanisms for the war-economy fine control of global resource consumption and reallocation, in service of ‘best’ managing the hard limits to growth we reached in 2019.

        Virology is the vehicle for the ‘medical’ tyranny that is one of the tools in the elite toolbox of manipulation and control. It’s awesome for manufacturing the masking of a pre-existing structural global crisis and tweaking that crisis with ‘disaster capitalism’ such that it funnels unprecedented amounts of wealth to the plutocrats very quickly. It also sets up the great global ‘anti-elitist’ political reversal (whether by the ballot box or color revolution or military coup) they have planned but that will not be implemented until the global, inverted perestroika –towards a rationing system of barebones nationalist planned economies — is complete. The Great Reset is a grand, neofeudal misdirection play with a hypercorrupt character being fake-floated in service of an engineered cultural reversal towards National Socialisms which is a much misunderstood politics but can be best characterized as a hardcore, militant, ‘green,’ insular, traditional conservative/libertarian, and highly efficient anti-Marxist socialism of syndicalist leanings. They’ve already laid all the groundwork for this in plain sight, with figures such as (as far as America is concerned ) Tulsi Gabbard, Elon Musk, Joe Rogan, Russell Brand, Tucker Carlson, Rand Paul, Tom Brady, Aaron Rodgers, Candace Owens. Trump was a vehicle towards nationalism, and the neoliberal Geat Reset was a vehicle towards socialism, so as to triangulate a Third Way national socialism for which there’s no true ontological referent in public consciousness because ‘Hitler.’

        That’s my story and I’m sticking to it!

        Like

      7. If Tulsi isn’t the next president and I don’t come up with another story right away (you know I will lol) then you better tell me to go back to the drawing board or you ain’t much of a friend. 🙂

        Liked by 1 person

    2. Mike Yeadon is not intending to make a point based on the scientific method there. He’s making a point about fairness because fairness is and always has been the paramount concern of humans, whether the animist kind or the ‘fallen’ unkind. He’s telling Christine that she can’t fairly discount the spreading dynamic of classes of symptomologies by just saying that there’s no scientific-method proof of viruses without replacing it with an earnest attempt at scientifically explaining spread otherwise. And he’s right – she’s not being fair (to my knowledge, but I haven’t followed her body of work).

      This is the same disagreement I have with our estimable host, here: we’re humans and there’s more to Reason than the scientific method – there’s also accurate deduction (higher order reasoning) based on triangulating direct observations, the proofs for which lie in the puddings: do they ‘work’ in reality? Which is why I’ve said that the bias is cutting both ways. That said, given the Spiegelman’s Monster experiments which are based on the scientific method (but only if one is willing to accept genomics as a legitimate object modeling), there is in fact an scientific-method-based reasoning for spread that we called conscious resonance. Furthermore, it’s not like Yeadon and the mainstream don’t believe in ‘mirror neurons;’ where are the experiments on skype-born spread?

      Like

      1. The problem is that one does not need to provide an alternate theory in order to critique the “evidence” presented for the current one. The scientific method must apply here as it deals with matters relating to cause and effect. The burden of proof is on those making the claim that invisible “viruses” exist and are the cause of disease. There is no scientific proof of this. We can call virology out without replacing it with our own theories.

        Liked by 1 person

    3. Thanks Jeffrey! Yes, Yeadon was definitely trying to do the whole burden of proof reversal. The burden is definitely on those who claim these invisible particles are going around and infecting us and causing disease. I was shocked that he tried that switcheroo but they always do when they don’t have an answer. 😉

      Like

  6. Superlative! I am already turning the page on monkeypox. This may be the last article I read about it. I don’t like monkeys but I still listen to a few Monkee’s tunes now and then.

    Looks to me that modern medical science has the same difficulties determining what “pox” is which much the same way they have trouble differentiating the various degrees or types of cold and flu.

    The symptoms and outcomes are specific to the individual depending on their overall state of health.

    I am hoping the CDC and WHO can invent something that is more entertaining in the future. These fake pandemics are becoming extremely tiresome and boring.

    Liked by 1 person

  7. I mean let’s get real about the root cause of the tower of high school clique-based babel. Me, you, we, and everyone we know, and everyone they know, are direct descendants of those of our ancestors that chose *not* to fight to the death against one imperial force or another. None of this is voluntary. And obviously as minority lovers of truth, we here at Viroliegy more closely track those of our ancestors who fought to the death for truth because they knew that living on their knees (instead of dying on their feet) would only bring a fate worse than death upon their children and their children’s children, and none of us are in a position to say that they were wrong because they were better positioned to know than us, because they were closer to the truth. And behold, the children of their brothers and sisters and sons and daughters and mothers and fathers that chose to kneel bore lineages that are now, Reason makes obvious, are now destroying whole swaths of the planetary biology. That’s what the warriors foresaw and why they fought to the death, because bearing kneeling children into that maelstrom was anathema to loving action.

    Now that we children of the maelstrom are here, and awakened to the fact that civilization represents a cataclysmic devolutionary bottleneck, it is incumbent upon us to not get caught up in kneeling to social politics.

    Virological fraud and the depopulation agenda: these are symptoms of a fundamentally unhealthy terrain. Trying to suppress these symptoms won’t get us anywhere. That’s just either bargaining with reality or trying to help the Machine become better adapted which is not just kneeling but serving, too. Investigating them, however, in and of themselves, so that they can catalyze learning and personal growth towards the holistic truth is a worthy endeavor that our warrior ancestors who died for that truth would be proud of. They are the ones we should be living for, so that humanity may cycle back around to such necessary, embodied joy.

    Liked by 1 person

  8. 👏🙏
    How you have the time for such in depth research .

    This article popped up.

    Same today just there are more brainwashed people thanks to the indoctrination via mass schooling and media. No-one has claimed the 1.5 million reward for proof that Sars-Cov2 exists.
    And many of the so called ‘scientist’ doctors , and “ alternative” media who are sort of aware of the scam have vested interest or are a bunch of cowards who keep the virology fraud going.

    The evidence is irrefutable, virology and virologist are a total fraud and has been known for decades by the true scientists in the independent circles.

    We have an Epidemic of

    -Obedience to the system and authority
    -people not thinking ie. choosing not to or are incapable to think and use basic logic
    -Affluenza ‘virus’- epidemic of satiety that has lead to an increase psychosomatic illnesses and delusional ideas of threat

    We have a population that is or chooses to stay scientifically illiterate similar to a cult where facts make no difference.

    Well worth checking out some of John Taylor Gatto videos, this brainswahicg was accomplished via 2-3 generation of mass schooling . The propaganda via the global media was the final touch.

    Try and do a few summaries / notes.
    Another problem I perceive , it could be the culture of our time as less people read. too many videos and also repeats.
    Much easier and less time consuming than to get through articles and also quicker and easier to refer back to the information.

    https://media2-production.mightynetworks.com/asset/40280798/What_s_an_Elite_Education_.pdf?_gl=1*q2bjxq*_ga*MTIzMTkzOTQ4OC4xNjI1NzM1OTcw*_ga_T49FMYQ9FZ*MTY1NDAwNzk0OS45ODAuMS4xNjU0MDA3OTUyLjA.

    https://media2-production.mightynetworks.com/asset/40280824/Mass_Schooling.pdf?_gl=1*hwvaj5*_ga*MTIzMTkzOTQ4OC4xNjI1NzM1OTcw*_ga_T49FMYQ9FZ*MTY1NDAwNzk0OS45ODAuMS4xNjU0MDA3OTUyLjA.

    ———-

    Smallpox Historical Account – 1901

    “The sanctimonious frauds and deceivers of the public (doctors) tried in every way, shape and manner to trace a case of smallpox to my actions, but with no avail. Even after I had exposed 30,000 people and rubbed my pus-covered hands over thirty-seven faces, they could find nothing against me. In the near future I will publish a few similar incidents which have happened to me in the past years, and which are far more interesting than this one.

    Why is not one out of the thousands of these medical scoundrels, murderers and deceivers ever turned up to win the prize which reads as follows: On thousand dollars will be given to anyone that can prove that the disease is contagious; also ten dollars for every day it takes him to prove it. The doctors know that by superstition, the people can best be held. Then I want to ask you, are not the people more to blame than the doctors?

    More than half the public do not believe in contagion, but they lack the courage to say so. Discussion and argument will never change the present conditions. They never settle a question where a powerful body of men have law and money on their side.
    A powerful public sentiment, combined with true knowledge is the only remedy.
    As long as you drowse in your old superstitions these murderers will continue to ruin you constitutions for the money there is in it. Does any sane man believe that God created such laws which, if disobeyed at any time by one person, would spread a loathsome disease over a whole nation? This superstition is a blasphemy upon Almighty justice.”

    Source: https://www.vaclib.org/news/rodermund.htm

    Liked by 1 person

    1. How do I have the time for the research? I apparently have no life. 😉 I have been on a fast pace updating many old articles I posted previously on Facebook. Much of the research was done over a year and a half ago. I have just been redoing the posts off Facebbok onto the blog which I started at the end of August 2021. I have been throwing in new articles as well and adding more information to my old ones as i update them. I will probably slow down a bit soon as I am almost complete with transferring the old research over but I hope to continue to get at least two articles a week. 🤞

      Like

      1. Great work to stay focused as so easy to get distracted with so many other issues. I went through a crash course myself the last 2 years, daunting but at the same time very exciting and empowering.

        As the saying goes
        ‘ The highest form of learning is unlearning’
        Wisdom from a mythological/ spiritual perspective.

        ‘All of us get lost in the labyrinth of ignorance’

        ‘The Blind leads the blind’

        ‘Everything that has name and form is transient’

        ‘ A devil knows more than a thousand Scientists’

        ‘ New world order, a global insanity’

        Source: Long but fascinating.https://www.youtube.com/watch?v=wGJ_FcDoFfw

        ———-

        From of the comments, it is critical for the virology fraud goes away as it is the easiest way to manipulate people via pathological fear and get people into a more meaningful reality out of the good/ bad mentality and the blame game.
        This will be turning point for humanity to move towards a more meaningful and harmonious living, harmony within oneself and and outside one selfs, to get confidence back in own’s biology, other people , nature .

        ——-

        From a 2014 article in W-Plus, Sources , mentioned by Dr Lanka

        “ Sir John Madox: As editor-in-chief of the leading science magazine Nature, he made it clear to me in 1992 that all genetic engineering is erroneous and has no rational basis, but that the patentability of life secures the economic supremacy of the West.

        -Ivan Illich: As an intimate connoisseur of the Vatican, the school system and Western medicine, he made two things clear to me through a meeting in 1995: 1. a medicine that is not strictly separated from economic and other interests becomes detached from reality, is directed against human beings, becomes increasingly lethal and leads to social collapse.
        2. a change in the situation of mankind is only possible when man understands his biology and thus himself.

        -Prof. Alfred Hässig: As the founder of Swiss immunology and an intimate connoisseur of the international blood trade, he made the misconceptions of immunology clear to me in 1996.

        -Dr. Karry Mullis: As the developer and Nobel Prize winner for the technique of arbitrary propagation of DNA (PCR), without which today’s genetic engineering would not be possible, he confirmed to me in 1997 that genetic engineering results and test procedures can be manipulated arbitrarily with this method.”

        —————-

        Ivan Illich warned already in 1975 in the Nemesis of Medicine
        “ In Medical Nemesis, Illich challenged the fundamental premise of medical progress, arguing that institutional medicine is overwhelmingly pathogenic and actively sickening.

        The concept of medicalization is attributed to Ivan Illich, who first wrote on the subject in 1976. He proposed that modern medicine had become detrimental to society, by amongst other things, “launching … an inhuman attempt to defeat death, pain and sickness”.[5] By doing so, he argued, medicine had deprived individuals and societies of their ability to cope with sickness and death.”

        https://www.medicdebate.org/node/2248

        Ask yourself how important the virus existence question is?

        Dr Lanka already warned in 2005 and 2009

        https://www.medicdebate.org/node/2987

        Belief is not Science, unfortunately many of the so called ‘scientist’ and medical staff , including those in the so called freedom movement are operating on faith / believe system and astonishingly do not understand basic scientific principles and cannot critically evaluate a scientific paper.

        https://www.medicdebate.org/node/2991

        ———
        The knowledge the human culture has acquired at this point in time is creating a wasteland as humanity has lost its way in the name of materialism and ‘science’/ technology.

        Erwin Chargraff

        https://media2-production.mightynetworks.com/asset/40288347/Erwin_Chargaff-_interview_1989.pdf?_gl=1*1f3nqb0*_ga*MTIzMTkzOTQ4OC4xNjI1NzM1OTcw*_ga_T49FMYQ9FZ*MTY1NDAxNjU2MS45ODIuMS4xNjU0MDE2NTYzLjA.

        “ We are in a ‘dead end street’ through which we view and try to explain the world. There are thousands of possibilities . The human history is full of wisdom, be it the Indians, Chinese, Persian, greeks. They all lived the way they could , sometimes better , sometimes worst, he thinks ‘happier’ , a stupid world to use , than we are now.
        -We have dedicated ourselves to this positivism , materialism, reductionism and we explain it as the only healing . The science says that only more research can cure what the science has produced ie. all the pollution , pesticides etc.
        – He even stared thinking that praying for health would be more useful, costs much less and consumes less inner energy.
        He does not believe that the sole saving power of natural science as the only answer. The western world is making a huge mistake by forcing it.”

        “ One needs to find the balance again.
        There were more great scientist in previous centuries eg, the great English physicists . They were slow . They went hiking at times, they did not even enter the lab for weeks, nowadays that is unimaginable.

        All now is about mechanistic achievement but for whom?
        Eg. research – 10,000 publications/ day but not much new. .
        He knew a researcher that produced 200 papers / year . He said to him, that is not difficult , you send 100 papers with the results and another 100 papers where you retract everything, he was upset for that.
        His lab could only produce at best 7-8 research papers/ year.”

        ————

        https://wissenschafftplus.de/cms/de/alles-was-lebt

        deepL translate

        “ Everything that lives.

        Biological life is about maintaining and increasing the flow of energy.
        All biological structures, perception and behaviour serve this goal.

        The basis of life is a substance that emerges from water.
        This substance is referred to by physics as ice form X and by its discoverer as
        dense water.

        This viscous substance is one of four states that water can assume.

        This substance, which is energy and at the same time the building and information substance of life,
        connects all matter, organisms and functions.

        This knowledge provides fundamental insights into the origin, development and meaning of life.
        meaning of life.

        These insights are practically applicable in medicine, research, technology and everyday life.”

        —————

        A species with Amnesia.
        We are so much a mystery to ourselves. Perhaps because of that we are so lost and troubles today,so haunted, the sense that there is something missing , something that we need to know about ourselves.

        For ancient Egyptians the essential mystery of human existence concerned our spiritual essence , that we are participating in this theatre of experience that we call life in the world in an immense endeavour aimed at the perfection of the soul.

        Shaman in the Amazon, what is the problem with the world, the problem with the west , it is simple , you severed the connection with the spirit, you cut the link and you have to restore that link of you are going to move forward.
        Seems the fundamental task that all of us face, not these exterior trapping of power that have brought such horror and misery to the world. This is the moment of crossroads that we stand at, none of us can change things at a macro level , it is impossible but we can make changes on a microlevel, n our lives , in our immediate surroundings. Changes for the better driven by love.
        Cannot stop global destruction but can stop what I am doing to contribute to it .If we all do that a huge change in consciousness will come

        Every soul is like a raindrop that falls from the sky into one bast ecean of consciousness. Most raindrops hit the surface and make a small ripple that fades away . But some ripples make waves.

        https://www.bitchute.com/video/8RXPXNoSfin5/

        ———-

        Like

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