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A Night with Venus: STIs and Their Treatment in the 1630s, Part One

Written by Gus Kritikos

 

Sexually transmitted infections (formerly called venereal diseases) caused a surprising amount of discomfort, loss of fertility, madness and even death in the early modern era. There was a lack of understanding of the diseases, of the corresponding public health measures that should have been in effect, and of reliable treatments. Advances in bacteriology and serology starting in the 1890s in this time line provided the first consistent ability to diagnose the infections early in their course. Effective treatment started a decade later, with the discovery first of arsenicals for syphilis. Several decades later the sulfa class drugs and finally penicillin and chloramphenicol were developed. All of these drugs are (by canon) producible with 1630's technology and guidance from up-time sources. It is important to note that one of the most critical tenets of public health is that treatment is needed for not only the presenting patient, but also all identifiable intimate contacts of that patient.

Please note that any prospective dates given in this article are my own personal first approximation SWAGs, and based on my estimation of the progress from 1631 to the 1660 time frame as compared to the 1900 to 1970 time frame in this time line. Iver Cooper's excellent article on Organic Chemistry (Industrial Alchemy Parts III and IV) contains references to the antibiotics in canon, and I have adapted those as the baseline.

 

Syphilis

 

Syphilis was named for a shepherd in the 1530 epic poem, "Syphilis, or the French disease" by Girolamo Fracastoro, an Italian physician trained at Padua. As a disease, syphilis was first characterized in 1494 with an outbreak in Naples that was linked to some of Columbus' crewmen. Other names for the disease include the Great Pox (to distinguish it from Small Pox), the French Pox (by the English, Italians and Germans), the English Disease by the French and South Sea Islanders, and the Turkish Disease by the Russians. Notice the pattern of blaming the disease on one's enemies!

The causative agent, Treponema pallidum, is a pale, spiral shaped, mobile single celled organism that normally lives in humans. Various ideas of the source of the original infection have been proposed, with arguments about the antiquity of this disease having extended for several centuries. Currently, there are two competing ideas, first, the Old World theory, where syphilis is derived from the skin disease bejel, which has been known since antiquity, mostly in the western end of the Mediterranean. It is caused by a Treponema that is closely related to T. pallidum. It, like most of the New World forms, is a skin infection not requiring intimate sexual contact. There is some suggestion that bejel may have been confused with leprosy at times, as both produce painless ulcers, can result in scarring with loss of sensation, leading to further risk of damage from recurrent minor trauma, and both cause soft tissue and bony destruction over time. Bejel is more transmissible than leprosy, and occasionally undergoes spontaneous cure, both of which are arguments towards bejel being the Biblical Tzaraath, not what we know as leprosy today. Possible evidence of Treponema related bony changes have been noted in pre-Columbian skeletons from Pompeii, among other places.

The New World, or Columbian, theory which theorizes that Columbus and his men brought the disease back after sexual contact with New World natives, is related to various treponemal New World tropical diseases, including yaws and pinta. As with bejel, these are skin infections not requiring intimate genital contact. Recent research tends to favor Columbian origin, as genetic testing suggests that syphilis is more closely related to yaws than bejel, and there appears to be an intermediate form (between yaws and syphilis) that occurs along the northeast coast of South America.

Wherever syphilis originated, the epidemic form was noted with numerous cases starting in the 1493-94 timeframe, and continued unchecked through the middle 1500s, and then, in a somewhat milder form, through the late 1800s. While the treponemal skin infections show evidence of having been long associated with humans, the epidemic suggests that during the change of the tropical form to a venereal form, suitable for transmission in the colder areas of Europe, a more aggressive subtype was selected. An interesting correlation can be noted here, as when experimental rabbits are partially shaved and then infected with T. pallidum, the shaved (cooler) areas of the rabbit's body show substantially more and worse lesions than the fully furred areas.

Similar problems with an aggressive disease were noted in the first stages of the AIDS epidemic, but the public health authorities in the 1632 universe, lead by Dr. Balthazar Abrabanel, are determined to avoid the mistakes made in the 1980s in this time line. Like AIDS and the viral hepatitis infections, syphilis can be blood borne, and this will be a major threat to the blood supply in the early stages of blood banking.

Several stages are associated with syphilis, which is one of the most important diseases in the 1632 time line. In the primary infection, a flat red patch (macula) is noted at the point of infection. This develops into a painless ulcer with a raw, red base, hard, smooth edges (called a chancre) and often no other symptoms. There is a latent period of 10 days to 3 months, with an average 3 weeks from the time of exposure to the appearance of the chancre. The patient is mildly infectious after the appearance of the ulcer. One to six months after the initial infection, with an average 6-8 weeks, the secondary stage starts with the appearance of a rash that occurs anywhere on the body. This is one of the very few rashes that shows up on the palms of hands and the soles of feet, and any patient in the 1632 universe with a rash on the palms and soles will be considered to have syphilis until proven otherwise.

In this time line, the rash is reddish pink and appears evenly on both sides of the body, extending to the extremities. In the 1630s, the rash was more pronounced, often with open sores that gave rise to the name "Great Pox" to differentiate it from smallpox. Flat, pale, fleshy masses, called condyloma lata, occur in skin folds and other moist areas of the body and, like the palmar rash, are considered diagnostic for the disease. Other signs of generalized inflammation including swollen lymph nodes, fever, sore throat, malaise and headache also occur. In about 2% of the cases in any stage of the disease, a form of meningitis may occur, which is a dire sign. Because infective treponema can be found in the rashes, condylomata and ulcers, the secondary stage is the most infective stage of the disease. An interesting sign is a patchy loss of hair on the head, where the rash interferes with hair growth, that occurs in about 5% of the patients. The outer edges of the eyebrows can also be affected.

The latent stage starts with resolution of rash and healing of any active ulcers and disappearance of any condylomata, which may occur two weeks after the rash starts, but is most often a month or more later. At this point, there is little physical evidence of the disease, however the patient remains infective, but much less so than secondary stage. The progression of the infection from here shows that roughly one quarter of the cases result in spontaneous resolution, another quarter remain in the latent state for long periods of time (possibly the rest of their life), and ultimately one half progress to the tertiary stage, from one year to a decade or more later.

It is at this stage that syphilis becomes known as "The Great Imitator," because the presentation of the disease is so variable. Rashes may occur across any area of the body, and again occur on the palms and the soles. In the 1630s, these rashes also included open sores. Gummas, formed of reactive granuloma tissue, occur in many areas of the body, most typically in the liver and on the face. These non-cancerous tumors (swellings) are firm, rounded, and not tender. They may resolve spontaneously, leaving either a scar or a lump, or may persist for years. Some of them will cause bone or cartilage damage, leading to such problems as collapsing of the nose or ears. Heart failure due to muscle damage, aortic arch aneurysms (which were noted in Sherlockian canon), stomach ulcers, nose bleeds and kidney damage were also common.

Neurosyphilis was one of the most feared complications of long-term syphilis, and was ultimately a terminal condition prior to the advent of antibiotics. While most common in the tertiary stage, neurosyphilis could actually occur in any stage. Common findings included tabes dorsalis (a wide based gait with "slapping" steps due to the loss of sensory feedback from the legs and feet), and Argyll Robertson pupils (or "whore's eyes," described as "accommodating, but not reactive" because the pupils of the eyes will narrow as the patient tries to track a finger moving closer to the patient's face (accommodation), but will not narrow when a light is flashed into the eyes (reactivity)). Ultimately, psychosis, insanity and a particular form of flaccid (limp) paralysis called general paresis of the insane will occur, leading to death. In this time line, the connection between general paresis and syphilis was not made until the late 1850s and finally confirmed by the finding of active spirochetes in damaged brains in 1913.

 

Diagnosis

 

A history of sexual contact with known infected persons or of birth to an infected mother (perinatal transmission) is the most important single factor in the diagnosis of syphilis until the development of serological tests for syphilis (STS), which will probably be sometime after 1636. Secondary history findings of the patient having any other sexually transmitted disease, or having what I will politely call a "rakehell" history, will be as highly suspicious for syphilis exposure in the 1630s as it is today. Additionally, a history of receiving a blood transfusion, followed by typical physical findings, will be highly suspicious for syphilis.

I have already discussed the physical findings above, starting with the chancre, the rash (especially on the palms and soles), the "Great Pox" and progressing to the findings of neurosyphilis.

 

Lab findings

 

Serologic tests for syphilis (STS) have been the mainstay of screening for syphilis in this time line since the development of the Wasserman test prior to WWI. All of the screening tests are based on the cross reaction of beef cardiolipin antigen (diphosphatidyl glycerol, an alcoholic extract of beef heart that has the same structure as part of the treponema cell membrane), and are thus referred to as non-treponemal antigen tests.

It must be noted that these tests are not specific for syphilis, but can also cross react to other antibodies produced by the body in response to autoimmune conditions such as rheumatoid arthritis, and a number of other infections, including non-syphilis treponemal infections, tuberculosis and viral diseases. Additionally, because of the peculiarities of serologic testing and the relationship between the antibodies and antigens as they are tested, high levels of antibodies can result in a false negative test, even in a highly infectious patient. If there is a high degree of suspicion, the patient's serum will be diluted (several times if needed) and retested.

The non-treponemal serologic tests for syphilis (STS) fall into two broad categories, hemolysis and flocculation.

Hemolysis testing, most notably the Wasserman test, is where sheep red blood cells (sRBCs) are mixed with the cardiolipin solution, which results in the blood cells being "tagged" with the cardiolipin. Antibodies in the serum being tested cause the sRBCs to break down or "hemolyse" in a process known as complement fixation. This hemolysis is measured on a scale from zero to four depending on the measurement of free hemoglobin in the solution after all of the sRBCs have settled out. Syphilis patients can expect to remain at least weakly positive for the rest of their lives. Several modifications of Wasserman's original test were developed before hemolysis testing was superseded in the 1940s by the development of flocculation testing.

Flocculation tests, developed initially by Hinton, and further developed to the Venereal Disease Research Laboratory (VDRL) test, and then the Rapid Protein Reagin (RPR) test, are easier to perform, as well as both more sensitive and more specific than the hemolysis tests. These tests depend on antibodies cross-linking small particles that have been tagged with cardiolipin, resulting in the fluid changing from a smooth appearance to a clumpy one. The big difference between the VDRL and the RPR tests is that RPR substrates are cross-linked in such a way as to allow for testing without a microscope. Both of these tests can be used with serum dilutions to quantify the degree of infection (titration or "titer"), and a four-fold decrease in the titer (say from a dilution of 1 part serum to 32 parts of saline to 1 part serum to 8 parts of saline) indicates that the patient is recovering from the disease. The RPR test, in particular, is suitable for rapid screening of blood donations, as well as prenuptial and prenatal testing.

The VDRL test can be also used with Cerebral Spinal Fluid (CSF—fluid around the brain and spinal cord) obtained by a "spinal tap" for the diagnosis of and evaluation of treatment for neurosyphilis. This is needed because the blood brain barrier, especially if inflamed from infection, will not allow the passage of the antibodies we want the test to find. As a result, someone may have an active, life-threatening neurosyphilis but without active infection elsewhere in the body the serum tests may well be negative.

The basic serologic tests for syphilis will probably be within 1630's tech after 1633, as the public health authorities will be pressing for their urgent development, to secure the blood supply if for no other reason. I expect that the hemolysis type tests will be used only long enough to develop the easier to use flocculation tests, which should not take more than another year once the cardiolipin is isolated. I am working up a more detailed timeline on serology and blood banking, which will have more detailed information on this subject.

The other class of serological testing for syphilis either uses live treponema organisms (immobilization tests) or specific antigens derived from treponema (FTA-ABS, and TPHA), and are thus more sensitive and specific for treponemal infections. Because T. pallidum will survive in rabbits, and form lesions that can be "harvested" for live treponema, the treponemal immobilization test may be available in the 1633 time frame, but it is a time consuming (approximately a full day) and fairly complex test. As an interesting aside, it was noted prior to 1973 that rabbits infected with the milder organisms of yaws initially developed skin lesions consistent with that disease. However, as other rabbits were infected from the initial carriers, more invasive lesions, more consistent with syphilis were noted, adding to the early arguments for the Columbian theory. I do not expect the other specific tests to be available until 165x based on expected expansion of tech based on developments in this time line. Look for more details in the serology and blood-banking article.

 

Other laboratory tests

 

Dark field microscopy of scrapings from open sores will be an important diagnostic and confirmation test for quite a while in the 1630s. This requires a special condenser set (light source) on an otherwise standard laboratory microscope, a number of which should be at the high school biology laboratory. If the laboratory does not have dark field or phase contrast condensers, the descriptions in the various encyclopedias should be enough for up-time machinists and down-time lens grinders to manufacture those items in short order, even as early as late 1632. Some special staining techniques are available in this time line that allow a technologist with a conventional microscope to identify the treponemal organisms, but these are more suitable for pathologic specimens (surgical tissues, post mortem brain samples, etc). The dark field technique using wet preparations made from scrapings of chancres or sores in rashes needs to be done rapidly on fresh specimens. While this takes some experience on the part of the examiner, it is faster and easier than the special stains.

 

Treatment

 

Metallic treatments were the first treatments developed in OTL, with mercury being current in 1632. This type of treatment will be mostly bypassed in Grantville, but I expect that they will continue to be used by areas not able to initially support adequate production of antibiotics and not able to obtain stocks of antibiotics from elsewhere. Both metallic mercury and the inorganic salts of that metal were used as early as 1025 and are mentioned in Avicenna's textbook. It wasn't until Prof. Paul Ehrlich's collaborators developed Salvarsan (compound 606, as there were 605 other organic compounds of arsenic tested before hitting on the effective one) in 1906, the same year that Dr. Wasserman described his test for syphilis, that an effective treatment was developed. Refinement to the point of marketing the drug took another four years or so, and the drug was released in 1910. It is well within 1630's tech once the structure and up-time tricks of making it are known. Both of the metallic systems require long term (months to years) treatment for full effect. Additionally, while Salvarsan is much less toxic than mercury, both cause significant toxicity in humans, and both depend on treponema being more sensitive to the heavy metal poisoning than humans. A point raised by Iver Cooper is that the information on producing Salvarsan is limited in Grantville, and that, in this time line there were many problems with the conversion of the drug from the shipped form into a form that can be delivered to the patient through an IV. Based on his comments, and further reading on the subject, I now expect that penicillin will be available in quantity well before Salvarsan can be produced.

 

Pyrotherapy

 

It was known for some years by 1632 that the use of heat treatments along with mercury treatments seemed to slow the progression of advanced cases of syphilis. This was usually delivered by using a "steam cabinet" type of apparatus (enclosing the body, but leaving the head exposed) with a bowl of mercury in the cabinet. Additionally, deliberate infection with malaria, shown in 1917 to slow or even reverse the progression of neurosyphilis in OTL, won the Nobel Prize for Wagner-Jauregg in 1927. Given the up-time information of how malaria is spread, this treatment will also be well within 1630's tech by the end of 1632. Various forms of pyrotherapy may also be of use with antibiotics in severe cases. Support for this includes the rabbit shaving experiments, and the point that the tropical forms are much more indolent than syphilis was in the 1500-1630's time frame.

 

Antibiotics

 

Chloramphenicol will be the first reasonably safe treatment for syphilis in the 1630s. Easiest dosing is orally, but it can also be used intramuscularly (IM) or intravenously (IV). Dosages are 50 milligrams per kilogram of body weight per day (mg/kg/day) for moderate infections, up to 100 mg/kg/day for more serious infections. Total doses for adults are about 500-1000 mg per dose, four times a day. Interestingly enough, chloramphenicol may work better than penicillin for severe cases of neurosyphilis due to improved penetration into fluid around the brain (CSF). Due to factors involved in the metabolism of the drug in the liver and elimination of the drug through the kidneys, generally the preference of therapy is oral then IM, and then IV. Due to these same factors, the blood concentration of the IV medication is only about one third of the others. Syphilis can be expected to be sensitive enough that the course of therapy will be a few days to a couple of weeks at the most, compared to the months or years of the metallic compounds.

Penicillin is, in this time line, the definitive treatment for syphilis, especially for pregnant women. In early cases, primary or secondary, the treatment is a simple, one dose of Benzathine Penicillin LA (long acting), 1.2 million Units, usually given IM (in the buttock). Later cases, late secondary or tertiary, will need several doses over days to weeks of IV or IM treatment. Even today, T. pallidum remains exquisitely sensitive to penicillin, and as stocks of this drug increase, it will essentially replace all others for the treatment of syphilis, unless a patient is actually allergic to the drug. Even then, there are techniques of desensitization that can be used to allow appropriate treatment.

Probenicid is not an antibiotic itself, but by actions on the kidney, it reduces elimination of penicillin class drugs from the body, extending the effectiveness of the antibiotics and thus conserving the initial limited stores. Even after penicillin is freely available, Probenicid will continue to be used with oral forms to increase their effectiveness.

The tetracycline group and streptomycin, when available, will be the primary alternate treatments for syphilis infections, especially in non-pregnant penicillin-allergic patients. That availability will depend, however, on finding the appropriate species of Streptomyces, a soil organism of the Actinobacter group. Most of the tetracyclines can be given orally, but streptomycin is only given IM in this time line.

 

Complications of treatment

 

Frequently, a Jarisch-Herxheimer reaction will occur as the antibiotic kills the treponema. This is due to the release of cell components (endotoxins) that cause fevers, chills, malaise and rashes and is not an allergic reaction. This normally occurs within 24 hours of initiation of treatment and resolves within another 24 to 48 hours. The reaction occurs in 50% of treated primary cases and 90% of treated secondary cases, the more aggressive form of syphilis seen in the 1630s could be expected to cause even more significant reactions in an even higher percentage of the patients. Teaching the patients and their families to expect this problem will go a long way to prevent a significant scare reaction from the families, which would probably result in a nasty backlash.

 

Prevention

 

Prevention of disease in this time line (from the 1906 Wasserman test up to the 1940s widespread use of penicillin for treatment), by the consistent and widespread use of prenuptial and prenatal testing, went a long way to reducing the transmission of disease. "Safer sex" and the use of latex condoms do help prevent transmission, however, since syphilis can infect any area of the body that has been in contact with an active infection, antibiotic cure will be much more effective. I expect that the down-time authorities will be much more willing to use physical quarantine of syphilitics and other folks with chronic, incurable infectious diseases much more readily than has happened in this time line since the 1950s. I base this on laws such as the Scots Grandgore act of 1497, where known syphilitics were sent to the Island of Inchkeith for the rest of their lives.

 

Sequale of untreated disease

 

Untreated, chronic syphilis infections will result in bone, joint and soft tissue damage, at least partially from the body's reaction to the infection. About one case of six infections develop gummas, inflammatory masses which can cause pressure effects and damage to bones and joints as well as soft tissues. One of the classic situations results in damage to the bridge of nose, causing a "ski slope" curve to that organ. There can also be significant joint damage from loss of sensation as well as the mass effect. About one case in ten will develop heart and blood vessel damage as noted in Sherlockian canon (a syphilitic aortic aneurysm was a major plot point in "A Study in Scarlet"). In addition to marked aortic aneurysms (abnormal balloon like weakening of the largest blood vessel in the body), significant heart enlargement and heart failure is known to occur, and is a frequent cause of death in late stage syphilis. About one case in fifteen will end up developing neurosyphilis, with the resulting central loss of sensation as shown by tabes dorsalis and Argyll Robertson Pupils, and ending up with madness and general paresis if untreated.

Congenital Syphilis displays multiple problems including various birth defects as well as a marked increase in preterm births and miscarriages. This was more common prior to the advent of effective STS and treatment in the First and Second Worlds, and continues to this day in the Third World. The initial situation in the 1630s is most similar to that of the Third World today. Early congenital syphilis (age less than 2 years at presentation) may appear as an exaggerated secondary stage, with a rash, mucosal lesions and enlargement of the liver and spleen. Notched teeth (Hutchinson's incisors) and problems with walking due to loss of nerve function and eventually joint problems (Clutton's joints), show up in the first 18 months or so. A number of characteristic facial changes have been documented over the years, including enlargement of the forehead (frontal bossing), palate changes, and saddle nose. Eighth nerve damage resulting in deafness may be present in less than 5% of the cases. Fortunately, congenital syphilis may be prevented by treatment of the mother, which is the reason for the requirement for prenatal testing.

A number of prominent persons who are relevant to 1632 are suspected of having advanced syphilis, including Henry VIII, Ivan the Terrible, and Henry Stuart, Lord Darnley.

 

Gonorrhea

 

Unlike syphilis, the infective organism of gonorrhea, Neiserria gonorrhoeae, also known as the gonococcus, only infects specific types of mucus membranes, which makes it a bit easier to prevent. Other common names for the infection include "the clap," "the drip," and "the pipe bending pee pains." There are several forms of gonococcal infections, depending on the area of infection. These include female cervical, urethral, tonsillar, and rectal forms in both sexes. Men pass the infection to women at a rate of 50-70% per episode of unprotected vaginal intercourse, while the reverse rate is only about 25% effective per episode.

 

Diagnosis

 

Contact tracing is one of the most important forms in history for this infection. Since the majority of women have no history of problems with infection, finding contacts (female and male) of symptomatic males is of primary importance. Routine screening of women at the time of physical exam ("pap and pelvic" when those are resumed), finds many cases (of both gonorrhea and Chlamydia) in this time line. The most important presenting complaints in men involve a purulent (pus) discharge from the penis (approximately 90% of cases) and marked pain on urination (75-80% of cases). The pain has been described as "peeing broken glass," or "pipe bending." These symptoms start between 3 and 10 days after exposure. Roughly 10% of the male cases have few or no symptoms, and it is felt that these male cases contribute to the continued spread of the disease.

 

Physical findings

 

In men, the classic discharge can be demonstrated by "milking" the penis (after retracting the foreskin of uncircumcised males), and then obtaining a swab for Gram's stain and culture. Mild irritation to the meatal opening may also be noted. ...