by Eric Flint
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 ph
ysical 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. Few other signs or symptoms are noted in otherwise uncomplicated infections. More serious cases may present with swelling or tenderness of the scrotum, indicating that epididymus (part of the tube between the testicle and the urethra) has become inflamed, either from the gonococcus or from a concurrent infection with another STI.
In women, there may be a similar purulent discharge from the cervix, from the urethra or from one or more of the various accessory glands of the female genitalia. Again, in mild disease, there may not be any other significant findings.
Concurrent infections of gonococcus and Chlamydia (see below) are so common that if there is evidence of one type of infection, treatment for both should be undertaken.
Laboratory findings
Classically, the discharge from the afflicted male's urethra is stained using Gram's technique, and show small, paired cocci (round bacteria), that are actually inside the white blood cells. If the female has a urethral discharge, it will be useful to Gram stain that material. However, because of the wide variety of normal bacterial flora in the throat, vagina and rectum, trying to stain material from those areas looking for these bacteria is useless.
If there is a suspicion of an infection, a quick microscopic examination of the patient's urine using a technique sometimes called a "split stream specimen," where two and sometimes three specimens are collected from a single urination, has the ability to quickly screen for a number of different urinary tract infections in both men and women. The specimens are obtained from the first, middle, and occasionally the final part of the urine stream. Part of each specimen is centrifuged to concentrate any pus, bacteria and/or sediment, and another portion is reserved for culture if indicated. If there are a large number of white blood (pus) cells in the initial urine specimen, but not in the middle or last parts, then urethritis is the most probable diagnosis. Pus in the middle portion of the specimen indicates an acute bladder infection, and pus, especially associated with certain types of crystals, in the last portion of the specimen can indicate chronic bladder or kidney problems. Gram's staining of the uncentrifuged second portion of the specimen can help different the different kinds of bladder infections, and offer predictions as to what the urine culture might be expected to show.
The use of urine screening to help decide further testing is used frequently in this time line, admittedly mostly with urine dipsticks. It is well documented as a technique, and has the advantage of being relatively simple, fast and available at the point of care. While not commonly used as such in this time line, it can be used as a quick test of cure after treatment (supplementing repeat cultures), something that will help prevent missed relapses or reinfections. Clearing of the discharge in both men and women is a good indicator of cure.
Cultures
A sterile swab or wire loop is used to transfer a small portion of the discharge or urine onto so-called "chocolate Agar" in order to make a more definite diagnosis. Chocolate agar is classically made by the addition of sheep's blood to a standard agar mixture and then slowly heating the mixture to 56 degrees C before making the plates. The antibiotics added to chocolate agar to make the more specialized Thayer Martin agar will probably not be available until the mid-1640 time frames, which means one or more repeat "sub cultures" might need to be made to finish making the diagnosis.. After swabbing the material on the plates, the plates are placed in a sealable jar, a lit candle is placed in the jar and the jar is sealed. The candle will snuff itself out in a few minutes, leaving an atmosphere that is moist and enriched in carbon dioxide at the expense of the oxygen in the jar. This "candle jar" technique is essential in preferentially promoting the growth of Neiserria species over most other bacteria. There are several other tests that will need to be made on the isolated bacteria to confirm t
he diagnosis, including the oxidase, and peroxidase tests; and sugar fermentation studies, but those tests are all within the capability of 1630's tech, as they were developed in the 1900-1930 time frame.
Treatment
Chloramphenicol will probably be the first line of treatment until adequate stores of penicillin are available. In this time line, the gonococcus was one of the more active bacteria in developing antibiotic resistance, perhaps second only to the common Staphylococcus. It was less than twenty years between the introduction of penicillin treatment for gonorrhea and the first cases of resistant forms being found during the Southeast Asian Conflict. This was as much due, like most bacterial development of resistance, to incomplete treatment with, inadequate dosages of, and/or inappropriate use of antibiotics. The use of probenicid will reduce the chance of resistance developing by extending the time that there is an effective concentration of penicillin class drugs in the system, and allows the use of either IM or oral penicillin or amoxicillin. When available, an advanced cephalosporin may also be used to treat the gonococcus, however, follow up with a tetracycline class drug is also needed to treat the common Chlamydia co-infection.
Silver nitrate or chloramphenicol eye drops at birth will prevent a possibly blinding infection called opthalmalagica neonatorum.
As noted above, the first resistant strains were noted in the 1960s, and the frequency of antibiotic resistance has continued to increase ever since, probably due to under treatment of gonorrhea in Third World countries. There will be public health efforts to combat this with a combination of more aggressive case tracking, an emphasis on adequate initial treatment, and follow up visits for test of cure.