- II. Diagnostic Approach
A. What is the differential diagnosis for this problem?
B. Describe a diagnostic approach/method to the patient with this problem
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- III. Management while the Diagnostic Process is Proceeding
- A. Management of Spirochete infections.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
Spirochetes are a group of six genera of spiral-shaped, slender bacteria of varying length. They are either free-living or host-associated. They are found in the human oral cavity, gastrointestinal tracts of humans, mammals, insects, and in marine environments. The most significant spirochetal infections for human disease are Borrelia burgdorferi (Lyme disease), also known as B. burgdoferi, the treponemes (syphilis and endemic treponematoses) and Leptospira interrogans (leptospirosis). They are all resistant to rifampin, and this is often used in microbiological isolation. Treponema are anaerobic, borrelia micro-aerophilic and leptospires aerobic.
Spirochetal diseases have remarkable similarities:
1. Portal of entry usually involves skin or mucus membranes.
2. They disseminate widely and early, via blood, tissue and body fluids, especially to cardiovascular, neurologic and skin tissues.
3. They lack surface proteins on their outer membrane. This helps them in immune evasion.
4. Neurotropic spirochetes enter the central nervous system (CNS)
5. T. pallidum and B. burgdoferi appear to lay dormant in the CNS until they activate. This makes therapy complicated. Leptospires and recurrent fever organisms appear not to lay dormant in the CNS, and therefore their therapy is more straightforward.
6. Spirochetal diseases occur in stages, with intervening latent periods.
7. Untreated infection may last in hosts from months to years.
Leptospirosis, relapsing fever (tick and louse-borne), endemic treponematoses and rat-bite fever will be reviewed in this section. Please see separate sections for syphilis and Lyme disease.
II. Diagnostic Approach
A. What is the differential diagnosis for this problem?
Leptospirosis - other bacterial infections (Q-fever, Ehrlichiosis, Rickettsiosis, plague, salmonellosis, brucellosis, tularemia, bacterial meningitis), viral infections (influenza, viral hepatitis, mononucleosis, hantavirus infection, Colorado tick fever, Dengue and other hemorrhagic fevers), protozoal infections (toxoplasmosis, Naegleria fowleri meningitis)
Relapsing fever - other tick-borne illnesses (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, rickettsiosis), viral infections (influenza, viral pleurodynia, viral meningitis/ meningoencephalitis), leptospirosis, other bacterial or viral meningitis, bacterial pneumonia, meningococcemia.
Endemic treponematoses - sexually transmitted syphilis, leishmaniasis, leprosy, skin cancers, bartonellosis, rat-bite fever
Rat-bite fever - other spirochetal diseases (Lyme disease, brucellosis, leptospirosis), protozoal infections (malaria), viral illnesses (Colorado Tick fever, yellow fever, Dengue), bacterial infections (brucellosis, bartonellosis).
B. Describe a diagnostic approach/method to the patient with this problem
The most useful diagnostic approach is a combination of carefully extracted clinical information to define the patient's clinical context, and judiciously ordered tests. Most tests in isolation do not provide a clear-cut plan of action, and may lead to inappropriate treatment or missed opportunities.
1. Historical information important in the diagnosis of this problem.
Potentially fatal zoonosis endemic in tropical regions
Wild and domestic animals serve as reservoir host but brown rat (Rattus norvegicus) is the most important for human infection
Risk factors include occupational (veterinarians, abattoir workers, farm workers, hunters, trappers, animal shelter workers, scientists), recreational (freshwater exposure), poor sanitation (epidemics seen after heavy rainfall and flooding)
Exposure to animals, especially rodents or to rodent urine
Abrupt onset fever/myalgia, headache, conjunctival suffusion and jaundice
Conjunctival suffusion and muscle tenderness especially in the lumbar areas and calves
Features of pulmonary-renal syndrome in a patient from an area endemic for leptospirosis
Fever, hepatitis or jaundice and renal failure occurring together without prominent leukocytosis
Hepatitis demonstrating only a modest transaminase elevation of less than 300 international units/liter (IU/L) with markedly elevated bilirubin; in viral hepatitides, transaminases may reach the thousands
Residence in or travel to endemic areas (western United States west of the Mississippi river, southeastern United States) and Canada, Africa and Asia
Characteristic fever pattern as described below
Myalgia, nausea/ vomiting, photophobia, conjunctivitis, meningismus, facial droop, pleuritic chest pain and hepatosplenomegaly in this clinical context
Chronic bacterial infection cause by yaws (Treponema pallidum subsp pertenue), bejel (T. pallidum subsp endemicum) and pinta (Treponema carateum)
Travel or residence in a developing country
Papules developing into plaques with regional lymphadenopathy and depigmentation
Destructive lesions to skin, bone and cartilage of the nose or legs in yaws
Mucus patches, skin papules, condylomata in a patient in a developing country who is unlikely to have had sexual contact (children)
Symptoms in animal handlers, pet owners, animal laboratory workers, or those living in rat-infested accommodation
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
Flu-like illness (fever, headache, myalgia) with or without conjunctival suffusion; jaundice, renal failure, myocarditis with arrhythmias and heart failure, meningitis/ meningoencephalitis, pulmonary hemorrhage with respiratory failure (multiorgan failure - Weil's disease).
Fever lasting 3-6 days, with an intervening fever-free period of up to 2 weeks. The fever may end in “crisis”. The “chill-phase” of the crisis is associated with fever of up to 41.5oC , delirium, agitation, tachycardia, and tachypnea and lasts 10-30 minutes. Followed by the “flush phase” characterized by rapid decrease in temperature and hypotension. Highest mortality is during or immediately after the crisis phase.
Yaws: highly contagious lesions “mother yaw” (large papillomoa or nontender ulcer on lower extremities, buttocks, arms, hands or face), in primary stage, “daughter yaws”, arthralgia, lymphadenopathy, nocturnal bone pain in secondary stage (weeks to 2 years), then skin, bone lesions and necrotic tissue destruction in tertiary stage (5 years or more).
Bejel: small, often overlooked, oropharyngeal papules in primary stage, painless oral ulcers, nocturnal bone, hoarseness, angular stomatitis, condyloma lata in secondary stage and destructive lesions of nose, nasopharynx, soft palate in latent phase.
Pina: non-ulcerating scaly plaque. No bone involvement unlike yaws and bejel.
Chills, fever, red or purple macular raised rash (75% cases), hemorrhagic vesicles, asymmetrical migratory polyarthralgia or arthritis usually of large joints, open wounds or sores at the site of animal bite, along with severe myalgia, fatigue, nausea, and vomiting.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
Serology in the appropriate clinical context. A positive test in itself is not proof of current leptospirosis. IgM antibodies can remain positive for several months. (a) Rapid screen - needs confirmatory testing by microscopic agglutination test (MAT) (see below) (i) Enzyme-linked immunosorbent assay (ELISA) for IgM - more readily available and more sensitive in early infection. (ii) Leptospira-specific immunoglobulin M by direct hemagglutination (iii) indirect hemagglutination assay for IgM and IgG antibodies. (b) Confirmatory test - microscopic agglutination test (MAT) is the gold standard. A titer of above 1:400 in the appropriate clinical context or demonstration of seroconversion or four-fold or greater rising titers with a second immunoglobulin assay test done approximately 14 days later.
Direct testing: (a) Culture isolation from aseptically collected blood, fresh (<2 hours old) clean urine or other body tissues is usually relatively slow. Collect specimens when patient is febrile and before initiating antibiotics. (b) Dark-field microscopy of blood, urine or fluid media in experienced operators. (c) Inoculation of experimental animals. (d) Polymerase chain reaction (PCR). (e) Immunohistochemical staining of biopsy samples.
Other non-specific findings: (a) Cerebrospinal fluid lymphocytic pleocytosis (usually <500/microliter), protein 50-100 milligrams/deciliter (mg/dL), normal or slightly low glucose. (b) Elevated transaminases (usually <200IU/L) with markedly elevated bilirubin.
Definitive diagnosis of tick-borne relapsing fever - direct observation of Borrelia spirochetes in a peripheral smear, bone marrow or cerebrospinal fluid (dark-field microscopy, Wright-Giemsa or acridine orange stained perparations). Samples best obtained during fever (70% have positive results).
Serum Borrelia specific antibody titers increase between acute (within 7 days) and convalescent (21 days). Unfortunately, serological testing is not standardized and false-positive tests for Lyme disease may occur.
Other less frequently used diagnostic methods include cultures (via animal inoculation or using Barbour Stoner Kelly medium) and PCR. Findings of normal or increased white blood cell count, elevated bilirubin, prothrombin and activated thromboplastin times, thrombocytopenia may be supportive of the diagnosis.
Mostly diagnosed clinically by experienced providers in the appropriate epidemiologic context. Confirmation may be made via:
Dark field microscopy of fluid specimens from lesions demonstrating characteristic chockscrew-shaped, spiral, thin organisms.
Positive syphilis serology – Rapid plasma regain (RPR) or venereal disease research laboratory (VDRL) at titers of above 1:4 confirmed with fluorescent treponemal antibody (FTA) absorption as in syphilis.
Amplification based methods in experimental stages.
Culture isolation of the bacteria (Streptobacillus moniliformis in United States or Spirilum minus in Asia) from skin, blood, joint fluid or lymph node tissue.
PCR or ELISA
Increasing titers of agglutinins
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Likely exposure, signs and symptoms consistent with leptospirosis, and positive serology confirmed with MAT or positive direct tests as above.
Direct observation of Borrelia spirochetes in peripheral blood, bone marrow or cerebrospinal fluid via dark-field microscopy, Wrige-Giemsa or acridine orange stains. Serology is not standardized.
Culture isolation or detection via PCR or ELISA. Rising antibody titers are diagnostic in the appropriate clinical context.
III. Management while the Diagnostic Process is Proceeding
A. Management of Spirochete infections.
1) A high index of suspicion is required.
2) In the appropriate clinical context, do not wait for confirmatory tests; obtain testing samples and start empiric therapy promptly.
3) Jarisch-Herxheimer reactions (fever, tachycardia, hypotension, dyspnea, rashes, myalgia) may occur with treatment and can contribute to mortality.
4) Initiate immediate supportive care (fluid management, renal replacement therapy, mechanical ventilation, etc.) as needed:
Severe leptospirosis - IV benzylpenicillin or ampicillin. 3rd generation cephalosporins (cefriaxone, cefotaxime) and quinolones may also be effective.
Less severe disease - oral doxycycline or tetracycline or amoxicillin.
Initiate supportive therapy with close monitoring especially in the first 4 hours after antibiotics are initiated, due to concern for a Jarisch-Herxheimer reaction which may be indistinguishable from a febrile crisis:
Seven day courses of antibiotics are usually adequate.
Choices include penicillin G, other beta-lactams (ceftriaxone), erythromycin, tetracycline, doxycycline or choramphenicol.
Intravenous penicillin G may be used in sicker patients.
In young children and pregnant women, tick-borne relapsing fever should be treated with erythromycin or IV penicillin.
Penicillin G benzathine, azithromycin, erythromycin, doxycycline and tetracycline.
Benzathine penicillin is the drug of choice. Late stage and early stages, as well as contacts of patients are treated with the same regimen. Those who are penicillin-allergic are treated with tetracycline or doxycycline for 14 days if greater than 8 years old, or erythromycin if less than 8 years old. Most patients get cured. Early lesions heal, late lesions stop progressing and RPR titers reduce.
Specific therapy needs to be prompt, otherwise mortality is upwards of 25%:
Penicillin G or V for 7 days, adults 400-600,000 IU/day IV penicillin G initially. Can be increased to 1.2million IU/day if no response
Streptomycin and tetracycline for penicillin allergic patients; Erythromycin has been associated with treatment failure
Doxycycline for 14 days
Benzylpenicillin 30 milligram/kilogram/dose (mg/kg/dose) up to 1.2 grams (g) IV every 6 hours for 7 days
Ceftriaxone 1g IV every 24 hours for 7 days
Ampicillin 0.5-1g IV every 6 hours for 7 days
Doxycycline 2 mg/kg/dose up to 100 mg oral (PO) every 12 hours for 7 days
Tetracycline 500 mg in an adult every 6 hours for 7 days
Amoxicillin 500 mg PO every 6 hours for 7 days
Erythromycin 12.5 mg/kg/dose up to 500 mg PO/IV every 6 hours for 7 days (14 days for endemic treponematoses)
Tetracycline 250 mg PO every 6 hours for 7 days
Penicillin G 600,000 IU IV daily for 7 days
Penicillin V 500 mg PO every 6 hours for 7 days
Benzathine penicillin 600,000 units intramuscular (IM) once (if < 10 years age) or 1,200,000 units IM once (if >10 years old)
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
Not identifying patients at risk promptly.
Delaying empiric therapy while waiting for confirmatory testing.
Falsely initiating therapy for leptospirosis while missing the alternative, also potentially fatal disease based on positive serology in patients without a history consistent with leptospirosis.
In some epidemics of the diseases listed under differential diagnoses, e.g., Dengue, concurrent leptospirosis may occur since it shares similar environmental risk factors. It may be missed when other diagnoses have been made, resulting in fatal outcomes.
Inadequate supportive therapy and monitoring during treatment
Inadequate supportive therapy and monitoring during treatment.
Failure to treat all household contacts of the patients.
In half of the patients, VDRL tests are falsely positive.
IV. What's the evidence?
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Sean, P. Elliott. "Rat Bite Fever and Streptobacillus moniliformis". Clin Microbiol Rev. vol. 20. 2007. pp. 13-22.
Hasin, T. "Postexposure treatment with doxycycline for the prevention of tick-borne relapsing fever". N Engl J Med. vol. 355. 2006. pp. 148.
MitjàO. "Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial". Lancet. vol. 379. 2012. pp. 342-7.
Giacani. "The endemic treponematoses". Clin Microbiol Rev. vol. 27. 2014. pp. 89-115.
Plank, R. "Overview of the epidemiology, microbiology, and pathogenesis ofleptospira spp. In humans". Microbes and Infection. vol. 2. 2000. pp. 1265-1276.
Adler, B. "Leptospira and Leptospirosis". Veterinary Microbiology. vol. 148. 2011. pp. 453-454.
Abela-Ridder, B. "Estimating the burden of human leptospirosis". International Journal of Antimicrobial Agents. vol. 36. 2010. pp. S5-S7.
Pappas, G. "The globalization of leptospirosis: worldwide incidence trends". International Journal of Infectious Diseases. vol. 12. 2008. pp. 351-357.
Palaniappan, R. "Leptospirosis: pathogenesis, immunity, and diagnosis". Current Opinion in Infectiouis Diseases. vol. 20. 2007. pp. 284-292.
Araujo, ER. "Acute Kidney Injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation". vol. 456. 2010. pp. 367-375.
Dellagostin, OA. "Recombinant vaccines against Leptospirosis". Human Vaccines. vol. 7. 2011. pp. 1215-1224.
Brett-Major, DM. "Antibiotic prophylaxis for leptospirosis". Cochrane Database of Systematic Reviews online. 2009.
Bharti, AR. "Leptospirosis: a zoonotic disease of global importance". The Lancet Infectious Diseases. vol. 3. 2003. pp. 757-771.
Lo, Y, Kintziger, KW, Carson, JH, Patrick, SL, Turabelidze, G, Stanek, D, Blackmore, C, Lingamfelter, D, Dudley, MH, Shadomy, SV, Shieh, W, Drew, CP, Batten, BC, Zaki, SR. "Severe Leptospirosis Similar to Pandemic (H1N1) 2009, Florida and Missouri, USA". Emerging Infectious Diseases. vol. 17. 2011. pp. 1145-1146.
Katz, AR, Buchholz, AE, Hinson, K, Park, SY, Effler, PV. "Leptospirosis in Hawaii, USA, 1999-2008". Emerging Infectious Diseases. vol. 17. 2011. pp. 221-226.
Evangelista, KV, Coburn, J. "Leptospira as an emerging pathogen: a review of its biology, pathogeneisis and host immune responses". Future Microbiology. vol. 5. 2010. pp. 1413-1425.
Kishimoto, M, Brown, JD, Chung, HH, Howman, S. "Leptospirosis Misdiagnosed as Pulmonary-Renal Syndrome". American Journal of Medical Science. vol. 328. 2004. pp. 116-120.
Meittes, E, Jay, MT, Deresinski, S, Shieh, W, Zaki, SR, Tompkins, L, Smith, DS. "Reemerging Leptospirosis, California". Emerging Infectious Diseases. vol. 10. 2004. pp. 406-412.
"World Health Organization, International Leptospirosis Society: Guidance for Diagnosis, Surveillance and Control". Human Leptospirosis. 2003.
Levett, PN, Mandell, GL, Bennett, JE, Dolin, R. "Principles and Practice of Infectious Diseases".
Hook, EW, Mandell, GL, Bennett, JE, Dolin, R. "Fulminant Leptospirosis (Weil's disease) in an urban setting as an overlooked cause of multiorgan failure". Principles and Practice of Infectious Diseases. 2011.
Nsanze, H, Lestringant, GG, Ameen, AM, Lambert, JM, Galadari, I, Usmani, MA. "Serologic tests for treponematoses in the United Arab Emirates". International Journal of Dermatology. vol. 35. 1996. pp. 800-801.
Koff, AB, Rosen, T. "Nonvenereal treponematoses: yaws, endemic syphilis, and pinta". Journal of the American Academy of Dermatology. vol. 29. 1993. pp. 519-535.
Meheus, A, Antal, GM. "The endemic treponematoses: not yet eradicated". World Health Organization Statistics Quarterly. vol. 45. 1992. pp. 228-37.
Englekens, HJ, Vuzevski, VD, Stolz, E. "Non-venereal treponematoses in tropical countries". Clinics in Dermatology. vol. 17. 1999. pp. 143-152.
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