Chlamydia are small Gram-negative cocci and are intracellular parasites. All three species; psittaci, pneumoniae, and trachomatis can cause respiratory tract infections. C psittaci and pneumoniae infections are more frequently found in older children and adults. C trachomatis is usually associated with ocular and genital infection as well as neonatal pneumonia. It rarely causes respiratory tract infections in normal healthy adults. The genus chlamydia comprises of 3 species - C psittaci, C trachomatis and the TWAR agent. C trachomatis is the most common member of the ch
lamydia genus known to infect man and is most common transmitted by the sexual route; an animal reservoir is not recognized. C psittaci is a zoonotic infection where avian species are the main natural hosts and man becomes incidentally infected. The TWAR agents were considered to be more closely related to C psittaci but now appears to be a single distinct species with no recognized animal reservoir.
Chlamydia_Psittaci
Human C psittaci infection acquired from psittacine birds (parrots) is termed psittacosis. It is called ornithosis when contracted from other sources. These terms can be unhelpful, particularly when patients with proven C psittaci infection have no known bird or animal contact. C psittaci infection can be acquired from pet birds and also turkeys and ducks. There had been outbreaks associated with duck processing plants.
The incubation period is usually 7 to 10 days. Patients present with a rapid onset of headache, chills, fever and non- productive cough. All patients with community acquired pneumonia should therefore be questioned about recent foreign travel and bird contact. Respiratory symptoms can be absent and these patients may often present with CNS features. Infection may also be associated with other extrapulmonary manifestations such as abdominal pain, vomiting, headache, myalgia, fever, hepatitis, endocarditis and Stevens-Johnson syndrome.
Chlamydia_Pneumoniae
Previously known as TWAR agents (Taiwan acute respiratory). Serological studies indicate that all C pneumoniae strains are very closely related and genetic studies have shown that they have more than 94% DNA homology with each other but less than 10% homology with the two other chlamydial species. The REA patterns of C pneumoniae isolates are similar to each other, but distinct from other chlamydial species. C pneumoniae infections are distributed worldwide and 20 to 70% of adults have serological evidence of previous infection. Infection is usually acquired by the respiratory route. C pneumoniae is rare in children less than 5 years of age and is most frequently found in schoolchildren and adults. Epidemics occur every few years. 70 to 90% of C pneumoniae infections are subclinical and reinfection may occur. C pneumoniae produces similar clinical symptoms to mycoplasma pneumoniae and respiratory viruses. There are reports linking C pneumoniae to myocardial and endocardial disease.
Laboratory_Diagnosis
1. Serology - the CFT is the most widely used method for diagnosing chlamydial infections in the UK. A result of 256 or more is consistent with are recent infection. The micro-immunofluorescence test can be used to distinguish between C psittaci and C pneumoniae species, as is the whole cell-inclusion immunofluorescence test.
2. Culture - all chlamydial species can be grown in cell culture. Extreme care must be exercised with respiratory samples as C psittaci is a category 3 pathogen. C pneumoniae is the most difficult species to grow.
3. Antigen detection - antigen detection techniques have been widely used to diagnose adult genital and ocular infections and neonatal C trachomatis infection. At present, sputum samples are not routinely submitted for chlamydial diagnosis. Some commercial assays can be used to detect chlamydia in sputum samples.
4. PCR - increasing importance is being placed on molecular techniques to diagnose respiratory chlamydial infections accurately, because of difficulties in interpreting serological results and the problems associated with culture of C pneumoniae.
Treatment
Patients with symptoms of lower respiratory tract infection and evidence of chlamydial disease are usually treated with tetracycline or erythromycin.
Chlamydia_Trachomatis
The chlamydia genus are antigenically diverse, possessing species, subspecies and type-specific antigens but share a common genus-specific lipopolysaccaride antigen (LPS). Within the C trachomatis species, numerous serotypes are recognized.
Serotypes Disease Complications
A-C Trachoma
1-3 Lymphogranuloma venerum
A-K
Male Non-gonococcal urethritis (NGU) Epididymitis
Post-gonococcal urethritis (PGU) Reiter's
Conjunctivitis sexually acquired
Proctitis arthritis (SARA)
Female Mucopurulent cervicites Salpingitis
Urethritis Perihepatitis
Conjunctivitis Endometritis
Proctitis Infertility
Ectopic Pregnancy
Neonates Conjunctivitis Pneumonia
C trachomatis (D-K) cause occulogenital infection and primarily infect the epithelium of the male urethra and the female cervix and urethra. Symptomatic genital infection, presenting as an urethritis, is common in males. Asymptomatic infection in females is much higher, with a reported incidence of approximately 60% in some groups.
A._Genital_Infection_in_Men
Genital C trachomatis infection in men usually presents as an urethritis which may occur concomittantly with a gonococcal infection.
Non-gonococcal_Urethritis_(NGU)
Non-gonococcal urethritis accounts for more than 100,000 cases reported each year by GUM clinics in England and Wales. It is estimated that 30 - 58% of these NGU cases are attributable to C trachomatis infection.
Post-gonococcal_Urethritis_(PGU)
This syndrome occurs in patients who have been infected with both N gonorrhoeae and C trachomatis. As antimicrobial therapy for N gonorrhoeae does not eradicate C trachomatis, post-gonococcal urethritis results from the replication of C trachomatis in the urethra. Isolation of C trachomatis in patients with N gonorrhoeae treatment ranges from 17.5 to 32%. In contrast, the detection rate of C trachomatis in patients treated for N gonorrhoeae infection with urethritis ranges from 38 to 88%.
Complications
A number of complications can arise following infection with C trachomatis. These include epididymitis, Reiter's syndrome, sexually acquired reactive arthritis (SARA), and possibly endocarditis.
There is convincing evidence that epidymitis in younger men (<35) is associated with C trachomatis infection and the organism has been demonstrated in epididymal aspirates. Approximately 50% of the estimated 500,000 annual cases of acute epididymitis in the United States are caused by C trachomatis infection.
The classical triad of Reiter's syndrome comprises of urethritis, conjunctivitis and arthritis. In Asia and Africa, it is primarily related to GI infections but whereas in North America and Europe, it is recognized as a sexually-acquired syndrome following C trachomatis infection. This syndrome is more common in males than females.
B._Genital_Infection_in_Women
In contrast to C. trachomatis infections in males, infection in the female is commonly asymptomatic. However, the consequences of female infection are far more serious. The organism infects and replicates within the epithelium of the cervix and urethra. An ascending infection with involvement of the upper genital tract can result in clinical or subclinical pelvic inflammatory disease (PID), presenting as endometritis, salpingitis or a perihepatitis (Fitz-Hugh Curtis Syndrome). Tubal damage may occur which may lead to infertility and ectopic pregnancy. C. trachomatis is the most important cause of PID in the developed world accounting for 25% - 50% of the one million cases in the U.S.A.
C. trachomatis is recovered from the cervix in 12% - 31% of women attending GUM clinics in the UK. The majority of infections are asymptomatic but C trachomatis has an important role in mucopurulent cervicitis. The recovery of C trachomatis from the cervix of pregnant women attending family planning clinics in the UK is much lower (3%), but is epidemiologically important in the light of the neonatal infections which occur at delivery. C trachomatis has been recovered from the cervix in 10% - 16% of women undergoing termination of pregnancy. This indicates the need to screen women prior to termination of pregnancy if PID following termination is to be avoided.
In addition to cervical infection in women, C trachomatis has also been isolated simultaneously from the urethra. In some cases, C trachomatis can also be isolated from the urethra only. The "acute urethral syndrome" presents as dysuria and frequency and occurs most commonly in young sexually active females.
Pelvic_inflammatory_Disease
C. trachomatis is the most important cause of PID in the Western world and the organism has been recovered from the cervix in 31% of cases. Canicular spread of C trachomatis from the lower genital tract gives rise to symptomatic or subclinical salpingitis. Definitive evidence for the role of C trachomatis in salpingitis has been demonstrated by the direct isolation of the organism from the fallopian tubes in 5% to 30% of women but not from the fallopian tubes of women without salpingitis. Risk factors for PID include the use of an IUD as well as termination of pregnancy in sexually active young women.
Infertility
The consequence of tubal damage may be infertility and the role of C trachomatis is now well recognized. Attempts to demonstrate C trachomatis in the endocervix of infertile women are usually unsuccessful because tubal damage has often occurred years earlier but serological tests are thought to be useful
Perihepatitis
N gonorrhoeae is well established as a cause of acute perihepatitis (Curtis-Fitz-Hugh Syndrome). Women present with right sided upper abdominal pain. There is now good evidence that C trachomatis is also involved. The precise incidence of this syndrome is unknown. The recovery of C trachomatis from endocervical swab is suggestive but not conclusive evidence of perihepatitis and treatment should nonetheless be instigated.
C._Conjunctivitis
Ocular infections caused by C trachomatis are common in sexually active individuals. Usually infection presents, after an incubation period of 1-2 weeks, as a follicular conjunctivitis which may be clinically indistinguishable from a viral infection. Laboratory diagnosis is essential to identify the causative agent.
D._Neonatal_Infection
The risk of neonatal infection at delivery may be more than 50% for pregnant women with active cervical infection. The most common clinical manifestation is neonatal conjunctivitis, which usually presents between the third and thirteenth day of life. The severity of the conjunctivitis may range from a mild "sticky eye" to severe inflammation and discharge and closure of the eye. Chlamydial opthalmia neonatorum is considered to be 3 to 5 times more common than gonococcal opthalmia neonatorum in the U.K. An untreated neonatal infection may lead to a severe pneumonitis between the fourth and twelve weeks of life.
Laboratory_Diagnosis
1. Cell Culture - cell culture is regarded as the "gold standard" for the detection of C trachomatis infections. Recent techniques attain a sensitivity rate of 80 - 90%. However, cell culture techniques are costly and time consuming and should be limited to certain high risk populations or for medical-legal purposes such as the investigation of rape cases.
2. Detection of Antigen - these tests are based on the use of monoclonal antibodies against C trachomatis. monoclonal antibodies had been produced against the genus specific LPS or the species-specific major outer membrane protein (MOMP). LPS monoclonal antibodies will react against C psittaci, TWAR and C trachomatis antigens, while the MOMP antibodies will react with C trachomatis only.
a. Immunofluorescence Techniques - IF techniques are subjective. The MOMP antibodies will only stain the elementary bodies. In contrast, genus-specific monoclonal antibodies react with both elementary bodies and genus specific LPS. Experience with these monoclonal antibodies has shown that cell-free LPS in addition to EBs is common in clinical samples. The LPS antigen is considerably smaller and more variable in size than EBs and thus more experience is required than with the species-specific antibody.
In general, genus-specific monoclonal antibodies are suitable for the diagnosis of C trachomatis conjunctivitis, where intracellular inclusions are readily visible as well as cell free EB s and LPS antigen. However, specimens from GUM clinics often possess a higher background of stainable material and thus in consequence are harder to interpret by IF. Because of this, species- specific monoclonal antibodies are more suitable for the examination of urethral/endocervical smears.
IF techniques are subjective and tiresome. However, they are suitable for the "one off" sample or for the examination of smears from patients with conjunctivitis, including neonates, where a definitive diagnosis can be made within one hour of receipt of the sample.
Enzyme_Immunoassays
These assays are gaining favour for the large scale screening of populations for C trachomatis infection. An interesting observation made with some of these enzyme-immunoassays is the lack of correlation between optical density readings and the number of C trachomatis inclusions detected in cell culture when comparative studies are carried. In particular assays which incorporate a genus-specific monoclonal antibody. This can be readily explained by the presence of cell-free LPS in the clinical samples.
10 different species of mycoplasma have been isolated from the human respiratory tract of which most are commensal organisms. Only M pneumoniae has been unequivocally linked to human respiratory tract disease. M pneumoniae is the most important cause of primary atypical pneumonia.
Clinical_Features
M pneumoniae is primarily a pathogen of the human respiratory tract, where it causes a range of illnesses from mild URTI to pneumonia. The most frequent manifestation is tracheobronchitis which is seldom recognized by clinicians as an indicator of M pneumoniae disease.
Patients characteristically presents with a sore throat, headache and fever. A non-productive cough of increasing severity follows. Pneumonia developed in 3 - 10% of patients and in epidemic years is responsible for approximately 20% of community-acquired pneumonias. M pneumoniae pneumonia usually has an insidious onset and is clinically indistinguishable from that caused by a range of organisms such as C psittaci, C pneumoniae and Legionella. Clinical signs of consolidation is unusual although X-ray often show extensive shadowing. The pneumonia is usually unilateral, affecting one of the lower lobes although bilateral and multilobe involvement is seen in 20% of patients. The course of the disease is variable but is often protracted, with a persistent cough being a common feature, along with relapses. 25% of M pneumoniae infections are asymptomatic. Complications include the following
1. CNS and PNS disease eg. Guillain-Barre
2. Myalgia
3. Erythema multiforme
4. Stevens-Johnson syndrome
5. Arthritis
6. Haemolytic anaemia
7. Hepatitis
8. DIC
9. Myringitis
These complications arise with varying frequency with haemolytic anaemia, Stevens-Johnson syndrome and neurological complications being found most frequently.
Epidemiology
M pneumoniae infections are found worldwide and arise in epidemics which last 1 to 2 years and occurs every 4 to 6 years. During epidemics, the frequency of infection may be 3 to 10 times that seen in non-epidemic periods. M pneumoniae infections occur most commonly in children aged 5 to 10 years, less in older children and young adults. Asymptomatic infections are found most frequently in children under 5 years of age and pneumonia is found most frequently in children between 5 and 15 years. M pneumoniae reinfections are relatively common. Naturally-acquired immunity to infection is of limited duration.
Laboratory_Diagnosis
1. Culture ;- M pneumoniae isolation is performed routinely in only a few laboratories. The most common method is to inoculate throat swabs (in virus transport medium) or sputum (mixed with an equal volume of N-acetyl cysteine to promote mucolysis) on to solid and liquid media. Plates are incubated at 37oC in 5% CO2 in nitrogen and examined at 3-4 day intervals for 3 weeks. Colonies are subcultured and confirmed as M pneumoniae by means by growth inhibition tests employing filter paper discs impregnated with M pneumoniae antiserum. Broth cultures are incubated at 37oC for 3 weeks. The disadvantage of isolation is that culture and identification may take 10-14 days. Isolation on its own is not a wholly reliable diagnostic procedure since M pneumoniae can be isolated from symptom-free individuals and is known sometimes to exist as an commensal organism in man.
2. Antigen Detection ;- Several techniques have been used to demonstrate M pneumoniae antigens in tissue or body fluids such as immunofluorescence and ELISAs. These ELISAs detected M pneumoniae in 90% of the samples from which the organism was isolated and M pneumoniae antigen was found in 43% of samples from patients with serological evidence of recent infection but from which M pneumoniae was not cultured. DNA probes have been developed for the detection of M pneumoniae DNA in clinical specimens. Although the probe method is sensitive, specific and rapid, it is labour-intensive, expensive.
3. Antibody Detection ;- Many methods have been employed for the detecting M pneumoniae antibodies in human serum. Methods used for the detection of rising titres of IgG are suitable for patients of all ages. However, methods used for detecting IgM are more suitable for use in younger patients, since IgM is found less frequently in patients experiencing re-infection (hence older patients).
CFT is the mainstay of routine laboratory diagnosis of M pneumoniae infections. However, antibodies may not be detected by this method 7-10 days after the onset of symptoms and not all culture-positive patients develop CF antibody or a significant rise in titre. It is also very difficult to determine the significance of CFT titres obtained with single samples of serum, unless they are very high. Such high titres can be found many months after infection and so particularly in the months following periods of high incidence of M pneumoniae infection. Demonstration of a fourfold or greater rise in antibody titre is required to be reasonably sure of the diagnosis.
Q fever was discovered about 50 years ago in Brisbane, where an outbreak occurred among workers in a meat processing factory. The disease was named Q (query) fever, and the organism isolated was a rickettsia named Coxiella burnetti. Q fever has a worldwide distribution and is the manifestation of overt infection by C burnetti; subclinical infections are common. The majority of cases occur in men of working age, but may occur in either sex and at all ages. C burnetti is a zoonotic infection affecting chiefly cattle, sheep, and goats, but has been found in a large number of species of animals and birds. Although it has also been isolated from various species of ticks, the role of these insects in the spread of the disease is not clear. Human infections generally result from the inhalation of infected aerosols, arising particularly from the products of conception of cattle or sheep, but it is possible that raw milk from infected cows may be responsible for human infections.
The_Causative_Organism
C burnetti can be cultured in the yolk sac or monolayers of chick embryo cells, and by the intraperitoneal inoculation of many species of laboratory animals. It has been isolated from the sputum of patients suffering from pneumonia, from infected heart valves from cases of endocarditis, and from the milk of infected animals. The inoculum is injected into the yolk sac of a hen's egg or intraperitoneally into guinea-pigs. The organism can be demonstrated in infected yolk sacs by making impression smears and staining with a Romanovsky stain. After intraperitoneal inoculation of a guinea-pig, antibodies develop which can be detected 2-4 weeks after injection by CFT or other tests. C burnetti has been associated with many laboratory infections and stringent safety precautions should be observed.
C burnetti undergoes a phase variation somewhat akin to the smooth-rough variation observed in many bacteria. The smooth hydrophilic organisms in phase 1 are stable in suspension and not phagocytosed in the absence of specific antibodies. After repeated passage eg. in yolk sac, they become rough, hydrophobic and agglutinable. These readily phagocytosable organisms are in phase 2. When phase 2 organisms are inoculated into laboratory animals, they rapidly revert to phase 1. Phase 1 organisms are virulent for guinea-pigs, whereas those in phase 2 are avirulent. In the great majority of cases of Q fever, antibodies are produced only against phase 2 antigens. In chronic Q fever, antibodies are produced against both antigens.
Acute_Q_Fever
C burnetti infection often gives rise to Q fever although inapparent infections are common. The acute disease is more common in men than women and varies from a trivial febrile illness to a full-blown pneumonia which may be fatal. After an incubation period of 2-3 weeks, a flu-like illness commences with a severe headache, arthralgia, shivering and anorexia. In some cases, the fever subside after 2 or 3 days and the patient recovers. In other cases, the illness progresses and a cough develops. The chest X-ray often shows one or more areas of opacity. The diagnosis is made serologically by the demonstration of a rising titre of antibody in paired sera against the phase 2 antigen of C burnetti. Treatment is symptomatic only but in severe cases, tetracyclines may be given.
Chronic_Q_Fever
1. Endocarditis ;- this is the most common manifestation of chronic Q fever, amounting to 11% of 839 cases of Q fever in one series in England and Wales. C burnetti causes 2-3% of all cases of infective endocarditis in England and Wales. Q fever endocarditis usually presents in men of working age. In the majority of cases, it is not possible to elicit a history of Q fever but this may be due to the fact that the period between infection and the development of endocarditis is very variable and may be as long as 20 years. There is usually a history of previous valvular damage or abnormality. The onset is insidious and the patient presents with signs and symptoms of chronic or subacute endocarditis, usually involving the aortic valve, though the mitral valve may also be attacked. Q fever endocarditis is often diagnosed as "blood culture negative endocarditis" and thus it is important to test all such cases serologically against phase 1 and phase 2 antigens of C burnetti. Untreated disease results in severe valvular destruction, leading to increasing heart failure. Embolic phenomenon are also common.
2. Hepatitis ;- many patients suffering from Q fever endocarditis have abnormal liver function tests without overt evidence of hepatitis, though some develop hepatomegaly. Granulomata and increasing fibrosis may be seen which may rarely lead to cirrhosis.
3. Glomerular Nephropathy ;- haematuria has been described in many cases of chronic Q fever. 3 cases of endocarditis complicated by glomerular nephropathy had been reported from Spain.
4. Osteomyelitis ;- this has occasionally been observed.
5. Thrombocytopenia ;- this was reported in 12 out of 16 patients in one series, six of whom had purpuric rashes.
6. Encephalitis ;- a case of endocarditis complicated by encephalitis had been described.
Diagnosis
The isolation of the organism is not practicable in the majority of laboratories and is less certain and more time-consuming than serology. CFT is the most widely used test but IF and ELISA techniques are also used. In acute Q fever, phase II antibodies are always present whereas phase I antibodies are usually transient and of low titre. In chronic Q fever, phase I antibodies are always present and are often very high. Phase II antibodies are usually present also, often at a considerably higher titre than phase I antibodies. A single serum is usually sufficient to produce the diagnosis; rising titres are rarely found in chronic infections. The differences in antibody responses between acute and chronic infections may be because the phase II antigen is more superficial, or perhaps because in chronic infections, organisms persist in phase I. There has been much discussion about diagnostic levels of phase I antibody in chronic Q fever. Serological tests differ in sensitivity from laboratory to laboratory but most authors accept a phase I CF titre of 1:200 or more as diagnostic of chronic infection.
Management
The prognosis of Q fever endocarditis is highly variable. There had been many reports of fatal cases. Some patients die within a few months despite appropriate antibiotic treatment. However, most patients respond satisfactorily to antibiotic therapy but treatment needs to be kept up for a long period or even for life. Tetracyclines are the mainstay of treatment, either alone or in combination with other antibiotics. There has been controversy over the duration of antibiotic therapy; some authors suggest that treatment should be continued indefinitely, while others suggest that treatment should be for periods of at least 12 months, or until there is clinical evidence of resolution of endocarditis or the phase I CF antibodies have fallen below 200. Each patient should be treated individually. Patients should be warned that antibiotic treatment should continue for at east 2 years or more. Surgical replacement valves is indicated where the valves are severely damaged. However, numerous cases of infection of prosthetic valves have been recorded.
The majority of cases of acute Q fever do not require follow-up. They make a rapid clinical recovery with or often without tetracycline treatment. Some of the more severe cases require more careful consideration especially if complications such as myocarditis, hepatitis, encephalitis or haemolysis are seen. In these cases, as well serological testing for phase II antibodies, tests should be carried out for phase I antibodies. Rarely, the antibody persists for months without any signs of chronic infection. To date, little is known about the development of chronic Q fever following the acute attack, and it is not possible to postulate any predisposing factors which may lead to the development of chronic disease. However, f a patient suffering from a valvular abnormality of the heart develops Q fever, this is clearly an indication for thorough and probably prolonged antibiotic therapy and follow-up.