Chlamydophila pneumoniae is important in the differential diagnosis of Lyme disease because it can cause nervous system disorders, myocarditis and reactive arthritis.

Chlamydias have special microbiological characteristics. The size of the pathogen is very small compared to other bacteria. Reproduction occurs within host cells and the pathogen is dependent on host cell ATP as it is not capable to produce its own. The pathogen exhibits two phenotypes, the elementary bodies and the reticulate bodies. The elementary bodies can exist extracellularly and represent the infectious form. Reproduction of the elementary bodies is only possible inside of host cells. Host cells phagocytize the elementary bodies, which intracellularly transform into reticulate bodies and undergo division. The elementary bodies are thus infectious, and the reticulate bodies reproductive. Some reticulate bodies can change back into elementary bodies, which are released subsequently to host cell lysis. The released elementary bodies infest then further host cells. Consequently, precondition for an adequate treatment is both the intra- and extracellular efficacy of the antibiotic. This is the case for tetracyclines and macrolides (Table 6).

The primary disease manifestation of Chlamydophila pneumoniae is pneumonia. The incidence is 1% and predominantly affects people older than 65 years [105,106]. The pneumonia is frequently accompanied by infections of the upper respiratory tract (pharyngitis, laryngitis, sinusitis). An initially slight disease expression, extrapulmonary manifestations [107] and a normal leukocyte count indicate atypical pneumonia, suggestive of Chlamydophila pneumoniae infection. Extrapulmonary manifestations include nervous system disorders including Guillain-Baré syndrome and meningoencephalitis, as well as reactive arthritis and myocarditis, which are significant with regard to the differential diagnosis of Lyme disease or Lyme neuroborreliosis.

The extrapulmonary manifestations frequently extend across a long period of time, i.e. through months or years. This also applies to the so-called reactive arthritis, whose differentiation from Lyme disease arthritis is sometimes difficult. Attention should also be paid to Guillain-Barré syndrome, which can last for months, and with a similar manifestation to that observed in Lyme disease. The association with a myocarditis is also similar, whereas meningoencephalitis occurs in the acute phase, almost simultaneously with pneumonia.

The chronic course of Chlamydophila pneumoniae infections is documented by several studies [108-114]. A relationship to Chlamydophila pneumoniae was also described in Alzheimer’s disease [115]. This finding is of importance with regard to chronic Lyme neuroborreliosis, for which the same associations have been demonstrated [116-119].

The laboratory diagnosis for Chlamydophila pneumoniae includes serology, the lymphocyte transformation test (LTT), and the detection of the microorganism using PCR.

The serological tests have severe inherent limitations. There is a considerable discrepancy between the serological findings, on the one hand, and pathogen detection using PCR, on the other hand [120,121]. A single test for IgG has a low sensitivity [122], whereas the sensitivity is quite good in cases of a definite increase in IgG between the acute phase and the further course of the disease. The diagnostic value of LTT for Chlamydophila pneumonia has not yet been validated in the literature. The chronic disease course obviously represents a chronic persistent infection. Chlamydophila pneumoniae could be detected both in the synovial fluid and in the liquor using PCR [108-110,113,114].

Antibiotic treatment of Chlamydophila pneumoniae is given in Table 6. The drug of choice is doxycycline; macrolides also exhibit good efficacy, particularly azithormycin; quinolones have a low efficacy [123], however, gemifloxacin has proven to be very effective [124].

The variable microbiological appearance of Chlamydia trachomatis is similar to that of Chlamyophila pneumoniae, described above. That the infectious form of Chlamydia trachomatis is present both intra- and extracellularly is decisive with regard to the efficient antibiotic treatment of the disease.

Chlamydia trachomatis is sexually transmitted and causes urogenital infection. The differential diagnostic problem with respect to Lyme disease results primarily from chronic arthritis, which is caused by persistent infection in both diseases. In Chlamydia trachomatis infection, this chronic arthritis is assigned to the so-called reactive arthritis even though that in some studies the pathogen was detected in the synovial fluid, which indicates persistent infectious arthritis [125,126]. Arthritis occurs in 1% of the cases with Chlamydia trachomatis urethritis. Reiter’s triad (arthritis, uveitis, urethritis) occurs in only 0.3% of the affected patients.

The disease can be easily detected by laboratory diagnostic tests in cases of existing urogenital infection. Nucleic acid amplification techniques (NAATs) for urethral smear or urine are available, which are also reliable for asymptomatic patients [127-129]. PCR has also a high sensitivity and specificity [130]. The diagnostic value of the serology and LTT has not yet been validated. Moreover, whether a chronic infection with Chlamydia trachomatis can be accompanied by seronegativity, as in Lyme disease, has not been clarified. Seropositivity can provide evidence of a previous infection, but does not allow conclusion with regard to a persistent infection with Chlamydia trachomatis. Theoretically, persistent or reproducible pathological LTT indicates prolonged infection, but scientific data for the diagnostic value of LTT are not yet available.

Treatment of Chlamydia trachomatis infection is similar to that of Clamydophila pneumoniae (Table 6). Duration of treatment is 3 months [108]. In case of arthritic Sulfasalazine [131] and treatment by TNF antibodies [132] were also proposed.

The infectious data and symptomatology of yersiniosis are compiled in Tables 1 and 7, respectively. Yersinia enterocolitica was already recognized as pathogen as early as the beginning of the 20th century. However, the true significance of the pathogen, in particular, under epidemiological aspects was first described in 1995 [133]. Acute illness due to Yersinia enterocolitica is subject to registration (according to German law). The pathogen penetrates into the intestinal wall and the mesenteric lymph nodes. Surface proteins and plasmid-bound virulence factors suppress immune system reactions of the host [134-137].

The early stage of yersiniosis is essentially characterized by gradually developing gastroenteritis and pharyngitis and mesenteric lymphadenitis.

In contrast to other bacterial gastroenteritis, Yersinia enterocolitic gastroenteritis develops gradually and often becomes stressfull or perceivable only after a week [138-140]. Frequently, the infection is associated with pharyngitis because the pathogens remain in the lymphatic tissue of the tonsils and the pharyngeal wall, where they can also be detected by means of smear test. The concurrent occurrence of gastroenteritis with pharyngitis is typical for a yersiniosis [141].

The mean disease duration is approximately two to three weeks, but distinctly longer disease course have been described. The acute illness can be associated with numerous gastrointestinal complications, primarily as a consequence of a severe bacterial inflammation of the intestinal wall [142-144]. In addition, the disease can also affect many non-gastrointestinal organs [142,143,145-148]. The patients frequently remain excretory for months, even when the gastroenteritis has long since abated [139].

Yersiniosis can result in so-called reactive arthritis and is thus an important infectious disease in the differential diagnosis of Lyme disease. Since the disease can also sporadically occur [139] and frequently remains unrecognized, the anamnestic search for the typical manifestations of yersiniosis particularly symptoms of the early phase is of considerable importance.

Differentiation between Lyme disease and yersiniosis is made even more difficult by the fact that both infections can cause multisystem disease. The study by Saebo und Lassen [149], which describe the various disease manifestations in a retrospective study of 458 patients, is of particular importance for the depiction of chronic yersiniosis: chronic persistent arthralgias, ankylosing spondylitis, rheumatoid arthritis, iridocyclitis, chronic abdominal pains, chronic diarrhea, ulcerative colitis, nervous disorders, nephritis, thyroid disorders, insulin-dependent diabetes mellitus, chronic hepatitis, (multisystem diseases) and a substantial reduction of the overall life expectancy. Many of the different relationships were reported in further publications by these authors [150-155]. Studies suggesting a possible direct relationship between Yersinia and inflammatory intestinal disorders [155] close the pathophysiological circle between Yersinia, inflammatory intestinal disorders and enteropathic arthritides. Despite this, it should be noted that the relationship between Yersinia infection and the above-mentioned numerous disease manifestations (except for arthritis) have been inadequately analyzed. This may be due to the fact that the significance of “yersiniosis” as a disease has only been recently recognized.

In the differential diagnosis of yersiniosis with respect to Lyme disease and other co-infections, the importance is primarily based on the manifestation of a so-called reactive arthritis. This arthritis can last for months, and exhibit recurrent and symptom-free intervals in the disease course. The so-called reactive arthritis in yersiniosis can occur alone, but occasionally also in connection with conjunctivitis and urethritis, previously termed Reiter's syndrome [156]. As in Chlamydia infections and possibly in bartonellosis, the arthritis is probably the consequence of chronic persistent infection [157, 158].

The so-called reactive arthritis primarily affects the hip, knee and upper ankle joints as well as the sacroiliac joints; occasionally there are additionally chronic pains in the lumbosacral region [159].

In the differential diagnosis of Lyme disease, it is of particular interest that in some studies Yersinia enterocolitica was detected in articular effusions in case of the so-called reactive arthritis [157, 158]. Sometimes these arthritides last for many years. In addition, there is a relationship between yersiniosis and thyroiditis. All these (chronic arthritides, multisystem disorders, disease course lasting for years, correlation with regard to thyroiditis) can also be observed in Lyme disease.

The laboratory diagnostics of Yersinia enterocolitica infection is based on the seriological findings, on the LTT findings and on pathogen detection by PCR and culture.

As in Lyme disease, there is often seropositivity in asymptomatic patients. Information on a possible seronegativity in chronic yersiniosis is not available. In the disease course the serological findings can correlate with disease expression [159]. It is not rare that a highly significant pathological Yersinia LTT is found in patients whose complaints are primarily consistent with chronic Lyme disease. Positive yersinia LTT could be an indication of chronic persistent infection especially when reproducible.

Pathogen detection is possible, particularly in articular effusion and in lymphatic tissue of the intestine and in early stages of the disease by throat swab. Data on the sensitivity of pathogen detection using PCR or culture methods does not exist in the relevant literature. In Yersinia-PCR-positive patients, the serology was positive in 70% and LTT in 50% of the cases analyzed [160]. In the initial detection of Yersinia enterocolitica using culture methods, IgA and IgG bands were found in immunoblot assay in patients experiencing a chronic course of the disease. The continuous detection of IgA antibodies was obviously an expression of persistent infection; in this context the pathogens were detected in the intestinal mucosa and in lymphatic tissue. Hence, this was a definitely chronic, persistent Yersinia enterocolitica infection [161]. The antibiotic treatment of Yersinia enterocolitica infection is presented in Table 8.

Yersiniosis frequently abates within a few weeks so that an antibiotic treatment is not generally recommended. This also applies with regard to excretors. Antibiotics are used only in cases with severe disease courses, in particular with sepsis. Y. enterocolitica produces beta-lactamases with the consequence that penicillin, ampicillin and cephalosporins of the first generation are ineffective [162,163]. Resistance to macrolides is also frequent. It is disputed whether early antibiotic treatment (i.e. for gastroenteritis) prevents reactive arthritis [164].

The differential diagnosis of chronic yersiniosis vs chronic Lyme disease, is thus extremely difficult because of the overlap of various clinical symptoms. In cases where both infections are present in their chronic form, a differentiation is often impossible.

The differential diagnosis between Lyme disease und Mycoplasma pneumoniae infection or the recognition of the co-infection by Mycoplasma pneumoniae is problematical because both diseases exhibit similar manifestations; this applies to the extrapulmonary manifestations of Mycoplasma pneumoniae infection: disorders of the CNS, musculoskeletal system, heart, kidney and eye.

Data related to Mycoplasma pneumonia infection are given in Table 1 and 9. In the foreground is the atypical pneumonia, frequently linked to symptoms of the upper respiratory tract. There are no data available in the literature with respect to the frequency of extrapulmonary manifestations.

Mycoplasma pneumoniae is considered to be the most important pathogen of atypical pneumonia. However, pneumonia only occurs in approximately 3% - 10% of the cases in Mycoplasma pneumoniae infection [165]. In most cases, the infection results in a banal bronchitis [165], pharyngitis, rhinitis, earaches, and sinusitis [163].

All the extrapulmonary disease manifestations listed in Table 9 are seldom [166-174]. In patients with arthritis, Mycoplasma pneumoniae was detected in the synovial fluid by PCR [171], which is an indication of a direct relationship to infection.

The detection of pathogen in articular effusion and many extrapulmonary manifestations of the disease document the chronic course of the disease in cases with Mycoplasma pneumoniae infection. However, precise data on the chronic course of the disease are not available in the literature. In particular, whether a chronic infection, especially with extrapulmonary disease manifestation, can persist with seronegativity is unclear. Seropositivity documents infection, but cannot serve as a proof for chronic persistent Mycoplasma pneumoniae infection.

The literature on the relationship between Mycoplasma pneumoniae infection and neurological disease manifestations is extensive. The publications primarily refer to neurological complications in pneumonia, i.e. the early phase of Mycoplasma pneumoniae infection. Neurological manifestations involve both the early phase, i.e. the point in time of existing pneumonia due to Mycoplasma pneumoniae, and later disease stages. Changes in the region of the brain stem [175, 176], myelitis [177-187], Guillain-Barré syndrome [188-193], encephalitis [185,187,194-200], meningitis [194], polyradiculopathy [178], peripheral facial paresis [201, 202], optical neuritis and hemorrhagic leukoencephalitis [190], peripheral polyneuropathy[194], cranial nerve neuritis [192], radiculitis [192] have been described.

The frequency of neurological symptoms in connection with Mycoplasma pneumoniae varies between 1‰ [203], 1% [204], and 5% [205]. The pathogen has been repeatedly detected by means of culture methods or PCR [182,193,194].

The detection of pathogen in the serum and liquor is considered to be proof that the neurological manifestations are mediated by direct infection and not by immunological responses [193]. However, the connection between Mycoplasma pneumoniae and neurological manifestations is not undisputed [203, 206].

Other extrapulmonary manifestations mentioned in the literature include hepatitis, hemolytic anemia, Schönlein-Henoch purpura, disorders of the muscular-skeletal system, of the skin and other organs [179], macula edema[194], bilateral uveitis [207], nephritis [208], arthritis, hepatitis and pericarditis [208].

The laboratory diagnostics for Mycoplasma pneumoniae include the serology, which as in most infectious diseases becomes positive after several weeks. Seroconversion is therefore significant for the chronic disease course. Seropositivity substantiates the infection, but not the disease. Whether a chronic infection can also exist in seronegative cases has not yet been scientifically clarified. The LTT for Mycoplasma pneumoniae has not yet been validated.

Detection of the pathogen, e.g. in articular effusion by PCR and culture is possible but difficult and has a low sensitivity. Consequently it is not part of the routine diagnostic procedures.

In the antibiotic treatment of Mycoplasma pneumoniae the drugs of choice are azithormycin 500 mg/day [209], levofloxacin 500 mg/day [210] and doxycycline 400 mg/day.

The pathological importance of human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA), which is also called human granulocytic ehrlichiosis (HGE), was discovered in 1986 and 1994, respectively [211, 212]. The two infectious diseases resemble each other clinically and with regard to the laboratory findings. The pathogens develop in monocytes (HME) or in granulocytic leukocytes (HGA). Thus, their localization is exclusively intracellular.

The pathogens are transmitted by infected ticks, primarily via Ixodes scapularis in the United States and via Ixodes ricinus in Europe. The reservoirs are the white-footed mouse for HGA and the red deer and human beings for HME (Table 1). Other modes of transmission are also discussed, including mother-child transmission, blood transfusions, direct contact with infected animals and transmission form person to person [213-219].

In connection with ehrlichiosis or anaplasmosis, two pathogens are to be noted, respectively, namely Ehrlichia chaffeensis [220] and Anaplasma phagocytophilum [221]. E. chaffeensis infects monocytes and Anaplasma Phagocytophila granulocytes.

Ehrlichia chaffeensis is the pathogen of human monocytic ehrlichiosis (HME), a rare infectious disease, which occurs primarily in the USA and in some regions of South America, but practically nowhere else on earth. Ehrlichia phagocytophila is the pathogen of human granulocytic anaplasmosis (HGA), another extremely rare disease in the USA with an annual incidence of approximately 10 / 1 million inhabitants [222]. HGA, is an important co-infection of Lyme disease in the USA, but not in Europe.

The pathogen can be simultaneously transmitted with Borrelia burgdorferi with the consequence of a double infection. HGA exhibits many symptoms, which also occur in Lyme disease.

Scientific reports on illnesses due to HGA in Europe are rarities [223]. However, studies in Northern Italy showed that 24% of the ticks (I. ricinus) were infected by Ehrlichia chaffeensis or Anaplasma phagocytophilum. Similar findings have been substantiated in the Netherlands and in Poland, whereas in Germany the frequency is approximately 2% [224-229]. In the East Coast of the United States it is much higher and reaches approximately 30% - 40% [230,231].

In Europe, in patients with Lyme disease the seroprevalence for Anaplasma phagocytophilum is approximately 10% [232-234]. Similar findings were also obtained in the USA [235]. Since seroprevalence merely expresses the frequency of the infection, but not an ungoing active infection of HGA, no reliable statements about the prevalence of the disease can be made. According to the laws of probability, a concurrent HGA infection in patients with Lyme disease might amount to a few percent at most. There are no data available in the literature on chronic HGA courses. However, subacute and chronic courses are discussed [236, 237].

The incubation period, i.e. the time between tick bite and emergence of acute illness, is approximately one week [238]. In the acute phase clusters of bacteria are located intercellularly (morale) [239].

The clinical symptoms comprise fever, influenza-like symptoms, headache, joint and muscle pains, coughing, CNS disorders, which include meningitis. Such changes occur frequently and are - particularly in cases involving a febrile clinical picture with the above-mentioned symptoms - an indication for HGA. Indications of HGA are the pathological laboratory findings of leukopenia, thrombocytopenia, and elevated transaminases. The pathogen is localized intracellularly. Anemia and elevated creatinine can rarely occur.

The diagnosis of HGA (also as co-infection) is based on the anamnesis, on the clinical symptoms and laboratory findings, including the serological findings [240-243] and the detection of pathogens. The specific antibodies appear two to three weeks after disease onset and persist following the decline of the disease. Therefore, a positive serology does not confirm ongoing infection of HGA. The pathogen is detected in blood smear, which is not often successful; [244-247], or by PCR from whole blood. The detection by PCR was successful in 20% - 80% of the cases analyzed, with a sensitivity of 60% - 80% [248-251].

Doxycycline is the recommended therapy, also for children. Precise literature with regard to an adequate treatment is not available.

Campylobacter jejuni is a small Gram-negative bacterium whose pathological significance was recognized around 1980. Campylobacter jejuni is among the most frequent pathogens worldwide, causing acute diarrhea. Sources of infection are game and domestic animals, especially poultry, various animal products and contaminated water [286]. The pathogen can persist in a coccoid form, but also in its normal form, for months in unfavorable conditions. It penetrates epithelial cells of the intestine causing their destruction, possibly by means of toxins [287, 288].

The main clinical manifestations of Campylobacter jejuni infection are gastroenteritis and abdominal complications in the early phase and reactive arthritis and Guillain-Barré syndrome in the late phase of the disease.

Campylobacter jejuni has differential diagnostic significance due to the late manifestations of the disease, namely due to reactive arthritis and Guillain-Barré syndrome.

Reactive arthritis in Campylobacter jejuni infections is seldom with a frequency of about 2.6% [289-292]. In connection with a Campylobacter jejuni infection, Guillain-Barré syndrome has an unfavorable prognosis [293]. Its incidence is approximately 1‰ [294]. Reactive arthritis occurs approximately one to two weeks after gastroenteritis [288] and Guillain-Barré syndrome approximately two months after the onset of infection [295].

Antibiotic treatment reduces the duration of gastroenteritis. The drugs of choice are erythromycin (1500 mg/daily), azithormycin (500 mg daily) and ciprofloxacin (1000 mg daily). Macrolides [296] and quinolones are primarily recommended, but resistance to them can occur [297]. Resistance to trimethoprim und beta-lactamases also exists [298].

The term “reactive arthritis” characterizes arthritides, which bear a relationship to certain infectious diseases. In former times the term “Reiter syndrome” was used in cases of concurrent infection of the urethra and the uvea. Arthritis, urethritis and uveitis were termed the Reiter’s triad [299,300]. Pathogens, which can induce reactive arthritis include Chlamydia trachomatis, Chlamydia pneumoniae, Yersinia enterocolitica, Salmonellae, Shigella, Campylobacter (usually Campylobacter jejuni), Mycoplasma pneumoniae and possibly Clostridium difficile.

The term “reactive arthritis” is not a defined disease (nosological entity), but rather a concept for the classification of disease relationships with respect to the pathophysiology. The term “reactive arthritis” is problematical. In various infections with reactive arthritis, the pathogens were detected in the synovia and joint fluid. This is true for Chlamydophila pneumoniae [108-110], Chlamydia trachomatis [125,126] and for Yersinia enterocolitica [157,158]. The pathogen was also found in the synovia in cases with arthritis in connection with Mycoplasma pneumoniae [171].

Reactive arthritis occurs days to weeks after the onset of infection. It predominantly affects the joints of the lower extremities. In cases with disease duration of less than 6 months, the term “acute reactive arthritis” was designated and for those with disease duration of more than 6 months, the term “chronic reactive arthritis" is used.

In 50% of the cases, the joints of the upper extremities are also affected, including the small joints, and the arthritis can be accompanied by tendonitis (enthesitis) [301-304].

One of the most important differential diagnoses of reactive arthritis is Lyme arthritis (chronic Lyme disease, Lyme disease in the late stage, stage III).

Reactive arthritis can be associated with other disease manifestations. These extra-articular symptoms in cases of reactive arthritis include urogenital symptoms, conjunctivitis, uveitis, aphthae, hyperkeratotic skin lesions in the region of the sole of the foot and the palm of the hand, nail changes as in psoriasis and genital lesions, such as balanitis.

In the diagnosis of a “reactive arthritis” anamnestic research is to be performed to determine whether there are indications of one of the above-mentioned infections. Accordingly, the following significant anamnestic considerations are important: Chlamydia trachomatis infection with and without symptoms, enteritis and atypical pneumonia.

Additionally, it should be remembered that arthritides are also found in Chlamydophila pneumoniae und Mycoplasma pneumonia infections and that in Chlamydioses, Yersiniosis and also in cases of Mycoplasma pneumoniae, the pathogen has been detected in the synovial membrane or in the articular effusions, respectively.

Using laboratory diagnostic tests (culture, serology), an existing or previous infection can be detected in 50% of the cases. Other laboratory tests, particularly inflammation markers, like the erythrocyte sedimentation rate (ESR), the C reactive protein (CRP) and leukocytosis are not relevant in cases of reactive arthritis. With regard to Chlamydia trachomatis, pathogen detection in a urethral smear or in urine using PCR or NAATs is appropriate.

Chronic courses, i.e. a duration of illness exceeding 6 months, are observed in nearly 20% of the patients [305].

NSAIDs are used for treatment, but only for pain relief since they have no influence on the disease course or disease duration. In contrast, sulfasalazines [131] and TNF antibodies have certain efficacy. Antibiotic treatment is recommended in cases of acute chlamydiosis with the objective of reducing the frequency of reactive arthritis. However, studies in this direction are needed [306]. In cases of chronic reactive arthritis, the efficiency of antibiotic treatment is a matter of controversy [304,307-312].