Systemic infections

If we diagnose uveitis, it’s because we see intraocular inflammation. In the majority of cases this represents the clinical precipitation of a humoral and/or cellular immune response.

  • GENERAL, EXPLANATION OF TERMS

    The antigen is often not known, or a pathogen is at best suspected in a specific clinical picture. Only in exceptional cases, the tissue damage is directly infectious; for example in cytomegalovirus retinitis of AIDS patients, or in incipient bacterial keratitis. As soon as the body can build up an immune response, and as soon as this response is activated against a specific antigen or pathogen, it determines the clinical picture. So, what we see correlates with the pathogen that has triggered this reaction, but it is mainly the immune response of the host. For this reason, any infection responds primarily to steroids and only becomes worse when the steroids interfere with the immune control of the pathogen, allowing it to proliferate again. Since anti-infective therapy influences pathogen replication but not the immune response, it is a prerequisite for calming the uveitis. However, an immediate therapeutic effect is not always present, since even with effective anti-infective therapy the dead pathogens maintain the immune response until they are broken down (note: even dead pathogens are good antigens!). For this reason, anti-infective therapy (for example, in toxoplasmosis) does not have to be continued consistently until the lesions have healed, but with a safety margin until all pathogens have been reached. Thereafter, the intensity of the anti-inflammatory or steroid therapy determines whether the risk of reactivating the infection justifies the continuation of anti-infective therapy or a recurrence prophylaxis.

  • BASICS

    Infectious uveitis, in contrast to keratitis, is probably almost always the cause or consequence of a systemic infection that secondarily affects the eye. Only seldom does the pathogen spread per continuitatem into other tissues and organs after penetration via the eye surface. For example, in individual viral infections and infections acquired in the birth canal or the very rare primary tuberculosis infection of the eye surface. Pathogen colonization of the mucous membranes with spread of the infection is occasionally observed in chronic fungal or bacterial colonization of the paranasal sinuses, usually the ethmoidal cells, and the lacrimal ducts.

    An infectious disease can be acquired either congenitally, perinatally or in the course of later life. Systemic infectious diseases that do not result from an infection of the ocular surface but enter the eye hematogenously almost always precipitate primarily as choroiditis with secondary spread to other intraocular tissues. This is due to the high blood flow in the uvea and especially in the choroid. This may not always be clinically evident. Exceptions, for example are, Roth spots, which presumably represent microabscesses in the chorioretinal transition area without recognizable choroidal involvement in bacterial sepsis. Or fungal infections in which the pathogens that have entered the choroid only proliferate after migrating through the retina and colonizing the vitreous. Furthermore, this does not apply to infections with the highly neurotropic herpes viruses that spread along the nerve fibers. After primary colonization of intraocular tissues, reactivated infections tend to originate from the local colonization centers. Thus, recurrent herpetic keratouveitis usually presents early in the area of old stromal scars. And in recurrent toxoplasmosis fresh lesions are usually found near old scars.

    It cannot be fully explained why a uveitism manifestation is much more often found in connection with a secondary wave of infection spread (toxoplasmosis) or with a chronic infection (syphilis, borrelia) than in primary hematogenic seeding. This is the reason why there are no good animal models for many infectious uveitides. An exception may be endogenous endophthalmitis, where the pathogen invasion is already observed under primary bacteremia. Therefore, in contrast to a reactivated infection, the pathogen can be detected relatively often from blood samples and blood cultures. At the latest in connection with serodiagnosis, the question of a primary or secondary infection and the time of the primary infection becomes very relevant. This because in the case of an intraocular reactivated infection, in contrast to a primary infection, IgM antibodies against the pathogen are not necessarily or usually not detectable in serum (serology “false negative”, since an active system infection is not present, which does not exclude local activity even in the absence of IgM).

    Since infectious uveitis is the consequence of a secondary manifestation of the pathogen in the eyes in more than 98% of cases, serology is obviously of little help in the majority of cases to prove local activity. So the ocular manifestation of a systemic infection depends on the patient’s medical history (risk and exposure profile of the patient, e.g. HIV, i.v. drug use, contact with infectious individuals and travel to endemic areas) and the clinical presentation of the clinical picture. On the other hand, a negative serology (no pathogen-specific IgG antibodies detectable) cannot ultimately rule out the diagnosis, but it does make it quite unlikely, which is why serology cannot be dispensed with. In the case of ocular toxoplasmosis, for example, one would not expect anti-toxoplasma IgM to be positive, but anti-toxoplasma IgG should be detectable. If this is also negative, a further differential diagnostic consideration must be made.

    A consequence of the fact that in the vast majority of cases uveitis does not occur during primary infection is that the general condition of the patients is usually good and the systemic infectiological clarification often leaves no evidence of infection activity. The search for a focus of infection is therefore only useful in cases of clinical suspicion or indications. A therapy is usually based on the clinical assessment or the clinical picture leading to the suspected diagnosis (gold standard in uveitis diagnostics), a positive serology with detection of specific antibodies against the pathogen and is usually only secondarily supported by the response to therapy. In unclear cases and in cases that do not show an adequate response to therapy, further, more invasive diagnostics are required. Parallel aqueous humor and serum diagnostics to detect local antibody production are very helpful in this context, in order to prove a certain diagnosis or make it unlikely if a sufficiently specific suspicion exists. Due to the small anterior chamber volume, aqueous humor analysis is not suitable for screening or analysis of several antibodies. However, when using the aqueous humor analysis, it should be noted that the patients who have the anterior chamber have a rather high turnover, so that antigens and pathogen DNA are eliminated quite quickly. In the case of viral retinitis, for example, it can be expected that no pathogens are present within 48 to 72 hours after the start of anti-infective therapy (PCR false negative). Often an intensive local steroid therapy is established before the patients come for aqueous humor analysis. Like an anterior chamber puncture, this can lead to false negative results in antibody diagnostics even before activation of a specific immune reaction. This is because a specific immune reaction is usually only detectable within 10 to 14 days after the onset of uveitis. Only rarely a vitreous body biopsy and very rarely a chorioretinal biopsy is required and necessary to detect the pathogens using PCR or cytological and histological measures from cells and tissue.

  • SPECIFIC DISEASES

    In addition to tuberculosis as an increasingly important systemic infection with eye involvement, syphilis is also gaining in importance. Especially among non-risk groups, and independent of the presence of HIV infection. In contrast, the importance of lyme disease as a cause of uveitis tends to decrease again in non-endemic areas. Leprosy, the second mycobacterial form of uveitis besides tuberculosis, does not play a role in our latitudes. A Bartonellose (cat scratch disease) manifests itself rarely at the eyes. Parasitoses are rather rare in Europe and North America, among them most frequently toxocariosis, very rarely cysticercosis and cryptococcosis. The latter especially in patients with severe immune defects or immunosuppression. Except for toxoplasmosis, which is still the most common infectious form of uveitis. Onchocerciasis as the cause of river blindness is hardly ever found in our latitudes (travel anamnesis!). Among the virus infections with eye involvement, the herpes viruses are clearly in the foreground. Herpes simplex and Varicella zoster virus rarely manifest themselves in the posterior segment of the eye, but predominantly in the anterior segment. Whereas CMV infections are more common on the retina of immunosuppressed and AIDS patients than as anterior uveitis in immunocompetent patients. Rubella virus has been primarily associated with congenital rubella infection (triad hearing loss, visual impairment and intellectual disability), but in recent years it has also been frequently identified as a cause in patients with heterochromic cyclitis.

  • DIAGNOSTICS

    The probability of infection as a cause of uveitis is sufficiently high that it should always be considered. The clinical impression is decisive for the diagnostic orientation. The following applies: frequent is frequent! In the case of atypical changes, syphilis and tuberculosis must be considered more often. The newly described predominantly viral infections (rickettsiosis, West Nile virus, Rift Valley and dengue fever, chikungunya and others) can occur in the most varied clinical manifestations; from conjunctivitis to severe retinitis. However, these are certainly so rare that they do not belong in a primary differential diagnosis of uveitis. In addition to the specific diagnosis, the disposition of the patient for the disease and comorbidities must always be evaluated. An underlying systemic infection need not be known.

  • TEMPORAL DYNAMICS

    The severity of the inflammatory reaction and the temporal dynamics of the disease depend on the pathogen density in the tissue. The virulence of the pathogen involved in the individual case on the one hand and the immunogenetic disposition and immunocompetence towards the infection on the other. The pathogen of a congenital or perinatal infection causes much more damage than in the case of an infection after maturation of the immune system. A healthy immune system reacts strongly on first contact, but often less strongly in reactivated infections, since a specific defense is already established, which is true for uveitis recurrences. Thus, if a patient shows foudroyant blossoming uveitis, an acute fresh infection with a rapidly replicating pathogen is to be assumed (example: viral retinal necrosis), whereas slowly proliferating pathogens induce a relatively low inflammatory reaction, which does not necessarily indicate an infection (example: tuberculosis). The aggressiveness of diagnostics and therapy is based on the dynamics and progression of systemic or local inflammatory activity. It should be noted that in many parasitoses and fungal infections a chronic irritant state persists even after successful therapy, so that residual activity cannot be ruled out. Such a state of irritation does not necessarily mean the presence of replicable pathogens but is often directed against still existing pathogen antigens and only comes to rest after antigen removal. The fungal endophthalmitis is a typical example of this.

  • SUMMARY

    Systemic infections as a cause of uveitis are common. Nevertheless, the clarification is difficult in most cases, because an ocular involvement with uveitis rarely occurs even once during the primary infection, and usually only during the reactivated infection. Therefore, serodiagnosis is only conditionally meaningful and not conclusive. Often the clinical picture of the uveitis presentation and course provide the most important information for the differential diagnostic limitation. During the clarification it is important to pay attention to which dispositional factors influence the current situation, as this has an influence on the therapy strategy. On the one hand, the therapy is directed against the infectious cause and is usually systemic, since the source of infection is the entire organism. On the other hand, it is usually necessary to additionally control the inflammatory reaction with local and possibly also systemic steroids in order to prevent inflammatory tissue damage as much as possible. A sole anti-inflammatory therapy in higher doses leads to an exacerbation of the infection activity and is therefore obsolete.