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Bacterial and Fungal Diseases


Key Concepts

  • Infection remains a common cause of uveitis. Better diagnostic tests are helping to identify specific bacteria as the cause of a number of uveitic conditions, such as bartonellosis as the cause of cat scratch disease.

  • Prompt diagnosis is critical so that appropriate anti-infective therapy can be started.

  • Clinicians should know the sensitivity and specificity of the diagnostic tests ordered for the infectious causes of uveitis. Clinicians must also know the pretest likelihood of disease to adequately interpret results (see Chapter 5 ). Otherwise, diagnostic tests for the infectious causes of uveitis can misinform the clinician and lead to inappropriate therapy.

  • Ocular involvement from tuberculosis occurs in about 1% to 2% of patients but remains difficult to diagnose. Active tuberculosis can occur as a complication of immunosuppressive therapy with anticytokine therapy.

  • Histoplasmosis is the fungal disease most commonly associated with uveitis.

  • Risk factors for fungal infections of the eye include ocular surgery, immunosuppression, systemic mycotic infections, intravenous drug use, and ocular trauma.

Introduction

The next two chapters will focus on uveitis resulting from ocular infections caused by bacteria or fungi. Although a number of infectious agents can invade the eye and lead to ocular inflammation, we will concentrate on the most common systemic bacterial and fungal causes of uveitis, including leprosy, tuberculosis, syphilis, and other related spirochetal diseases; Lyme disease; relapsing fever; leptospirosis; bartonellosis; brucellosis; candidal infections; and aspergillosis. Spirochetal diseases, as a group, are discussed in detail in Chapter 11 . Postsurgical bacterial and fungal endophthalmitis are also discussed in Chapter 19 .

Half a century ago, bacterial diseases, such as tuberculosis (TB) and syphilis, were thought to cause the majority of cases of uveitis. Despite improvements in the diagnosis and treatment of infectious diseases, ocular infections are still important causes of uveitis. Because specific antimicrobial therapy can be curative and prevent long-term visual sequelae, early diagnosis of infectious causes of uveitis should be a priority for all practitioners. Furthermore, as immunosuppressive therapy can exacerbate an underlying infection, leading to blindness and rarely even to death, diagnosing and treating an infectious cause of uveitis can be both sight saving and lifesaving.

Infections may cause uveitis through a number of pathogenic mechanisms. Direct infection of ocular tissues, usually as a result of trauma or surgery, leads to an inflammatory response manifesting as signs and symptoms of uveitis. Injection of bacterial endotoxins at sites far from the eye will also elicit intraocular inflammation in the absence of ocular infection. Endotoxins generate a number of harmful biologic effects, including fever, hypotension, disseminated coagulation, and shock. In the same year that Murray Shear elucidated the basic structure of endotoxin, Ayo demonstrated that a single intravenous injection of endotoxin could induce ocular inflammation, and this inflammatory response was ascribed to “Schwartzman toxins.” Although this endotoxin-induced uveitis (EIU) was easily elicited in dogs, cats, and rabbits, smaller laboratory animals were resistant to development of the disease. In 1980, Rosenbaum et al. demonstrated EIU in Lewis rats after intravenous, intraperitoneal, or intrafootpad injections of lipopolysaccharide (LPS), and Forrester et al. showed EIU after intraocular LPS injection in Columbia–Sherman rats. EIU has since been described in C3H/HeN mice. EIU is now a useful animal model for the study of acute ocular inflammation and is characterized by iris hyperemia, miosis, increased aqueous humor protein concentration, and inflammatory cell infiltration into the anterior uvea and anterior chamber ( Fig. 10.1 ). Inflammatory cell infiltration into the vitreous in the area of the optic nerve head also occurs. As you will see in the chapter on anterior uveitis ( Chapter 20 ), uveitis can occur after bacterial infections, such as bacterial dysentery, and the mechanism of some of these occurrences may be the result of an immunologic response to endotoxin.

Fig. 10.1, Histologic section of anterior chamber of mouse with endotoxin-induced uveitis shows infiltration with neutrophils, macrophages, and occasional lymphocytes.

Leprosy

Leprosy was the first documented bacterial infection in humans and was described in Indian texts from the sixth century b.c. The etiologic agent of leprosy, Mycobacterium leprae, is a gram-positive, acid-fast intracellular bacillus, first identified by Hansen in 1874; however, the disease has been a scourge of society for thousands of years. It is found predominantly in developing countries, but it is estimated that from 10 to 15 million people have leprosy and that from 500,000 to 700,000 persons have been blinded by this condition. Most of the cases come from a small number of countries, including India, China, Myanmar, Indonesia, Brazil, Nigeria, Madagascar, and Nepal. The organisms have a tropism for parts of the body with low temperatures, particularly organs of ectodermal origin, such as the skin, peripheral nerves, nasal mucosa, and eyes. The mode of transmission of leprosy remains unclear. Although most of the population is exposed to the bacillus in endemic areas, greater than 90% are immune to the disease and do not develop symptoms. Leprosy is often divided into two major subtypes: tuberculoid and lepromatous. In patients with tuberculoid leprosy, the organism induces a strong cell-mediated immune response, and few organisms are found invading organ tissues. Little immunity follows the infection in patients with lepromatous leprosy, and a plethora of organisms are found throughout the body. Borderline forms of the disease also exist in some classification systems.

Clinical Findings and Prognosis

From 50% to 70% of patients with leprosy have the tuberculoid form, which tends to be localized to the skin and nerves. The disease in these patients is characterized by granuloma formation and the absence of a large number of bacilli because of their active cell-mediated immune response. The skin test with lepromin is highly positive (Mitsuda reaction). The lepromatous form of the disease is characterized by a severe generalized condition with massive bacterial infection. In contrast to patients with tuberculoid leprosy, these patients have a poor cellular immune response, and macrophages are predominantly found on histologic examination. Intraocular inflammatory disease occurs more commonly in lepromatous leprosy. In addition, severe disfiguring changes of the limbs and face are associated with lepromatous leprosy. In patients with borderline forms of leprosy, a sudden shift to the lepromatous state can occur. The differential diagnosis in patients with uveitis associated with suspected leprosy includes other disorders with similar skin lesions, including sarcoidosis, lymphoma, syphilis, and yaws.

A list of the ocular complications of leprosy is given in Box 10.1 . In one study, over half the patients with multibacillary leprosy had ocular involvement. Structural damage to the eyelids, poor lid closure as a result of facial nerve involvement, and impaired corneal sensation often lead to exposure of the cornea. Loss of the temporal portion of the eyebrows (madarosis) is a typical finding and a stigma in those affected. It is important to remember, however, that trachoma can exist in the same population with leprosy and can compound the external disease in these patients. The keratitis associated with leprosy starts superiorly and first appears as subepithelial chalky infiltrates surrounded by gray stromal opacifications. Corneal exposure predisposes patients to development of corneal ulcers ( Fig. 10.2 ) that are often difficult to manage.

BOX 10.1
Ocular Manifestations of Leprosy

  • Prominent corneal nerves

  • Decreased corneal sensitivity

  • Madarosis

  • Ectropion

  • Entropion

  • Episcleritis/scleritis

  • Trichiasis

  • Glaucoma

  • Cataract

  • Blocked nasolacrimal ducts

  • Pterygium

  • Conjunctivitis

  • Granulomatous anterior uveitis

  • Iris pearls

  • Iris atrophy

  • Facial nerve palsy (tuberculoid leprosy)

  • Ptosis

  • Exposure keratitis

  • Orbicularis oculi weakness

  • Lagophthalmos

  • Trigeminal nerve involvement

  • Corneal anesthesia

  • Lid lesions and deformities (lepromatous leprosy)

  • Choroidal lesions

Fig. 10.2, Severe bacterial corneal ulcer in a patient with leprosy.

Intraocular inflammatory disease is a known complication of leprosy. In a retrospective study of 531 patients with leprosy, 4% had iritis. The organisms can directly invade the iris and the ciliary body, and chronic anterior uveitis is commonly seen in these patients. If uveitis is not aggressively treated, cataract and hypotony frequently result. Less frequently, patients present with acute anterior uveitis. In a study of 100 patients with leprosy in Brazil, 72 had ocular complications. Seventeen had a chronic anterior uveitis, whereas only two had acute anterior uveitis. In a study in Nepal, 8% of patients with tuberculoid leprosy had uveitis, whereas 16% of patients with lepromatous leprosy had anterior chamber inflammatory disease. Spaide et al. found that uveitis was uncommon in patients with leprosy in the United States, possibly reflecting the results of more aggressive treatment with antilepromatous and anti-inflammatory agents. Granulomas form in the iris and appear as iris “pearls” on the anterior surface ( Fig. 10.3 ). Iris atrophy also occurs in many patients but can be more subtle ( Fig. 10.4 ) compared with the iris atrophy observed with herpes infection (see Fig. 3.7 ).

Fig. 10.3, ( A) Iris “pearl” of leprosy seen as a small white object on iris edge. ( B) Many of these objects can be seen just right of the slit beam.

Fig. 10.4, Multiple areas of iris atrophy (arrowhead) in patient with iritis caused by leprosy.

Although less common, changes to the retina have been described in patients with leprosy. Patients with long-standing lepromatous leprosy can have large numbers of organisms that invade not only the anterior segment but also the adjoining peripheral pars plana and retina. Pars planitis has been reported in patients with leprosy. Chovet et al. demonstrated segmental vasculitis in the posterior pole on fluorescein angiography in patients with lepromatous disease. Blindness can occur from a number of the ocular complications of leprosy. In a series of patients treated for multibacillary Hansen disease, unilateral or bilateral blindness occurred in almost 10% of patients.

Immunology and Pathology

Humans are the only natural host for M. leprae. After entering the host, the organism reproduces in mononuclear cells, particularly skin histiocytes. The doubling time for the organisms is extraordinarily long, about 20 days, and attempts to culture the organism in a cell-free environment have not been successful. Some work has centered on the use of the nine-banded armadillo as an experimental model. This animal has a low basal temperature that seems to permit large numbers of M. leprae to propagate.

The immune characteristics of patients with this disorder have been extensively studied. Imbalances in T cells, antigen-specific suppressor T cells, and defective production of monocyte-activating cytokines have all been described. CD4+ T cells predominate in tuberculoid lesions, but CD8+ T cells are almost exclusively found in lepromatous lesions. Family studies with human leukocyte antigen (HLA) typing have suggested that there is an HLA-linked recessive gene that may predispose patients to the tuberculoid form of the disease.

The reactional states of leprosy have been divided into two categories: type I and type II. The type I reaction is also known as the reversal reaction and is a delayed hypersensitivity response directed against bacillary antigens. The type II reaction is also known as erythema nodosum leprosum and is an immune-complex reaction. Patients with the reversal reaction (type I) may be more likely to present with orbicularis oculi weakness and lagophthalmos.

Therapy

Although a number of drugs to treat leprosy are available, treatment regimens remain somewhat controversial. The World Health Organization (WHO) recommends multidrug treatment regimens because of the existence of dapsone-resistant strains of M. leprae. The WHO developed consensus guidelines for a multidrug therapy with dapsone and rifampin for 6 to 12 months for paucibacillary leprosy with the addition of clofazamine and longer duration of treatment for multibacillary disease. Although a number of treatment regimens for leprosy have been proposed, a systematic review and meta-analysis failed to show better regiments that those implemented by WHO. The use of thalidomide was reported to be useful in patients with recurring and persistent erythema nodosum leprosum. Vaccination at birth with Bacille Calmette-Guérin (BCG) has variable efficacy in preventing disease. Despite efforts to eradicate the disease, long-term recurrences remain high. Ocular care of patients with leprosy requires careful management of the external disease, including surgical management of eyelid deformities and judicial use of ocular lubrication. If intraocular surgery is planned, great care must be taken to be sure that the eye has no active inflammation.

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