Introduction to infectious diseases

Suppurative thrombophlebitis

Suppurative thrombophlebitis, also known as septic thrombophlebitis, refers to the development of venous thrombosis in the presence of bacteremia. In this setting, the thrombus provides a nidus of infection for colonization and growth of the bacteria. In the peripheral veins, the presence of an intravenous catheter is the most common precipitating factor although burns and intravenously injected drugs are also predisposing factors. Suppurative thrombophlebitis of the vena cava largely occurs in the presence of central venous catheters (CVCs). Staphylococcus aureus is the most common pathogen responsible but other bacteria including Streptococcus pyogenes (also known as group A Streptococcus or GAS) and enteric gram-negative bacilli have been described. Candida species are the most common fungal cause of infection.

Suppurative thrombophlebitis may also develop secondary to other ongoing infections. Osteomyelitis, particularly in children with subperiosteal abscesses secondary to S. aureus , can induce thrombophlebitis in nearby veins. Pylephlebitis, suppurative thrombosis of the portal vein, can occur secondary to any intra-abdominal infection with drainage through the portal vein and septic dural sinus thrombosis can occur following head and neck infections. ^, Escherichia coli and Bacteroides species are most commonly associated with pylephlebitis but other enteric bacteria can also be present. S. aureus remains the most common cause of septic dural sinus thrombosis, but streptococci and anaerobes such as Bacteroides and Fusobacterium are also noted. ^,

Suppurative thrombophlebitis of the jugular vein is known by a variety of names including Lemierre syndrome, postanginal sepsis, and necrobacillosis. It is primarily associated with a preceding episode of pharyngitis. Septic emboli to the lungs are common, and lung abscesses and empyema can result. The most common etiologic agent is the anaerobe Fusobacterium necrophorum , but other oral microbiota including streptococcal species (particularly S. pyogenes ), Eikenella corrodens , and other Fusobacterium species can be responsible.

Infective endocarditis

Infective endocarditis is infection of the endovascular surfaces of the heart. The infection is most frequently established on the heart valves, but it can also develop directly on the wall of the chamber, often in locations where septal defects create turbulent flow. Although technically not part of the endocardium and hence not true endocarditis, infections of cardiac shunts or those related to coarctation of the aorta are considered in this group of infections due to their similar clinical manifestations, microbiologic causes, and treatments.

The clinical manifestations of infective endocarditis typically include fever along with nonspecific findings such as malaise, headache, myalgias, night sweats, vomiting, and abdominal pain. Signs of emboli including splinter hemorrhages, Janeway lesions (nodular erythematous macules of the palms and soles), kidney and splenic infarcts, lung abscess/empyema, osteomyelitis, septic arthritis, embolic stroke, and intracranial hemorrhage. Systemic immune reactions such as glomerulonephritis, Osler’s nodes (tender subcutaneous nodules on the fingers and toes), and Roth spots (hemorrhagic lesions of the retina) may also be present. Diagnosis is made using the modified Duke criteria to stratify patients into definite or possible infective endocarditis or to reject that diagnosis outright. Major criteria include two or more blood cultures with microorganisms associated with infective endocarditis or echographic evidence of endocarditis. Minor criteria include a predisposing condition, fever, evidence of emboli, immunologic phenomena, and a positive blood culture that does not meet major criteria.

The vast majority of infective endocarditis cases are secondary to gram-positive organisms. S. aureus is the leading cause worldwide and was responsible for 31% of cases in a large cohort of ∼2800 cases. Streptococci were responsible for 29% of cases with viridans group streptococci causing 17% and Streptococcus bovis leading to 6% of total cases respectively. Enterococci were responsible for 10% of cases as well. Although not considered an endocarditis-associated organism by the modified Duke criteria, coagulase-negative staphylococci are a relatively common cause of infective endocarditis at 11% of cases.

Gram-negative organisms are much less commonly associated with infective endocarditis than gram-positive organisms and only comprised 4% of cases in the same study. The most common organisms are a collection of gram-negative bacteria that colonize the oral-pharyngeal cavity called the HACEK organisms. Members of this group include H aemophilus spp., A ggregatibacter spp. (primarily A. aphrophilus , A. paraphrophilus , and A. actinomycetemcomitans ), C ardiobacterium hominis and C. valvarum , E. corrodens , and K ingella kingae . Historically, the fastidious nature of these organisms may have prevented them from growing in blood culture broth within a 5-day period, but with modern automated blood culture systems, the HACEK organisms are reliably isolated within the 5-day window, generally in 2 to 3 days.

Fungal endocarditis is even less prevalent than gram-negative cases and is usually secondary to Candida species. Cases of Aspergillus endocarditis, which is likely the second leading cause of fungal endocarditis, have also been reported.

Immunocompromised patients and health care–associated bloodstream and endovascular infections

The rate of endovascular infection rises dramatically in the health care setting. One of the leading causes for this is the presence of CVCs. Although these lines provide a location for the development of suppurative thrombophlebitis as discussed earlier, CVCs can also lead to infection in the absence of clots. CVCs both serve as a portal for direct access to the bloodstream and as a nidus of biofilm formation and ongoing infection. Central line-associated bloodstream infections (CLABSIs) are largely introduced in one of three ways: skin colonization leading to migration of organisms along the intracutaneous tract and through the fibrin sheath surrounding the catheter, intraluminal colonization of the catheter or hub, and hematogenous seeding from another location. The organisms associated with CLABSIs reflect those routes of infection. S. aureus and coagulase-negative staphylococci, which are key components of the skin microbiota, are leading causes of CLABSIs. However, considerable effort has been placed on infection prevention methods, including skin cleansing and catheter care. There is evidence that these preventive methods have been effective at reducing rates of CLABSI. Enterobacterales (particularly Klebsiella , E. coli , and Enterobacter ) and Candida species are now the leading groups of organisms responsible for CLABSIs in the United States based on reporting to the National Healthcare Safety Network. Enterococcus species and Pseudomonas aeruginosa are also key causes of CLABSIs.

The rate of infective endocarditis is increased dramatically in the presence of indwelling foreign material, which lacks many of the protective barriers of normal tissue and can thus better serve as a nidus for infection. Prosthetic valves in particular have high rates of infection, with older studies suggesting rates ranging from 1 to 6%. A more recent study still shows similar rates of 1.9%. Causative organisms are similar to those with native valve endocarditis.

Immunocompromised oncology and transplant patients demonstrate endovascular infections at much higher rates than immunocompetent individuals due to high rates of CVC usage and loss of intestinal mucosal barrier function, in addition to loss of immune function. Immunocompromised patients are also at increased risk of bone marrow infections caused by hematogenous seeding. Viridans group streptococci are a major concern in this population, but a wide variety of bacteria and fungi can lead to endovascular infection in these patients.

One set of immunocompromised patients worth noting here are asplenic and functionally asplenic patients. The spleen plays a critical role in the prevention of bacteremia from a number of encapsulated bacteria ( Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae most prominently), and the absence of a functional spleen greatly increases the risk of bacteremia and subsequent complications from these organisms. Management of that risk includes vaccinations against these organisms and antibiotic prophylaxis in high-risk asplenic patients. Of note, the spleen is also important in helping to control the parasitic infections of malaria and babesiosis discussed later in this section; asplenic patients with those infections exhibit more severe symptoms.

Pediatric considerations

For the most part, pediatric endovascular infections are caused by similar organisms as adult infections. However, otherwise healthy neonates are particularly prone to higher rates of bacteremia and may present with fever or a period of hypothermia as the only symptom. Bacteremia and corresponding sepsis in these neonates is divided into early-onset (less than 7 days of age) and late-onset (greater than 7 days of age). Historically, Streptococcus agalactiae (also known as group B Streptococcus or GBS) was the leading cause of neonatal sepsis. Maternal screening and antibiotic prophylaxis have dramatically decreased the rate of early-onset GBS sepsis but has not changed the rate of late-onset sepsis. E. coli is the second leading cause of sepsis in the neonatal period and now has similar rates to GBS. Listeria monocytogenes is also well known to cause early-onset infection, but today only causes rare sporadic cases.

Parasitemia

Although the number of cases of bacteria and fungi causing isolated bloodstream infections in otherwise healthy individuals is low, there are a number of significant parasites that do cause such infections. The most significant of these infections is malaria, which is caused by parasites of the genus Plasmodium . In 2018, there were an estimated 228 million cases of malaria worldwide resulting in 405,000 deaths with two-thirds in children under 5 years of age. Malaria is spread to humans via the bite of female mosquitoes of the genus Anopheles . Infections are found throughout most of the tropics with ongoing transmission in 89 countries. The vast majority of cases (92%) occur in Africa with six countries (Nigeria, Democratic Republic of the Congo, Uganda, Côte d’Ivoire, Mozambique, and Niger) being responsible for more than half of all infections worldwide.

Malaria is caused by four Plasmodium species that primarily infect humans: P. falciparum, P. vivax, P. ovale, and P. malariae . Two other species that are simian parasites have been shown to infect humans, although it is unclear if natural human-to-mosquito-to-human transmission occurs: P. knowlesi and P. simium . P. falciparum is responsible for the vast majority of cases and tends to have the most severe presentation. Over 99% of cases in Africa and a majority of cases in the Eastern hemisphere are caused by P. falciparum. P. vivax is the second most common cause of malaria worldwide causing 3.3% of cases, including almost half of the cases in India. P. vivax is also the leading cause of malaria in the Americas causing 75% of cases. P. ovale is endemic to tropical western Africa and can also be found in Southeast Asia and Oceania although at much lower levels than either P. falciparum or P. vivax . P. malariae is a relatively rare cause of malaria that is distributed throughout a similar area as P. falciparum. P. knowlesi is similar in morphology to P. malariae , sometimes resembling a mixed P. malariae and P. falciparum infection, and has been shown to cause malaria, including severe malaria, in Southeast Asia. Likewise, P. simium is similar in form to P. vivax and was recently discovered in patients in Brazil. Both P. vivax and P. ovale have life cycle stages as hypnozoites, which are dormant stages that reside in the liver. These Plasmodium species require additional treatment to clear the hypnozoite stage, without which patients are at risk for recrudescence of disease.

The clinical manifestations of malaria are usually nonspecific such that malaria should be suspected in any febrile patient with exposure to a malaria endemic region. Initial symptoms of uncomplicated malaria include fever, headache, fatigue, nausea, vomiting, diarrhea, arthralgias, and myalgias. Severe malaria can lead to severe anemia, hypoglycemia, metabolic acidosis, acute respiratory distress syndrome, liver failure, renal failure, disseminated intravascular coagulation, and circulatory collapse. An encephalopathy with impaired consciousness, delirium, or seizures known as cerebral malaria can also be present.

Babesiosis is another parasitic disease that affects the circulatory system. Parasites from the genus Babesia invade and infect red blood cells similarly to Plasmodium species. Humans are infected primarily through Ixodes scapularis tick bite and are dead-end hosts. A variety of other mammals serve as a reservoir for the parasite. Babesia microti is the main agent of babesiosis in the United States, primarily located in the northeastern and upper Midwestern areas of the country. Cases in Europe have been associated with B. divergens, while B. venatorum is endemic in northeastern China. Symptoms range from asymptomatic to mild disease with fever, fatigue, and myalgias to severe disease. Severe disease is largely limited to elderly or immunocompromised patients, particularly asplenic patients. Acute respiratory distress syndrome and disseminated intravascular coagulopathy are the most common presentation of severe babesiosis. Infection often resolves without treatment in immunocompetent individuals, but treatment is recommended for all symptomatic patients.

African trypanosomiasis, also known as sleeping sickness, is caused by parasites that are transmitted by the tsetse fly. These parasites then infect the bloodstream, enter the lymphatics and distribute widely throughout the body, ultimately entering the cerebral spinal fluid (CSF) and brain. There are two forms of trypanosomiasis: Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense . T.b. gambiense is found in 24 countries in western and central Africa and is the cause of 97% of all trypanosomiasis. This species causes a chronic infection where symptoms do not develop until months or years after infection. T.b. rhodesiense is found in 13 countries of eastern and southern Africa. Infection results in clinical presentation weeks to months after initial infection. Early symptoms of African trypanosomiasis include intermittent headache, fever, fatigue, myalgias, and arthralgias. A painless skin lesion (chancre) may also develop at the site of the infected bite, which is more common with T. b. rhodesiense than with T. b. gambiense . Lymphadenitis can also occur. Late-stage disease is classified as involvement of the CNS. A diffuse meningoencephalitis develops leading to encephalopathy with psychosis, seizures, delirium, and increasing somnolence, hence the sleeping sickness name. Fatality of late-stage disease is nearly 100% if untreated. Due to sustained efforts including surveillance, vector control, and case treatments, reported cases of African trypanosomiasis continue to drop with fewer than 3000 cases reported in 2015. ^,

The related parasite Trypanosoma cruzi causes a different infection known as American trypanosomiasis or Chagas disease. These parasites are spread by insects of the Triatominae subfamily (kissing bugs). The disease is found throughout the Americas from the southern United States to northern Argentina and Chile. Acute infection consists of a phase typically lasting 8 to 12 weeks after infection characterized by circulating parasites. Most patients are asymptomatic or have mild nonspecific symptoms during this phase and do not present for medical attention. A very small percentage may develop severe acute symptoms, most prominently acute myocarditis. After the acute phase, parasitemia will drop to an undetectable level, and infection will only be identifiable by serology. Patients can remain in an asymptomatic phase called the indeterminate form for decades. However, 30% to 40% of chronically infected patients will develop additional complications. The most common are cardiac issues where conduction system abnormalities occur and lead to development of heart failure. Involvement of the GI system is the other major complication of chronic Chagas disease occurring in 10% to 15% of patients infected. These complications include megaesophagus (with dysphagia, regurgitation, epigastric pain, and malnutrition) and megacolon (with constipation, abdominal distension, and sometimes large bowel obstruction).

Meningitis

Meningitis is inflammation of the meninges, the membranes that cover the brain and spinal cord. They contain the CSF, which bathes the brain. To enter this space, pathogens must cross the blood-brain barrier, entering either by direct extension from the sinuses—a situation which occurs most frequently in the presence of anatomical defects—or by way of trauma. Once in the CNS, pathogens multiply and are recognized by circulating immune cells causing the recruitment of additional immune cells to the CSF and the release of large amounts of proinflammatory cytokines. This inflammation causes increased pressure in the CNS, resulting in the symptoms of meningitis.

Viruses are the most frequent cause of acute meningitis with enteroviruses, arboviruses such as West Nile virus, and herpesviruses being the most common etiologies. Patients with acute meningitis present with fever, headache, neck stiffness, and/or altered mental status. Viral infections cause mild to moderate symptoms and self-resolve in otherwise healthy individuals. Symptoms are much more severe in acute bacterial meningitis, such that most patients seek medical attention within hours to a day of onset. The most common causes of bacterial meningitis in the community setting are S. pneumoniae , N. meningitidis , and H. influenzae , although the use of vaccines for these organisms over the last 20+ years has led to marked decrease in the rates of meningitis due to these organisms. L. monocytogenes is another important cause of acute meningitis, primarily infecting the very young and old. S. aureus very rarely leads to isolated meningitis but is an important cause of acute meningitis in patients with endocarditis or paraspinal abscess. Parasitic causes of acute meningitis are rare in the United States but the free-living amoeba Naegleria fowleri is the most common in immunocompetent patients. Worldwide, the roundworm Angiostrongylus cantonensis is an important cause of eosinophilic meningitis. ^,

The presence of CSF hardware such as ventriculoperitoneal shunts increases the risk of infection and dramatically changes the types of pathogens responsible for infection. Gram-positive skin microbiota such as coagulase-negative staphylococci and Cutibacterium acnes (formerly Propionibacterium acnes ) are much more prevalent. Gram-negative infections, particularly with enteric gram-negative bacteria such as E. coli and Klebsiella species also happen more frequently in the presence of CSF hardware, albeit at lower rates than with gram-positive skin microbiota.

Chronic meningitis shares many of the symptoms seen with acute meningitis, but symptom onset is gradual over weeks to months. Often patients will present with low-grade fevers and lethargy in addition to headache and altered mental status. Chronic meningitis is most often caused by mycobacteria, spirochetes, and fungi. Mycobacterium tuberculosis meningitis is the most common form of chronic meningitis, although it can present in an acute manner in children. For spirochetes, Treponema pallidum and Borrelia burgdorferi, the etiologic agents responsible for syphilis and Lyme disease, respectively, cause chronic meningitis although their most common presentation is encephalitis. Fungal causes of chronic meningitis include Cryptococcus species and endemic fungi such as Coccidioides and Histoplasma. The parasites Acanthamoeba and Balamuthia are rare causes of chronic parasitic meningitis.

Encephalitis

Encephalitis is irritation, inflammation, or swelling of the brain. It differs from meningitis in that the brain parenchyma is directly affected. As such, altered mental status including speech disturbances, confusion, agitation, hallucinations, and decreased levels of consciousness are strongly indicative of encephalitis. It can also cause seizures and partial paralysis. In reality, the distinction between meningitis and encephalitis is blurred with many patients often having both features, a condition referred to as meningoencephalitis. However, it is important to note the difference in presentation as the differential for the conditions are quite different. In terms of infectious encephalitis, viral infections are overwhelmingly the most common cause. In the United States, West Nile virus is the most common proven cause of infectious encephalitis. Other arboviruses such as St. Louis encephalitis, La Crosse encephalitis, Eastern equine encephalitis, and Western equine encephalitis play roles in the US while Chikungunya, Japanese encephalitis, and Venezuelan equine encephalitis are among the many important arboviral agents of encephalitis worldwide. The herpesviruses, especially herpes simplex virus-1 (HSV-1) are also significant causes of encephalitis. Enteroviruses and other respiratory viruses, particularly influenza, are also known causes of encephalitis. Most bacterial causes of CNS infection lead to a meningitic rather than encephalitic presentation, but Mycoplasma pneumoniae, Bartonella henselae, Rickettsia rickettsii , and Ehrlichia chaffeensis are bacteria that can lead to a presentation of encephalitis.

Brain abscesses

Pathogens causing brain abscesses gain access to the brain by hematogenous spread through the blood-brain barrier, trauma to the brain, or contiguous spread to the brain from infections such as sinusitis, otitis media, or mastoiditis. Individuals present with symptoms of headache, nausea, vomiting, and neurologic findings such as seizure. Fever is present in less than 50% of patients with brain abscesses, much lower than for patients with meningitis and encephalitis. Bacteria are the most common cause of brain abscesses. Infections resulting from direct spread are usually polymicrobial including both facultative anaerobic bacteria such as streptococcal species (particularly Streptococcus anginosus group), S. aureus , and H. influenzae and obligate anaerobic bacteria such as Bacteroides , Fusobacterium , and Prevotella species. Neurotropic fungi causing brain abscesses include Cladophialophora bantiana and Rhinocladiella mackenziei. ^, Infections from hematogenous spread are more likely to be monomicrobial and secondary to other infections such as endocarditis. Parasitic infections are common in the developing world, but very rare in the United States, with cysticercosis due to the tapeworm Taenia solium being the most common. Entamoeba histolytica, Schistosoma japonicum , and Paragonimus species are also associated with brain abscesses.

Immunocompromised patients

Immunocompromised patients are susceptible to a broad differential of pathogens causing CNS disease. Human immunodeficiency virus (HIV) can directly affect the CNS leading to HIV encephalitis. Additionally, HIV-infected patients with severe immunosuppression are very susceptible to CNS infection with the fungal pathogen Cryptococcus neoformans and the parasite Toxoplasma gondii , both of which cause chronic meningitis or encephalitis. Immunocompromised patients are also at risk for encephalitis due to herpesviruses, particularly cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6). Other types of fungal meningitis that are very rare in immunocompetent individuals such as Candida meningitis and Scedosporium meningitis, which is associated with near-death drowning, are seen at higher rates in immunocompromised patients. The JC polyomavirus, a very common virus with few effects in immunocompetent individuals, is associated with progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that leads to rapidly progressive focal neurologic deficits.

Pediatric considerations

The first month of life has a greater risk for CNS infection than at any other point in an individual’s life, as the blood-brain barrier is inadequately developed at that time. Classically, S. agalactiae (GBS) was the leading cause of bacterial meningitis in these infants, but maternal screening and intra-partum antibiotic prophylaxis has decreased this rate. Today, the rate of GBS meningitis in neonates is similar to that due to E. coli. Combined, GBS and E. coli meningitis account for more than 80% of neonatal bacterial meningitis. Other gram-negative organisms, including Klebsiella and Enterobacter species, are the next most common with gram-positive organisms such as Listeria comprising a small number of cases. The more common causes of bacterial meningitis in elderly patients, S. pneumoniae, N. meningitidis, and H. influenzae , are also the most common causes of meningitis between 1 month and 1 year of age.

Viral encephalitis and meningitis are also more common in young infants than older individuals, with enterovirus being particularly frequent. Parechovirus, which is closely related to the enteroviruses, is a cause of meningitis and encephalitis that is largely isolated to infants. Finally, a special note should be made of neonatal HSV meningoencephalitis. This infection, most commonly seen in the first 3 weeks of life but possibly as late as 6 weeks, can be caused by either HSV-1 or HSV-2 but is more commonly associated with HSV-2. With this infection, HSV enters the CNS either from retrograde spread from the nasopharynx and olfactory nerves or through hematogenous spread. Once present, it causes a profound meningoencephalitis often associated with lifelong neurologic impairment or death.

Conjunctivitis

The conjunctiva is the mucous membrane that covers the inner surface of the eyelid and the globe of the eye up to the junction of the sclera and cornea. Inflammation of this mucous membrane is termed conjunctivitis, and infectious conjunctivitis is the most common type of eye infection. Both viral and bacterial etiologies of conjunctivitis are common while fungal or parasitic causes are quite rare.

Viral causes are thought to be the most frequent infectious causes of conjunctivitis, which is often called “pink eye” and classically presents with copious watery discharge and conjunctival erythema. It can be unilateral at presentation but usually spreads to become bilateral. Fever, rhinorrhea, and pharyngitis may be present. Adenoviruses are the most common etiologic agents, as they are highly contagious. Symptoms typically resolve spontaneously within 2 weeks, but some adenovirus serotypes can lead to epidemic keratoconjunctivitis, which includes involvement of the cornea and where symptoms can last weeks to months. HSV and varicella zoster virus (VZV) can also lead to conjunctivitis, with few clinical complications when these infections are limited to the conjunctiva. Both HSV and VZV can extend to other parts of the eye, however, and these infections will be discussed further later in this section. Other rare viral causes of conjunctivitis are self-limited and include influenza, Epstein-Barr virus (EBV), measles, mumps, rubella, papillomavirus, and molluscum contagiosum.

Determining the incidence of acute bacterial conjunctivitis is difficult, as many cases of viral conjunctivitis are treated as bacterial in origin. Classically, unilateral presentation is thought to be more common, but bilateral bacterial conjunctivitis also occurs. S. aureus , S. pneumoniae , H. influenzae , and Moraxella catarrhalis are the most common bacteria associated with conjunctivitis. In adults, S. aureus predominate while other organisms have historically been more common in children. Bacterial conjunctivitis from these organisms is largely self-limited as with viral conjunctivitis and the benefit of antibiotic therapy is unclear. Topical antibiotics are typically prescribed when therapy is given. Neisseria gonorrhoeae and to a lesser extent N. meningitidis can cause hyperacute bacterial conjunctivitis. Infection is marked by copious, thick, yellowish-green discharge and requires systemic antibiotics for successful therapy.

Chlamydia trachomatis is another critically important cause of conjunctivitis. Infection is typically sexually acquired and inoculation into the eye results in redness and mucopurulent discharge. C. trachomatis serotypes A, B, Ba, and C are associated with trachoma, which is the leading infectious cause of blindness worldwide. Blindness occurs following repeated bouts of infection, leading to eyelid scarring and ultimately corneal scarring. C. trachomatis is highly contagious and spread rapidly among families through secretions on fingers and fomites. In 1998, the World Health Organization launched a global initiative to eliminate trachoma using a combined strategy abbreviated “SAFE”: s urgery for trichiasis (in turned eyelashes), a ntibiotics for active infection, f acial cleanliness, and e nvironmental improvement. These efforts have made a significant global impact, bringing the population at risk of blindness down to 142 million in 2019 (from 1.5 billion in 2002) and decreased the number of people requiring surgery from 7.6 million to 2.5 million over that same time frame.

Keratitis

Keratitis is inflammation of the cornea, which can have an infectious or noninfectious source. Infectious keratitis can be caused by bacteria, viruses, fungi, or parasites. The most common risk factor for the development of microbial keratitis is contact lens use. Other risk factors include other disruptions of the cornea including surgical and nonsurgical trauma, dysfunctional tearing such as secondary to Sjögren syndrome, diabetes mellitus, and systemic immunodeficiency.

Bacterial keratitis is thought to cause approximately 90% of microbial keratitis with P. aeruginosa being the most common causative agent. S. aureus , S. pneumoniae , and Serratia marcescens are also common causes of keratitis. A variety of other species are found at lower rates including other Streptococcus, Haemophilus, Moraxella, Proteus, Klebsiella, Enterobacter, and Citrobacter species. Patients typically present with severe eye pain that is often accompanied by significant conjunctival infection and tearing. Edema and infiltration of inflammatory cells result in a loss of corneal transparency resulting in reduced vision.

Mycobacterial keratitis can also occur, although it is rare. This includes infections both from M. tuberculosis and other nontuberculous mycobacteria (NTM). Rapid growing NTM such as Mycobacterium fortuitum, Mycobacterium chelonae , and Mycobacterium abscessus make up the majority of cases with trauma, particularly laser-assisted in situ keratomileusis (LASIK), almost always serving as a risk factor. Outbreaks of NTM keratitis have occurred worldwide following LASIK secondary to improper sterilization techniques. Diagnosis is difficult due to the chronic and indolent nature of these infections compared to more common bacterial keratitis.

Fungal causes of keratitis are much less frequent than bacterial causes but can be quite severe and difficult to treat. Furthermore, as with NTM keratitis, the presentation can be indolent and chronic. A huge spectrum of fungi can lead to cases of fungal keratitis including Fusarium, Candida, Aspergillus, Paecilomyces, Phialophora, Curvularia, Alternaria, Sporothrix, Blastomyces, and Scedosporium among others. Fusarium and Aspergillus though seem to be the most common causes worldwide. A multi-state outbreak of Fusarium keratitis associated with contaminated contact lens solution occurred in the United States in 2006. Outbreaks have also been noted in Singapore, France, and Spain.

Parasitic keratitis can also be associated with contact lens use. Acanthamoeba are free-living amoeba found commonly in water and soil. They are resistant to desiccation, freezing, and standard chlorination techniques. There have been outbreaks associated with contaminated contact lens solution, but sporadic cases continue as Acanthamoeba can be found in tap water. Presentation typically involves photophobia and eye pain.

Other parasites including Leishmania and the obligate intracellular parasites known as Microsporidia have been found to induce keratitis in patients infected with HIV. Historically, the most important parasitic cause of keratitis is the microfilariae Onchocerca volvulus . This parasite leads to the disease onchocerciasis, or river blindness, which is transmitted by the black fly. The name river blindness refers to the fact that the black fly lays their eggs on rocks and vegetation in rivers and streams. The vast majority of onchocerciasis is found in Africa, but it is also endemic within small areas of Brazil, Venezuela, and Yemen. Although WHO efforts including insecticide treatment against the black fly vector and anti-helminth treatments directed against O. volvulus have reduced transmission, there remained a reported 1.15 million cases of vision loss in 2017.

Viral keratitis is overwhelmingly the result of infection with HSV and to a lesser extent VZV. Approximately 500,000 people in the United States and 1.5 million globally are affected by HSV keratitis. Infection can be due to primary infection with either HSV or VZV, but in both instances infections are more common with recurrences of these viruses in the form of reactivation of latent virus. Both viruses can lead to a variety of corneal lesions along with causing decreased corneal sensation. Unlike most other kinds of keratitis, the latent nature of these viral infections can lead to chronic and recurrent infections.

Endophthalmitis

Infection of the vitreous or aqueous humors is known as endophthalmitis. It is exclusively caused by bacteria and fungi, as viral and parasitic infections that may involve the vitreous or aqueous humors are classified under uveitis. Patients present with decreased vision and eye pain can also be present.

Most bacterial cases of endophthalmitis are associated with eye trauma caused by surgical or medical treatment for cataracts, glaucoma, or macular degeneration. Depending on the type of surgery, the microbial causes of infection change. Infection occurs most frequently following cataract surgery and coagulase-negative staphylococci comprises about 70% of infections. S. aureus , S. pneumoniae , other Streptococcus species, Enterococcus species, and H. influenzae can all also play a role in postsurgical endophthalmitis. Nonsurgical trauma can also lead to endophthalmitis; these infections have a much wider variety of microbial causes with Bacillus cereus as the leading cause of significant infection.

Besides trauma, the other route of developing bacterial endophthalmitis is secondary to bacteremia and seeding of the eye. Endocarditis and urosepsis are often the source of bacteremia. In North America, S. aureus is the most common pathogen but viridans group streptococci, S. pneumoniae, S. pyogenes, E. coli , and K. pneumoniae can also be causes. In East Asia, hypermucoid K. pneumoniae associated with liver abscess is the leading cause of endogenous bacterial endophthalmitis.

Fungal endophthalmitis is divided into infections caused by yeasts and filamentous fungi. Endophthalmitis secondary to yeast is almost exclusively due to Candida species, although Cryptococcus and other yeasts have caused rare infections. Candida endophthalmitis is primarily acquired through endogenous infection secondary to active fungemia. It is the most common cause of fungal endophthalmitis in North America and Europe. Risk factors are the same as those for candidemia including neutropenia, receiving total parental nutrition, having indwelling catheters, and receiving broad-spectrum antibiotics. Endophthalmitis caused by filamentous fungi is more common in tropical regions, where it exceeds Candida endophthalmitis in frequency. Although endophthalmitis caused by filamentous fungi can be acquired endogenously through fungemia, it is more commonly acquired through exogenous methods either by direct extension from fungal keratitis or secondary to penetrating trauma to the globe. Fusarium species, the most common cause of fungal keratitis, is the leading cause of filamentous fungal endophthalmitis. Aspergillus species also are a major cause of endophthalmitis.

Uveitis

Inflammation of the uvea, the pigmented, vascular middle layer of the eye between the cornea and the retina, is known as uveitis. The uvea consists of the iris, the ciliary body, and the choroid which supplies oxygen and nutrients to the retina. Although the retina is structurally distinct from the uvea, retinitis is considered part of uveitis as it commonly occurs in conjunction with involvement of the choroid. Most causes of uveitis are idiopathic or autoimmune, but a number of infectious etiologies can lead to uveitis.

The most common cause of infectious uveitis worldwide is the parasite T. gondii . In contrast with CNS T. gondii infection, most patients with ocular T. gondii infection are immunocompetent. Infection typically begins in the retina and spreads to the choroid. Patients usually present with floaters and vision loss.

The herpesviruses HSV, VZV, and CMV are all causes of infectious uveitis. HSV can induce an anterior uveitis, most commonly affecting the iris. These patients often also have complications of HSV keratitis. HSV and VZV can both induce a rapidly progressive necrotizing retinitis known as acute retinal necrosis. This condition typically starts with anterior uveitis before spreading posteriorly. Patients usually have mild eye pain or photophobia, followed by decreasing vision in the affected eye. CMV is classically associated with CMV retinitis, which presents as painless vision loss. CMV retinitis occurs in immunocompromised patients, most commonly those with advanced HIV infection. Fortunately, increases in the use of highly active antiretroviral therapy for HIV has led to decreased rates of CMV retinitis. Other rare viral causes of uveitis include West Nile virus, chikungunya virus, and Ebola virus.

Bacterial causes of uveitis are relatively rare. Syphilis is the most common, and it can be the presenting feature of syphilis infection. Ocular syphilis can also lead to keratitis, but uveitis involving any portion of the uvea is more common. Other rare bacterial causes of uveitis include M. tuberculosis (tuberculosis), B. burgdorferi (Lyme disease), B. henselae (cat scratch disease), Leptospira species (leptospirosis), Brucella species (brucellosis), and Mycobacterium leprae (leprosy).

Pediatric considerations

For the most part, children suffer from similar eye infections as adults. Conjunctivitis is an incredibly common issue with adenovirus being the most common causative agent. However, in the neonatal period, infants are prone to ocular infections of sexually transmitted organisms. Specifically, neonatal conjunctivitis secondary to N. gonorrhoeae and C. trachomatis requires prompt recognition. HSV can lead to ocular infection both in the form of conjunctivitis and keratitis in the neonatal period. However, unlike in adults, where 80% of ocular HSV infections are secondary to HSV-1, HSV-2 is the more frequent cause of ocular infection in the pediatric time period. Some congenital infections, specifically CMV, toxoplasmosis, and syphilis can have ocular involvement, primarily in the form of uveitis/retinitis.