on 05-May-2022 (Thu)

simple procedure of mixing together India ink and biologic fluids to identify the 5- to 10-micron-diameter encapsulated yeasts remains a rapid and effective method for diagnosing cryptococcal meningitis (Fig. 262.6).

Approximately 50% of non-AIDS patients with cryptococcal meningitis and over 80% of patients with AIDS have a positive India ink examination of the CSF.

India ink smears of urine, sputum, and bronchoalveolar lavage specimens are almost impossible to interpret.

Gomori methenamine silver fungal stain identifies the narrow-based budding yeast in tissue (Fig. 262.8), and a Gram stain usually reveals a poorly stained gram-positive yeast.

Most C. neoformans isolates from untreated patients can be detected in culture 3 to 7 days after the specimen is collected and placed into or on culture media.

Quantitative CSF yeast counts have been used for evaluation of antifungal therapy. 280,281 Initially, this counting of viable CSF yeasts was an effective research tool to determine the impact of various treatments on the burden of yeasts, but recently this quantitative CSF culture strategy has begun to show clinical relevance and correlation with outcome. 282–284 It may become attractive to utilize in individual therapeutic strategies. 285

The tests for detection of cryptococcal polysaccharide antigen in serum and CSF are extremely accurate for the diagnosis of invasive disease. 295

Both latex agglutination and enzyme-linked immunosorbent assay tests are greater than 90% sensitive and specific. 296

False-positive latex agglutination tests are usually negative by EIA, and vice versa. An occasional false-positive test is observed when there is a cross-reactive antigen in the specimen, and this may occur with microorganisms such as Trichosporon asahii (beigelii) 299 or other infections.300

The false-negative tests may be present in early asymptomatic meningitis and in chronic, indolent meningitis.

The clinical experience with, and preciseness of, antigen detection has been carefully studied and validated in sera and in CSF for clinical practice, and it is not recommended to detect polysaccharide antigen in the urine and bronchoalveolar lavage fluid, despite some reports to the contrary. 301

Recently, a new lateral flow assay (LFA) has been introduced into clinical practice. It is cheap, rapid, and simple. The LFA has been found to be more sensitive than the Meridian Premier EIA and at least as sensitive as the Meridian CALAS latex agglutination test. 302

Like other tests for cryptococcal polysaccharide antigen, false-positives can be observed in sera from the rare cases of T. asahii infection. 305,306

A number of clinical issues are related to the use of cryptococcal polysaccharide antigen. Serum cryptococcal polysaccharide antigen tests have been used successfully to screen high-risk, febrile AIDS patients, particularly those with headache, in areas where the incidence of cryptococcal meningitis is high, 307 but these tests may be less useful in areas where the prevalence of infection is low. 308

In patients with cryptococcal infection of the lung who have a positive serum polysac- charide antigen test, there is heightened concern that the infection has become extrapulmonary

In fact, there are occasional cases of meningitis in which CSF antigen is detected early in infection before there is a high enough yeast colony count for the routine clinical laboratory to detect a positive culture, particularly with small volumes of CSF. There are also isolated cases of serum cryptococcal polysaccharidemia in asymptomatic HIV-infected patients with negative fungal cultures from CSF and urine.

As a strategy in the clinic where lumbar punctures are limited, recent studies suggest that a positive serum antigen titer of 1 : 160 or greater reflects a clinically relevant risk of CNS involvement in asymptomatic patients and demands an aggressive approach to manage cryptococcal CNS disease. 314

Despite its excellence as a diagnostic test, the cryptococcal polysac- charide antigen test is not sufficiently accurate to use in making specific decisions during treatment. In fact, serial polysaccharide antigen titers are imprecise and should not be used to develop treatment guidelines. 315

The cryptococcal polysaccharide antigen titer, however, does give general prognostic information. Initial high titers (≥ 1 : 1024) demonstrate a high burden of yeasts in the host, poor host immunity, and a greater chance of therapeutic failure

Furthermore, it is encouraging when consideration of an IRIS diagnosis is being made that the cryptococcal antigen titer is stable or dropping.

The chest radiograph of pulmonary cryptococcosis can show a variety of characteristics, including local or diffuse infiltrates, nodules, hilar lymphadenopathy, cavitation, and pleural effusion(s). 316–320

Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain are frequently used in the management of cryptococcal meningitis. 323–327

Approximately half of CT scans are normal during CNS infection. However, a CT scan can reveal hydrocephalus, gyral enhancement, or single or multiple nodules that may or may not be enhancing. Cryptococcomas may be single or multiple, and in some populations, such as those with C. gattii infection, they can occur in more than 25% of non-AIDS and apparently immunocompetent patients.

The MRI scans are more sensitive than CT scans for detecting abnormalities in cryptococcal meningitis. MRI findings can include numerous, clustered foci that are hyperintense on T2-weighted images and nonenhancing on postcontrast T1-weighted images in the basal ganglia or midbrain. Rarely, there may also be multiple miliary enhancing parenchymal and leptomeningeal nodules.

First, there is no pathognomonic scan, and patients with cryptococcal meningitis may simply present with evidence of idiopathic hydrocepha- lus. 32

Third, follow-up scans may actually show worsening of lesions, with enlargement, new lesions, or persistence of cryptococcomas or more leptomeningeal enhancement. These findings are not necessarily a sign of treatment failure. They may simply represent enhancement by inflam- mation as microscopic yeast foci are being eliminated.

However, before the availability of antifungal agents, there were several reports of patients who survived for years before succumbing to infection. 332 In contrast, with the severe immunosuppression of HIV infection and if adequate treatments are not available, a high percentage of untreated patients die within the first 2 weeks of hospitalization. 333

In fact, there appears to be some correlation between MICs and clinical resistance, 336–338 and by molecular typing methods, most of the refractory cases represent relapse isolates rather than reinfection. 339,340

Methods for in vitro susceptibility testing of C. neoformans and C. gattii have been modified and standardized, and the epidemiologic cutoff values for the cryptococcal complex to azoles have been established. 334,335

When MICs of isolates rise while the patient is being treated, or when the MICs were initially greater than 16 μg/mL for fluconazole or 128 μg/mL or greater for flucytosine, failure of treatment might possibly be related directly to drug resistance. 345

However, there is as yet no specific therapeutic MIC breakpoint for antifungal drugs validated for cryptococcosis.

However, unstable drug resistance with aneuploidy formation during in vivo stress may be lost in vitro and thus might be missed with in vitro cultures and direct drug susceptibility testing. 60

Psittacosis, also known as ornithosis, is usually a disease with prominent systemic manifestations and some respiratory symptoms. This infection, caused by Chlamydia psittaci, is transmitted to humans predominantly from birds

C. psittaci is an obligate intracellular bacterium. There are 10 known genotypes based on sequencing of the major outer protein gene, ompA [1]. Each genotype has host preferences and virulence characteristics, although these overlap

Psittacosis has been recognized throughout the world, including the United States, the United Kingdom, Europe, the Middle East, and Australia.

In a meta-analysis of observational studies, C. psittaci, the causative agent of psittacosis, was estimated to cause approximately 1 percent of cases of community-acquired pneumonia [3]

Birds are the primary reservoir, but transmission from other animals has also been reported. The disease usually occurs sporadically, but outbreaks caused by contact with an infected bird are not uncommon [9]. Outbreaks related to pet shops, aviaries, veterinary facilities, poultry flocks, and turkey and duck processing have been described [10-15].

Most patients with psittacosis have a history of contact with birds. C. psittaci has been documented in at least 460 species from 30 bird orders, including turkeys, pheasants, chickens [16], and even ostriches and penguins [17]. Migratory birds, including geese, may carry this pathogen [18]

In France, mule ducks are associated with human disease through heavy shedding, although the ducks are asymptomatic [19]. Each bird order tends to be infected by a predominant genotype of C. psittaci

Of 1136 patients reported to the United States Centers for Disease Control and Prevention (CDC) between 1975 and 1984, 72 percent had a history of contact with birds as pets or in a domestic setting, 6 percent had contact with wild birds, 12 percent were poultry workers, and only 10 percent had no recognized avian contact [9]

The incubation period in birds is extremely variable, from three days for acute disease to years for reactivation of latent infection, often at a time of stress. Infection in birds is usually asymptomatic or may cause lethargy, anorexia, ruffled feathers, ocular or nasal discharge, or diarrhea. Some birds die rapidly; others become wasted or dehydrated. The organism is shed in feces, urine, and respiratory secretions. Once feces dry, the organism may become airborne as droplet nuclei. Dried organisms remain viable for months at room temperature

Transmission of infection from other animals to humans is rare. Certain strains of C. psittaci may infect sheep, goats, cats, dogs, dairy cattle, and horses, causing placental insufficiency, abortion, and a chronic respiratory infection.

Humans are usually infected by inhalation of organisms in dried feces when caged birds exercise their wings or in bird feather dust. Cage cleaning may pose an infection risk [14]. Bird bites, mouth-to-beak contact, and even transient exposure, such as visiting a bird park, have also been implicated in the transmission of this infection.

Outbreaks associated with chicken slaughter plants have occurred, with those working with eviscerating birds most at risk. Some workers experienced severe illness requiring intensive care unit admission [21]

Human-to-human transmission may occur. In Sweden, one severely ill patient with psittacosis transmitted infection to 10 others, including a hospital roommate and 7 hospital staff [37]

Psittacosis is most common in young and middle-aged adults, although it has been described in all age groups.

Infection is not always associated with a major illness. When avian chlamydiosis was detected in a large shipment of pet birds, households exposed were investigated. Eleven percent of exposed persons developed an acute respiratory illness. Clinical or serological evidence of infection was found in 30 percent of households. In many, infection led to mild illness or was asymptomatic [41]. However, deaths are occasionally reported [42].

In 2014, a total of 8 psittacosis cases were reported in the United States [43], compared with an average of 10 cases (range 2 to 21) reported annually during the period 2005 to 2011 [44].

C. psittaci infection of humans most commonly presents in young or middle-aged adults as fever of abrupt onset, pronounced headache, and dry cough. Infection can also be asymptomatic.

Patients usually have a recent history of bird exposure. The incubation period is usually between 5 and 14 days but can be as long as 39 days [45]

In one study of 135 patients, systemic manifestations were prominent with fever in all patients, rigors occurring in 61 percent, and sweats and myalgias in most patients [38]

Though cough was present in 82 percent of patients, it frequently developed late. Other respiratory symptoms, including dyspnea, chest pain, and hemoptysis, were present in 24 percent of patients. Eighteen percent of patients had no respiratory symptoms

Headache is common, usually severe, and may be accompanied by photophobia. One-third of the 135 patients in the above series underwent lumbar puncture for possible meningitis [38]

Other less common but important symptoms include pharyngitis, diarrhea, and altered mental status. Diarrhea may be seen in up to 25 percent of patients and is typically mild. It can be quite severe, however, and may even be the most prominent symptom in some patients [38]. Twelve percent of patients present with altered mental status, which can range from mild confusion to, rarely, overt encephalitis [46].

Most patients have some abnormalities on chest examination (usually rales), occasionally have evidence of consolidation, and uncommonly have a pleural rub. Pleural effusions occur infrequently and are rare enough to prompt reconsideration of the diagnosis. Splenomegaly and hepatomegaly occur in approximately 10 percent of patients [38].

Complications in a number of organ systems may arise in patients with psittacosis. These are uncommon manifestations of the illness, but some can be severe.

Patients with fulminant pneumonia often also manifest neurologic, renal, and gastrointestinal complications [47-49]

Hematologic complications in fulminant disease include disseminated intravascular coagulation [50,51] and hemophagocytic syndrome [52].

Mild renal involvement with proteinuria and occasional oliguria is well recognized [53]. Rarely, acute tubular necrosis may occur in fulminant psittacosis with respiratory failure. Acute tubulointerstitial nephritis and acute proliferative glomerulonephritis have also been reported [54].

Cold agglutinins are sometimes noted in psittacosis, but hemolytic anemia with jaundice is rare [55]. Acute thrombocytopenic purpura, severe pancytopenia secondary to hemophagocytic syndrome, and thrombotic thrombocytopenic purpura in a patient with respiratory failure have also been described.

Icteric hepatitis occurs uncommonly [56]. One patient with multiple nodules in the liver and spleen who had a pericardial rub but no evidence of pulmonary disease was found to have hepatic granulomas and serological evidence of psittacosis [57].

A wide range of neurologic syndromes are infrequently seen, although abnormal neurologic findings are less common than with mycoplasma infection

Encephalitis was seen in 2 of 156 patients in a series from the United Kingdom [58]. Cerebellar disturbance may be prominent. Psychiatric symptoms and intracranial hypertension have been described [9]

True meningitis with a cerebrospinal fluid pleocytosis may occur rarely [59]

Uveitis has been seen in association with meningitis. Palsies of the 4 , 6 , 7 , and 12 cranial nerve have been described, often accompanying overt encephalitis [61]. Diplopia may persist for months. Transient sensorineural deafness associated with pneumonia has been reported [62].

Transverse myelitis with fever can also be the clinical presentation of psittacosis [63]. The neurologic deficit may or may not resolve. In addition, Guillain-Barré syndrome can follow acute infection [46]

Reactive arthritis, though rare, has been reported. The onset may be a week or more after the first symptoms of psittacosis [64]. Migratory small and large joint arthritis, symmetrical polyarthritis, and reactive arthritis (formerly Reiter syndrome) have been described [65,66].

Rhabdomyolysis has also occurred [38,68].

Dermatologic manifestations are infrequent. Erythema nodosum is the most frequent, but erythema multiforme, erythema marginatum, "Horder spots," and panniculitis also have been reported [69]

Conjunctivitis with enlarged preauricular nodes and punctuate epithelioid keratitis, without any associated systemic symptoms, has been

Endocarditis caused by C. psittaci is rare [73]. It should be considered in the differential diagnosis of culture-negative endocarditis usually lasting weeks or months, especially if there is a history of bird exposure.

Infection in pregnancy may be life-threatening, particularly in the late second or third trimester [79]. Respiratory failure, liver dysfunction, and disseminated intravascular coagulation may threaten the life of the mother. Eleven of 14 pregnant women died in a psittacosis outbreak in 1938. Fetal outcome is poor, with fetal death in 11 of 14 reported cases [80]

The white cell count is usually normal, but the differential may show toxic granulation or a "left shift." Occasionally, there is a marked leukocytosis. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are very often elevated. In an Australian series, the mean peak ESR was 50 mm/hour, and CRP was 129 mg/L [38].

The liver enzymes are abnormal in approximately half of hospitalized patients, usually with mild elevation of the aspartate transaminase and low serum albumin levels

Hyponatremia is quite common, as is mild elevation of serum creatinine and blood urea nitrogen. Serum creatinine kinase levels are infrequently elevated [83]

The chest radiograph is abnormal in approximately 80 percent of cases, most often with lobar changes; such changes were observed more frequently in the lower lobes in some series [84]. Approximately one-quarter of patients have multilobar changes, and slightly fewer have a normal chest radiograph [39].

On high-resolution computed tomography, the pulmonary infiltrates may be nodular surrounded by ground-glass opacities [86]

In patients undergoing lumbar puncture, elevation of cerebrospinal fluid protein levels is frequently observed. Elevated cerebrospinal fluid white blood cell counts occur rarely

The typical clinical features (fever, headache, myalgias, dry cough) in a patient with a history of bird contact should suggest the diagnosis and should prompt the initiation of appropriate treatment

In a patient presenting with pneumonia, severe headache, splenomegaly, and failure to respond to beta-lactam antibiotics may be other clues to the diagnosis

When atypical pneumonia, the other etiologies to consider include Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella infection.

If the patient primarily has a febrile illness without localizing signs, influenza, endocarditis, septicemia, vasculitis, Coxiella burnetii infection, leptospirosis, and brucellosis should also be considered

When extrapulmonary manifestations predominate, the patient should be evaluated for the causes of the most prominent manifestation such as gastroenteritis, hepatitis, meningitis, or encephalitis

The diagnosis of psittacosis is typically established by serologic testing. Culture is discouraged since C. psittaci is highly infectious when cultured and is only performed in specialized laboratories. All of the available diagnostic tests have major limitations, as discussed below

Since culture is both difficult and dangerous, serology is the principal method of confirming the diagnosis. There are two types of serologic tests available: complement fixation (CF) and microimmunofluorescent (MIF) antibody test. When available, we favor MIF testing, but CF testing may be used as an alternative

The MIF test is the most sensitive and specific serologic test for C. psittaci but is only available in specialty laboratories [89]

The antigen used is Chlamydia species- specific surface antigen. An MIF test showing a fourfold rise in antibodies or an immunoglobulin (Ig)M antibody titer ≥16 is interpreted as diagnostic.

As the serologic response seen in both CF and MIF is often unimpressive, a single antibody titer of ≥32 in either test combined with a typical history is sufficient for a diagnosis of "probable psittacosis."

A number of studies reevaluated by MIF cases that were diagnosed as psittacosis based upon clinical history and a positive CF test. C. psittaci was confirmed in 32 to 77 percent of patients [89-91]. A history of bird contact increased the probability of the diagnosis of C. psittaci, and clustering of cases in a family increased the probability of C. pneumoniae

The CF test is the test that has been used traditionally to make the diagnosis. It is the most widely available test but unfortunately cannot differentiate among the chlamydial species. The antigen used is a lipopolysaccharide present in the outer membrane of all Chlamydia spp. Paired acute and convalescent sera should be obtained at least two weeks apart, and a fourfold rise in antibody levels is significant. If there are clinical grounds for suspecting psittacosis and no antibody response is detected, the CF test should be repeated in another two weeks. Treatment with tetracycline may delay or diminish the antibody response.

Polymerase chain reaction (PCR) methods for the detection of C. psittaci have been developed [93,94]. They have been used in outbreak investigations and give a rapid and specific diagnosis [95-97]. Initial results from nested PCR for C. psittaci suggest good specificity but less sensitivity than for C. pneumoniae [95].

DNA may be detected in whole blood, throat specimens, and urine [100]

PCR testing of sputum, when available, in all community-acquired pneumonia patients in a Dutch study led to an increased recognition of psittacosis as a pathogen compared with previous studies of pneumonia in that setting (4.8 versus 0 to 2.1 percent) [101].

Commercial multiplex PCR assays do not test for C. psittaci [103,104].

The tetracyclines are preferred for the treatment of psittacosis, but other agents have been proposed as alternatives. Macrolides are frequently used in the treatment of community- acquired pneumonia in the absence of a microbiologic diagnosis and are highly likely to be effective for psittacosis

Doxycycline (100 mg orally twice daily) usually produces a rapid clinical response in patients with mild to moderate disease. Doxycycline can be given intravenously in critically ill patients. In one series, 92 percent of patients defervesced within 48 hours of commencing treatment with one of these agents [38]

Although the optimal duration of therapy for psittacosis has not been determined, we generally treat for 7 to 10 days when using a tetracycline.

A macrolide, such as erythromycin or azithromycin, is usually recommended as the second-line therapy when the tetracyclines are contraindicated. In one study of five patients treated with erythromycin, the response appeared equivalent to tetracyclines [105]. If azithromycin is used, treatment duration may be shortened to five days if there is a prompt clinical response.

We favor azithromycin over erythromycin since azithromycin is better tolerated

Ofloxacin proved effective in the treatment of 13 patients [107], but the role of quinolones in this infection requires further evaluation.

Many health authorities require clinicians to report patients with psittacosis [9]. Reporting facilitates the recognition of outbreaks and the evaluation and treatment of the birds that are the source

Patients recovering from psittacosis will often ask if they should destroy their pet bird if they developed psittacosis following exposure to the bird, but this is not usually necessary. Psittacosis of the bird can usually be cured or suppressed with antibiotic treatment alone. If the bird is kept in poor or crowded conditions, stress may be contributing to the shedding of organisms and should be corrected

C. psittaci is a "category B" bioterrorism agent. Disease could be spread by aerosol [113]

Psittacosis is a disease with prominent systemic manifestations and some respiratory symptoms. This infection, caused by Chlamydia psittaci, is transmitted to humans predominantly from birds.

Humans are usually infected by inhalation of organisms in dried feces when caged birds exercise their wings or in bird feather dust. Cage cleaning may pose an infection risk. Bird bites, mouth-to-beak contact, and even transient exposure, such as visiting a bird park, have also been implicated in the transmission of this infection. The incubation period is usually 5 to 14 days.

C. psittaci infection of humans most commonly presents in young or middle-aged adults as fever of abrupt onset, pronounced headache, and dry cough. Patients usually have a recent history of bird exposure. Most patients have some abnormalities on chest examination (usually rales), may have evidence of consolidation, and uncommonly have a pleural rub. (See 'Clinical features' above and 'Physical examination' above.) ●

The chest radiograph is usually abnormal, most often with lobar changes.

The typical clinical features (fever, headache, myalgias, dry cough) in a patient with a history of bird contact should suggest the diagnosis and should prompt the initiation of appropriate treatment. In a patient presenting with pneumonia, severe headache, splenomegaly, and failure to respond to beta-lactam antibiotics may be other clues to the diagnosis.

We recommend the tetracyclines as first-line therapy for psittacosis. Doxycycline (100 mg orally twice daily) usually produces a rapid clinical response in patients with mild to moderate disease. Tetracycline hydrochloride or doxycycline (4.4 mg/kg per day divided into two daily doses) is given intravenously in critically ill patients. We generally treat for 7 to 10 days.