Psittacosis

Etiology

C. psittaci is a gram-negative, obligate intracellular bacterium of both mammals and birds with multiple genotypes, which can be sequenced by genotype-specific real-time PCR for identification and epidemiological studies. Each genotype is associated with a specific animal host, and all can be transmitted to humans, causing psittacosis.[1] There are ten known genotypes to date based on the sequencing of gene ompA.[2] Data regarding psittacosis is quite limited, which hinders a deeper understanding of pathologic serotypes and their virulence. For example, from 2006 to 2012, only 58 human cases of psittacosis were reported to the Centers for Disease Control and Prevention (CDC) in the United States. According to the CDC Weekly Morbidity and Mortality report from September 2014, only 2 of these cases were confirmed by culture. The remaining were diagnosed based on serologic testing only.

As stated above, contact with birds appears to be the primary risk factor for psittacosis in humans.[1] Psittacosis can also occur from indirect exposure via environmental factors such as feces, urine, and other secretions of infected birds.[3] Among birds, these organisms are most commonly isolated from cockatiels, parrots, parakeets, and budgies. Poultry birds have periodically led to psittacosis outbreaks in poultry farmers. Chickens, ducks, and turkeys have all been identified as a source of psittacosis. 

Epidemiology

Psittacosis can affect any age group and gender, but incidence tends to peak in middle age, with an age range of 35 to 55.[4] The first outbreak of psittacosis linked the disease to pet parrots and finches in 1879, with pandemics occurring in 1929 and 1930. Despite this, psittacosis is regarded as a rare zoonotic infection. Thus, there is a decreased awareness of this disease entity among the public and health care professionals. When coupled with the need for specialized testing, underdiagnosis of psittacosis is likely when examining reports of prevalence and incidence.[5] 

The Centers for Disease Control and Prevention (CDC) in the United States classifies psittacosis as a reportable condition in most states, with estimated confirmed cases numbering fewer than ten annually. This is likely due to underdiagnosis and underreporting. Individuals with exposure to pet shops, veterinary hospitals, bird exhibitions, and occupational exposure in the poultry industry are considered at the highest risk of contracting the disease.[5] The incidence of psittacosis in the United States from 1999 to 2006 was reported as 0.01 per 100,000 population.[6] Studies examining hospitalized patients with pneumonia have traditionally found psittacosis to be the etiologic agent in less than 5% of cases.[7][8] 

Psittacosis has been reported throughout the world. In a meta-analysis review of community-acquired pneumonia (CAP) worldwide, C. psittaci was reported to be the causative agent in 1.03% of the cases, with a range of 0 to 6.7%.[9] A meta-analysis reviewing studies from multiple countries similarly reported that 1% of all hospitalized CAPs were caused by C psittaci.[9] The reported incidence, however, was noted to be far lower on an annual basis suggesting underdiagnosis of this infection. Psittacosis is usually sporadic, but outbreaks have been reported as well. These outbreaks tend to be associated with pet shops, poultry farms, and veterinary facilities.[10][11]

Improved diagnostic techniques and strategies will likely lead to an apparent increase in the incidence of psittacosis. A 2022 study from China, using combined molecular techniques to identify pathogens in severe community-acquired pneumonia cases, revealed that Chlamydia psittaci was the causative agent in 6.8% of the patients (15 out of 222).[12]

Pathophysiology

C. psittaci is a gram-negative, obligate intracellular bacterium with a developmental cycle that entails two forms. The organism consists of an extracellular infectious elementary body and a larger metabolically active intracellular reticulate body. After exposure to a host’s eukaryotic cell, the infectious, elementary body is endocytosed into the cell through interaction with the cell membrane receptor of the host cell, thereby evading the host immune system response. The endocytosed elementary body increases in size to form the metabolically active reticulate body.[13][14] 

These reticulate bodies can undergo binary fission utilizing ATP from the host cell to form new reticulate bodies. These inclusion reticulate bodies then restructure back into an intermediate state and finally into elementary bodies and are released by cell lysis as well as reverse endocytosis, which can leave the host cell intact, and is thought to allow a chronic and silent infection.[14] These released elementary bodies then infect new host cells, propagate the disease cycle, and spread via the hematogenous route to various organ systems.[15]

Although the exact pathophysiology has yet to be fully elucidated, recent studies using a bovine model show that upon inoculation of C. psittaci, there is an initial infection of the alveolar epithelial cells.[16] This initiates a complex host response leading to a large influx of neutrophils, thought to be mediated through chemokine release, especially interleukin-8, a pro-inflammatory cytokine, from the infected host.[16] This acute-phase reaction mediated through chemokines leads to the activation of an inflammatory cascade and reactive oxygen species, which triggers further recruitment and accumulation of phagocytes and immune cells from the bloodstream to the site of the infection. This is thought to result in tissue damage and breakdown of the alveolar-capillary membrane enabling the hematogenous spread of C. psittaci.[16] The localized infection and resulting inflammatory cascade also result in a relative barrier for oxygen transfer within the alveoli leading to hypoxemia and limitations in lung compliance and resultant alveolar hypoventilation.[16]

Histopathology

Microscopically, exudates form and consist of fibrin, neutrophils, and hemorrhage. The bacteria are visible with light microscopy as basophilic cytoplasmic inclusion bodies of 0.25 to 0.5 mm in diameter.[14] 

History and Physical

Despite the strong link to bird exposure, it is not necessary for a diagnosis. This is especially true in areas with large numbers of wild birds. For example, there have been two outbreaks in Australia with towns surrounded by a large avian flora.[17][18] Regardless, a large part of the diagnosis relies on a thorough history with special consideration for the patient's occupational and travel history and hobbies, as well as a high index of suspicion. Symptoms of psittacosis are mainly respiratory but can vary tremendously. After replication in the respiratory system, the infection can spread hematogenously to affect multiple organ systems. It is often described initially as an influenza-like syndrome characterized by fevers, chills, headaches, and a cough. Case studies have shown that the infection can range from an asymptomatic state to a fulminant invasive disease with an average incubation period of 5 to 14 days.[19]

Symptom onset is typically abrupt, with a headache cited as the most prominent complaint, in addition to fever, myalgias, nausea, vomiting, diarrhea, and cough.[4] The cough is typically nonproductive.[20] Studies have cited the presence of a severe headache as being a characteristic feature.[1] Other signs of psittacosis that have been documented include altered mental status, mild neck stiffness, photophobia, hepatosplenomegaly, and pharyngitis.[1]

Psittacosis can affect multiple organ systems, and a multitude of manifestations have been reported in case reports of psittacosis.[1] These include:

• Central nervous system manifestations of meningoencephalitis, cerebellar ataxia, cranial nerve palsies, transverse myelitis, Guillain-Barre syndrome, and status epileptics
• Respiratory manifestations of pneumonia, acute respiratory distress syndrome, respiratory failure, and septic shock
• Cardiac manifestations are rare but can include myocarditis, pericarditis, culture-negative endocarditis, and aortitis
• Renal and gastrointestinal manifestations include acute interstitial nephritis, acute renal failure, glomerulonephritis, hepatitis, and pancreatitis
• Hematological manifestations include disseminated intravascular coagulation (DIC), splenomegaly, and hemophagocytic syndrome
• Rheumatological manifestations include reactive arthritis and polyarteritis
• There have also been cases of gestational psittacosis with poor fetal and maternal outcomes, as well as an association with ocular lymphoma

The physical exam will usually reveal rales or evidence of consolidation on pulmonary auscultation. Traditionally, pleural rubs and pleural effusions have been uncommon in psittacosis and, when present, warranted considering an alternate diagnosis.[4] However, recent retrospective analyses reported that more than 50% of the patients (27 out of 52) had pleural effusions on presentation.[20] Auscultatory findings, however, frequently underestimate the extent of pulmonary involvement in psittacosis.[3] Hepatosplenomegaly occurs in 10% of the patients affected with psittacosis.[4] Dermatologic manifestations are rare in psittacosis.[21] A pulse-temperature dissociation (fever without tachycardia) is also present, with one study reporting the presence of relative bradycardia in patients with psittacosis to be as high as 71% (34 out of 48 patients).[3][22]

Evaluation

Psittacosis is noted for a normal white cell count with toxic granulation or a left shift on laboratory testing. Leukocytosis is uncommon but can be seen. Other markers of acute inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are often elevated.[4] Creatine level is usually elevated, and hyponatremia is quite common.[23] Liver function testing, specifically aspartate and alanine aminotransferase and gamma-glutamyl transpeptidase (AST, ALT, GGT), are also variably elevated.[24] Although hemolytic anemia has been reported in case studies, it is a rare finding in psittacosis.[25]

Chest imaging is abnormal in the majority of the cases, most often revealing lobar infiltrates.[26] However, it should be noted that a normal chest X-ray does not rule out psittacosis. Chest computed tomography (CT) often reveals unilateral lung involvement, with single lobe involvement in more than 50% of the cases.[22] If cerebrospinal fluid is obtained, it usually reveals elevated proteins without significant elevation in white blood cell count. 

Psittacosis Specific Testing

Traditionally, serologic testing has been used to confirm suspected cases of psittacosis. Available serologic tests for psittacosis include complement fixation (CF) testing and micro-immunofluorescent (MIF) antibody testing with paired sera. MIF testing is more sensitive and specific for C. psittaci when compared to CF.[27] A MIF test with an immunoglobulin (Ig)M antibody titer greater than or equal to 16 or a four-fold increase in antibody titer two weeks apart is considered diagnostic for psittacosis. CF testing does not differentiate between chlamydial species and is much less specific for psittacosis. The diagnostic threshold for CF is a four-fold increase in antibody titer two weeks apart. 

Monoclonal antibody techniques are being developed for diagnosing psittacosis, but studies demonstrating the sensitivity and specificity of these techniques are still lacking. DNA-based polymerase chain reaction (PCR) techniques have also been developed. They show promise as rapid diagnostic tools for diagnosing psittacosis but are not widely available. A 2016 study from the Netherlands that performed real-time polymerase chain reaction (PCR) testing in all patients hospitalized with CAP reported PCR testing to be highly reliable with a rapid turnaround time compared to traditional serologic testing.[28] Moreover, it led to increased recognition of the disease, with psittacosis causing 4.8% of all CAPs in that study. 

An emerging diagnostic tool is metagenomic next-generation sequencing (mNGS), which was shown to increase the rate of pathogen identification in severe community-acquired pneumonia cases from 40.8% (when using PCR) to 74.2% (when using mNGS).[12] This study showed that both molecular techniques were far better at identifying causative pathogens when compared to routine cultures, which were only 14.4% positive. A recent study identified mNGS as an accurate and reliable method for diagnosing psittacosis in CAP.[29] In a family outbreak of 3 patients in China, CAP negative for COVID-19, H1N1 flu virus, parainfluenza virus, Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae was noted. Blood and sputum cultures remained negative, but mNGS of blood and bronchoalveolar lavage fluid identified C. psittaci within 48 hours in all three patients. The subsequent history of pet parrots who had recently been sick was identified.[29] 

A 2022 study reported higher sensitivity of mNGS than PCR in blood for diagnosing psittacosis because mNGS can detect pathogens with an extremely low DNA load in the sample.[30] Although promising, limitations to its use as a widespread, reliable diagnostic tool include a higher cost and lack of an authoritative guide to interpret its results. It detects a broad spectrum of pathogens, resulting in the inability to distinguish between colonization and microbial infection.[29] 

Culture is the most specific and accurate method to diagnose psittacosis; however, it should be noted that isolation of C. psittaci requires a biosafety level three facility due to the risk of transmission to laboratory personnel.[30]

Diagnostic Criteria for Psittacosis 

The Centers for Disease Control and Prevention (CDC) has published guidelines for diagnosing psittacosis. In the appropriate clinical scenario, a diagnosis is made by meeting any one of the criteria listed below:

• Isolation of the causative organism from respiratory secretions
• A noted four-fold or greater increase in antibody titer between serum samples collected two weeks apart via the complement-fixation test (CFT) or micro-immunofluorescence (MIF)
• A single IgM antibody titer detected by MIF of 1:16 or higher

Treatment / Management

Treatment for this bacterial infection is based on intracellular activity, pharmacokinetics, and evidence from clinical trials that recommend tetracycline antibiotics, particularly doxycycline, as the preferred treatment. Case studies have shown that with treatment, most infected individuals will have an improvement in fever and clinical symptoms within 48 hours.[4] Doxycycline 100 mg orally or intravenously every 12 hours for 7 to 10 days is the preferred treatment for psittacosis.[30] Beta-lactam antibiotics are ineffective in the treatment of psittacosis.[20](B2)

In pregnancy and in patients where doxycycline is contraindicated, the infection is best treated with macrolide antibiotics, such as azithromycin (a 5-day course if clinical response is seen) and erythromycin for a 7-day course. Third-line antibiotics active against C. psittaci include fluoroquinolones, which are less effective than tetracyclines and macrolides. 

Macrolides remain the agents of choice in children with mild to moderate infection. However, as has been proposed for the treatment of Rocky Mountain spotted fever, in cases where the benefit of treatment with doxycycline outweighs the potential risk, especially if the alternative therapy is found to be ineffective against psittacosis, a tetracycline, such asdoxycycline can be considered in pediatric patients.[3] 

The role of corticosteroids in severe psittacosis is unclear. A case report published in 2021 outlined a case of severe psittacosis, which progressed to organizing pneumonia after 11 days of symptoms and reported poor response to doxycycline. Failing appropriate antibiotic therapy, corticosteroids were eventually added, which resulted in improvement in clinical symptoms; however, the patient did not survive.[31] The authors recommended the use of corticosteroids early in patients with severe psittacosis and emphasized the need for further research to determine the appropriate management of severe psittacosis to help improve patient outcomes.(B3)

Differential Diagnosis

• Mycoplasma pneumonia
• Legionella pneumonia
• Q fever (Coxiella burnetii)
• Tularemia (Francisella tularensis)
• Influenza
• Typhoid fever
• Brucellosis
• Bacterial pneumonia
• Fungal pneumonia
• Viral pneumonia (COVID-19, H1N1, etc.)

Prognosis

The prognosis of psittacosis will depend on the patient’s clinical disease severity, comorbid conditions, as well as the time of treatment. Before antimicrobial agentswere available, approximately 15% to 20% of humans with Chlamydial respiratory infection died, but it is not clear how many of those were attributable to psittacosis.[3] Since the advent of antibiotics, mortality secondary to psittacosis has been rare. When appropriate antibiotic therapy is given, the cure rate of psittacosis is reported to be as high as 94.23%.[20]

Some cases, however, present with a fulminant disease, and an estimated mortality rate of 1% or less is reported in the modern era.[9] Gestational psittacosis is rare but can result in fetal and maternal mortality.[32]

Complications

Patients infected with psittacosis can present with many manifestations due to its hematogenous spread after initial inoculation. Please refer to the “History and Physical” section above for a thorough outline of different complications. In short, complications of infection with C. psittaci include acute respiratory distress syndrome, respiratory failure, as well as endocarditis, myocarditis, sepsis, DIC, meningoencephalitis, hepatitis, and pancreatitis; rarely, the patient may present with a fulminant disease course characterized by multi-organ failure.