Humans can be infected by Chlamydia psittaci (C. psittaci) via the respiratory tract through air or aerosols, resulting in atypical community-acquired pneumonia (CAP) (1). However, C. psittaci is challenging to be identified by traditional methods such as microbial culture or microscopic examination. C. psittaci pneumonia is often underdiagnosed or misdiagnosed in humans, with an estimated incidence rate of at least 1.03% (2).

Chlamydia psittaci infection causes severe pneumonia in some patients (3). The inflammatory reaction imbalance in their body would lead to cytokine storm (4), resulting in diffuse alveolar injury (DAD) and pulmonary capillary endothelial injury, causing acute respiratory distress syndrome (ARDS) (5). Early etiological diagnosis and timely and effective treatment can improve the prognosis of patients. In recent years, metagenomic next-generation sequencing (mNGS) has become increasingly essential for etiological diagnosis. The researchers analyze nucleic acids from bronchoalveolar lavage fluid (BALF), sputum, and other clinical samples, then create a biological reference database and rigorous sequence read mapping and finally identify pathogens like Mycobacterium tuberculosis (6–8). Currently, mNGS has gradually been used for the diagnosis of difficult-to-diagnose severe pneumonia (9). Additionally, mNGS can quickly and accurately identify most pathogens, especially atypical pathogens such as Legionella and C. psittaci.

With the increasing popularity of mNGS applications, more and more patients with CAP have been detected with C. psittaci infected. A multicenter prospective cohort study in China included 329 patients with severe community-acquired pneumonia (SCAP), 264 of whom were immunocompetent, and 8% of whom were infected with C. psittaci (10). Previously, this was unheard of. Nowadays, C. psittaci pneumonia has become a public health concern in China. According to a comprehensive review of recent papers, it has a variety of clinical features, and the severity of C. psittaci pneumonia ranges from mild flu-like symptoms to life-threatening diseases (1, 11). In this article, we attempt to provide an updated description of patients with C. psittaci pneumonia. It will deepen the clinicians’ understanding of the diagnosis and treatment of C. psittaci pneumonia, diagnose as soon as possible, treat in time, and improve the prognosis.

This is an extended retrospective study of the epidemiology and clinical characteristics of C. psittaci pneumonia. A total of 55 patients were examined at four major medical facilities in Wuxi. It presents the latest status of C. psittaci pneumonia infection in Wuxi, China. In this paper, we summarized the clinical characteristics of C. psittaci pneumonia, identified predictors of severe pneumonia, and pointed out that mNGS is a means to provide early diagnosis.

As everyone knows, C. psittaci pneumonia is rare, accounting for one to 8% of CAP cases (2, 16). However, with the increased use of mNGS in recent years, it has been discovered that the detection rate of C. psittaci in CAP patients is not low. We can find 14 cases with severe C. psittaci pneumonia diagnosed by mNGS (3) and 32 other patients diagnosed with C. psittaci pneumonia by mNGS during the COVID-19 pandemic (15). We have reason to suggest that physicians should be vigilant about atypical pneumonia caused by uncommon pathogens such as C. psittaci.

The clinical features of these patients in this retrospective study were not the same, but they had many symptoms in common. It was found that the most prominent symptom was fever, which occurred in all patients; most were high fever, their body temperature was over 39.1°C, and most with chills. Other typical symptoms of C. psittaci pneumonia include cough, expectoration, weakness, etc. This report is similar to previous ones (17). On the other hand, it differs from previous studies in that most patients had flu-like symptoms, such as fever, fatigue, muscle aches, headaches, and sore throats (7, 18). Aside from fever, other flu-like symptoms were uncommon in this study. The study found that only 12.7% of patients suffered from chest tightness and shortness of breath. The proportion was significantly lower than in other studies (1, 7). Different diagnostic classifications of dyspnea and treatment approaches may explain this.

When a patient with a high fever has a chest CT that shows patchy consolidation with an air bronchogram and ground-glass opacity, C. psittaci pneumonia is highly suspected. According to this study, 76.4% of patients had patchy consolidation with the air bronchogram sign and ground-glass opacity on chest CT, the consolidation performance reached 87.3%, and pleural effusion was not uncommon. Several imaging characteristics, such as consolidation of the chest with a bronchogram obtained via chest CT, have been reported (19). Most patients have bilateral, middle-lower lobe, or multilobar lesions, usually presenting as consolidation, and have pleural effusions (7). Moreover, bilateral lung consolidation and numerous lobe infiltration were observed primarily in severe cases. However, these signs differ from our understanding of atypical pathogen pneumonia, such as Chlamydia pneumoniae. In contrast to C. psittaci pneumonia, thickening of the bronchial walls is most common in M. pneumoniae pneumonia, followed by nodules (tree-in-bud and centrilobular) (81%) (20). Identifying these CT signs can help diagnose C. psittaci pneumonia.

The erythrocyte sedimentation rate, rapid C-reactive protein, CK, and LDH were significantly elevated in laboratory tests. It is known that CK is distributed in many tissues, mainly muscle tissue. High CK levels occur in C. psittaci pneumonia, but the mechanism is unclear, and high CK levels are an independent risk factor for severe C. psittaci pneumonia (11). Other studies have found that CK levels greater than 174 U/L are a risk factor for severe C. psittaci pneumonia (7). Our study found most patients had CK levels higher than 196 U/L, and one of the 55 patients had a significant increase, as high as 34,035 U/L, coupled with rhabdomyolysis in our study. We also found that LDH was significantly increased in most patients (70.9%). This discovery has also been proposed previously (7). The LDH level in the severe group was higher than in the non-severe group, and the difference was statistically significant. These are similar to previous studies (1). Additionally, we found from binomial logistic regression analysis and ROC curve analysis that significant increases in CK and LDH levels may indicate the severity of the disease and both may be predictors of severe pneumonia. This is a discovery that needs to be studied further in the future.

More than half of the patients in this study had electrolyte disorders, primarily manifesting as hypokalemia (54.5%), hyponatremia (56.4%), and hypophosphatemia (65.5%). Since there are few studies on electrolyte disorders, we are interested in learning whether more case reports can provide diagnostic information. Additionally, 21 patients (48.4%) were in ketosis, 5 of whom were diabetic.

It is consistent with the previous reports that the leukocyte increase is not noticeable (4), the neutrophil ratio and NLR increase, the lymphocyte ratio decreases, the PCT increases, the transaminase increases, the creatinine and urea nitrogen increases, and the hypoproteinemia increases, etc. (1, 7). However, in our study, further binomial logistic regression analysis and ROC curve analysis showed that both the increase of neutrophil ratio and NLR were risk factors of the severe group, with ORs of 10.057 and 9.750 respectively, both statistically significant, and AUCs of both were over 0.8, both also statistically significant. This result implies that neutrophil ratio and NLR elevation are indicators of severity and predictors of severe pneumonia.

When a CAP patient with a high fever has the above characteristics, such as a CT showing consolidation with an air bronchogram sign and ground-glass opacity, laboratory tests reveal a significant increase in rapid c-reactive protein, no significant increase in white blood cells, significant increases in CK and LDH, hypokalemia, hyponatremia, hypophosphatemia, and so on. In this patient, there is a high probability of C. psittaci pneumonia, and the history of bird exposure should be verified, although this history of bird exposure should be clarified at the initial visit. However, most patients dispute that we should follow up on their history during diagnosis and therapy and are encouraged to recall previous contact information. A study conducted in this study found that 30 patients had a history of exposure to pigeons or parrots or their internal organs. The research discovered that nearly all patients had had close contact with birds or poultry (16). Several reports showed that most patients had a history of poultry contact (7, 15). Among 116 patients studied, only 18 (15.5%) had a history of exposure (1). Sometimes it is difficult to determine the exposure history. As in our study, one patient denied any history of bird contact. However, after being diagnosed with C. psittaci Pneumonia, the patient replied that he walked in a park where pigeons were around. This may be an indirect exposure. It reminds us to ask about the patient’s hobbies and habits.

How is the diagnosis of C. psittaci pneumonia confirmed when clinical features and exposure history are highly suggestive? We know that conventional methods of diagnosing C. psittaci have poor sensitivity and specificity (21). To identify pathogenic bacteria, PCR or mNGS is needed. Nucleic acid PCR assays, which do not rely on culture techniques, are rapid and accurate, but these methods require a priori knowledge or assumptions about the pathogen type. mNGS has the main advantage of unbiased sampling, the ability to detect all potential pathogens in the same sample simultaneously and the avoidance of pre-defined detection ranges. Therefore, mNGS has a clear advantage in the diagnosis of unexplained and co-infected lower respiratory tract infections (22). For mNGS testing, BALF is usually used, but sputum or serum can also be tested if bronchoscopy is not an option. In this study, a patient admitted to the intensive care unit was too ill to undergo bronchoscopy in the early stages. Therefore, a serum mNGS test was performed, which revealed a C. psittaci infection. Following this test, the appropriate antibiotics were immediately adjusted, enabling the patient to survive and receive effective antimicrobial treatment. Additionally, the symptoms of C. psittaci pneumonia are not unique and can be seen in other diseases as well. Furthermore, not all patients can give a history of their exposure. As a result, the diagnosis is not straightforward. In this situation, mNGS is still required. Since mNGS is unbiased and hypothesis-free, it has been widely used in the diagnosis of respiratory tract infections (22). In the case of unexplained pneumonia, mNGS could help identify rare pathogens and shorten diagnosis time. mNGS assays in the lower respiratory tract or pleural effusion samples can provide a rapid and early diagnosis of severe M. pneumoniae pneumonia with ARDS (23). In contrast to traditional microbial culture methods, mNGS detects pathogens within 3 days (24). More evidence suggests that mNGS is an effective tool for diagnosing C. psittaci pneumonia (7, 25). But for some patients, mNGS testing is unaffordable due to its high cost.

Our study was fortunate to have no deaths among the patients. An intensive care unit admitted three patients, one of whom required tracheal intubation with mechanical ventilation and ECMO, and the outcome was positive. This could be due to the fast etiological diagnosis of these patients using mNGS, which allowed them to receive effective antibacterial therapy. The treatment of C. psittaci is straightforward. C. psittaci can be treated with tetracyclines, macrolides, and quinolones (26). In this study, each patient received either doxycycline, moxifloxacin, or nenofloxacin malate. A few patients with poor results on oral moxifloxacin were switched to oral doxycycline, and some patients with allergic reactions to oral doxycycline were switched to quinolones. Tetracycline-resistant chlamydia strains have been reported in recent years due to the widespread use of tetracycline in poultry (27, 28). A new generation of quinolones, moxifloxacin is highly effective against C. psittaci (1). However, the antibiotics must be personalized to the particular condition.

A total of three patients in our study had vascular embolism events, namely pulmonary embolism, cerebral artery thrombosis, and bilateral lower limb vein thrombosis. The literature search did not yield any relevant articles. It is unclear whether C. psittaci infections cause vascular emboli, and further observation and research are needed.

There are several limitations to this study. First, only 55 patients with confirmed C. psittaci pneumonia were included; those with strong clinical suspicion but no evidence of pathogens were excluded. As a consequence, some information may be missed. Second, most patients were diagnosed with BALF mNGS but did not receive standard laboratory tests. Not all patients can afford mNGS. Third, several factors regarding the use of medication, such as drug combinations, different types and manufacturers, and irregular application of antibiotics against C. psittaci, such as one patient being administered moxifloxacin and doxycycline consecutively, were included. These might lead to bias in the analysis of drug efficacy. Research on these drugs’ efficacy in C. psittaci pneumonia requires more in-depth prospective studies.

There were 55 hospitalized patients with confirmed C. psittaci pneumonia in this multi-centre case series in Wuxi, China. We found that many clinical indicators were typical. Meanwhile, significant increases in neutrophil ratio, NLR, LDH, and CK predicted severe pneumonia. Timely detection of mNGS provides substantial help for clinical diagnosis and early treatment. This provides clinicians with a better understanding of the disease and some useful information for the CDC to help them carry out effective epidemiological control measures.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

TB and SH: conception and design of the experiments. YG, DX, LB, XD, and CM: collection of clinical data. YG and DX: analysis of the data. YG and YW: writing the text of the main manuscript. LB and LL: preparation of tables and figures. All authors contributed to the article and approved the submitted version.

The authors thank all patients involved in the study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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