Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was firstly reported in China in December 2019 and is an ongoing pandemic³³. Although the number of confirmed global cases of COVID-19 now exceeds 4.4 million, several studies have noted that co-infection and superinfection with other respiratory pathogens is relatively common39, the clinical features of co-infection and its impact on patient outcomes is yet to be clarified.

As the majority of symptomatic patients with SARS-CoV-2 infection develop an atypical pneumonia syndrome with fever, cough, and shortness of breath, bacterial and viral co-infections are likely obscured, therefore, being difficult to make a differential diagnosis only based on clinical presentation57. Co-infections and/or superinfections are common in respiratory viral infections37,42. It has previously been documented that the mortality rate associated with respiratory viral infections can be influenced by different factors, such as bacterial co-infection^{4,26,28,38,46}.

Pneumonia is an infection of the lung parenchyma caused by a variety of pathogens such as viruses, bacteria, fungi, and parasites. C. pneumoniae is known to be a cause of community-acquired pneumonia (CAP) that spreads from human to human via respiratory droplets without any known animal reservoir18. The prevalence of C. pneumoniae varied widely in previous studies of patients with CAP. It is important to know its prevalence because this atypical pathogen does not respond to p-lactams and can cause severe complications in some patients. Therefore, we performed a review to describe the updated literature regarding the co-infection or secondary infections between SARS-CoV-2 and this atypical pathogen.

Severe acute respiratory syndrome (SARS) was initially reported in Southern China in 2000 63,64. It received international attention after the individuals exposed to an ill patient in a Hong Kong hotel traveled and infected other persons in 200358. In Toronto other individuals were infected, triggering the first outbreak of SARS in Toronto45. The causative agent has since been identified as a novel coronavirus [SARS-associated coronavirus (SARS-CoV)]14,44. However, a SARS study using serological assays failed to detect atypical respiratory pathogen co-infections, in Hong Kong10. Nevertheless, the initial report from China before SARS-CoV, documented "Chlamydia-like” particles in addition to coronavirus by electron microscopy of respiratory specimens obtained from autopsied SARS patients24. Moreover, in the Toronto SARS outbreak, the serological evidence among SARS patients showed the co-infection with C. pneumoniae (30%) and Mycoplasma pneumoniae (9%)62.

Moreover, the co-infection of the Middle East respiratory syndrome coronavirus (MERS-CoV) and C. pneumoniae was reported3. In this multicenter retrospective cohort study in Saudi Arabia of 349 critically ill patients with MERS, the authors identified atypical bacterial co-infection in 5/349 (1%) on admission. Atypical organisms identified were Mycoplasma spp. (3/5), Legionella sp. (1/5) and Chlamydia sp. (1/5). However, 6 out of 17 patients were investigated for atypical organisms and these may reflect physician screening preferences based on clinical presentation3.

The literature on CAP documents reported a dual pathogen infection incidence between 3% and 40%, predominantly with pathogens causing atypical pneumonia62. These findings raised the question of whether co-infection with Chlamydia in SARS-CoV-2-infected patients played a role in disease severity and mortality. However, there are limited studies reporting this clinical phenomenon.

Methods

Literature review

On August 13, 2021, we searched Medline and Google Scholar for articles describing the clinical features of patients infected with SARS-CoV-2, using the search terms "Chlamydia pneumoniae and COVID 19’’ or "2019-nCoV and Chlamydia” or "COVID 19 coinfection’’ or "COVID-19,’’ "coronavirus and bacterial infection’’, "SARS-CoV-2 co-infection’’ or "SARS-CoV-2 and bacterial co-infection’’ or "SARS-CoV-2 and Chlamydia pneumoniae”. We also searched using the same terms in Spanish. We included articles written in English or Spanish (the primary languages of the investigators). We also reviewed the reference lists for review articles identified by our search, and those of any included studies. We also included all studies using culture, polymerase chain reaction (PCR) or serology, to identify C. pneumoniae.

We principally sought to analyze the proportion of patients with confirmed COVID-19 disease who were coinfected simultaneously with C. pneumoniae and other pathogens, and to describe the co-infecting pathogens.

Separate analyses were conducted for studies reporting laboratory-confirmed bacterial and viral co-infections. Laboratory-confirmed co-infections were those identified in blood, or through antigen detection methods or PCR detection of respiratory pathogens.

Data abstraction

All investigators reviewed each abstract to identify articles that should be reviewed in full. Any article selected for full review was examined by all investigators. For each included article, study characteristics and data regarding detection were abstracted by the authors. For detection data, definite cases were included and possible cases were excluded. For each report, we documented the type of surveillance used, number of cases reported and total population studies.

Results

The recognition of SARS-CoV-2 infection is important as it enables the implementation of appropriate infection control measures; however, clinicians should not neglect the possibility of SARS-CoV-2 co-infection. Therefore, this study aimed to better understand the prevalence of Chlamydia co-infection among COVID-19 patients.

Table 1 summarizes the current evidence of Chlamydia co-infection in patients admitted to hospital with coronavirus. Eleven studies reported the prevalence of COVID-19 and co-infection or secondary infections for C. pneumoniae, five of which were cross-sectional studies.

Two of the abovementioned studies were conducted in China16,34, while, two others were conducted in the United States48, and one in Russia52. Six of the studies were retrospective, three of which were conducted in China15,54,66, two in Italy12,41 and one in Saudi Arabia2.

The laboratory-confirmed COVID-19 cases were identified in these studies, and the study population ranged from 42 to 10222 cases. In the study of 182 patients in Italy, 3.8% (n = 7) were coinfections or secondary infections, and the antibodies for C. pneumoniae were detected in 5 of the 7 patients41. By contrast, Schirmer et al.51 showed that 1 (1.78%) of 56 patients with co-infections had C. pneumoniae in a study of 10222 COVID-19 patients in USA (1/10 222 = 0.01%)51. Among the remaining 9 studies, the prevalence of COVID-19 co-infected with C. pneumoniae or secondary infections ranged from 2.5% to 52.6%. Eight studies reported the occurrence of bacterial co-infections, and Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa, Bordetella pertussis and Klebsiella pneumoniae were identified as co-pathogens2,15,34,41,48,52,54,66. Eight studies reported viral co-infections; influenza A and influenza B virus, respiratory syncytial virus and adenovirus were the most common co-pathogens, and rhinovirus/enterovirus, coronavirus, Epstein -Barr virus, herpes simplex virus, human bocavirus, adenovirus, parainfluenza, metapneumovirus, and non-COVID-19 coronavirus, were also reported as co-pathogens2,15,16,34,48,51,54,66. In three studies also fungal.

Table 1: Summary of studies that reported the incidence of C. 

Table 2: Clinical, epidemiological, laboratory and radiologic features of patients with bacterial coinfection and SARS-CoV-2. 

Data regarding co-infections and/or secondary respiratory infections in the severe diseases caused by SARS-CoV-2 coronavirus are limited due to the still ongoing spread of the disease worldwide. Epidemiological and clinical characteristics of COVID-19 patients and co-infections are listed inTable 2. Of the eleven studies that reported co-infections with C. pneumoniae’ nine were included in this review’ because demographic data’ co-morbidities’ treatments and patient outcomes were not reported in the remaining two studies. SARS-CoV-2 as unique pathogen and COVID-19 coinfection populations did not show any differences.

The median age of co-infected COVID patients ranged from 35 to 71 years old and most of them were male2-12-15'16'41'51'66. A single study analyzing the ethnicity of COVID-19 patients reported higher odds of COVID-19 coinfection in White, Black or African American individuals and >80% of COVID-19 patients with co-infections came from urban areas51.

Most studies reported one or more pre-existing comorbidities' mostly hypertension' cardiovascular disease' diabetesand hyperlipidemia2-12-15'16'34'41'54. Similarly to what has been reported in the literature' the majority of the patients presented with fever' cough and dyspnea12'15'34'41'54.

Patients with SARS-CoV-2 and Chlamydia had lower level of lymphocytes12'15'54 and De Franchesco et al.' 202112 reported higher leukocyte counts (Table 2). Eosinopenia was also described in COVID-19 co-infected patients15'54. An increased ALT serum level was found in patients with SARS-CoV-2 and C. pneumoniae12'15. Furthermore' Du et al. (2020)15 reported increased levels of creatine kinase and lactate dehydrogenase in the patients. Different degrees of impaired renal function with elevated blood urea nitrogen or serum creatinine' C-reactive protein54 and procalcitonin levels above the normal ranges were described12'15. Additionally' Alosaimi et al.2 found that troponin T was strongly associated with disease severity; therefore' troponin T could be used as a predictor for disease severity.

The most common chest CT scan manifestation is ground glass density enhancement along the outer bands of both lungs' consolidation and bilateral pneumonia12'15'41'54.

Antibiotic use was only reported in five studies12'15'34'41'54; however' in several COVID-19 reports most patients received empirical antibiotics. In China' for COVID-19 patients in whom bacterial co-infection could not be ruled out' empirical antibiotics' such as amoxicillin' azithromycin or fluoroquinolones were recommended for mild cases. Moreover' broad-spectrum antibiotics covering all possible pathogens were suggested for severe cases27.

De Franchesco et al.12 showed that the proportions of critical COVID-19 patients with atypical pathogen coinfection were higher than those of patients only infected with SARS-CoV-2. Furthermore' requirement and use of a nasal cannula' high flow oxygen support and non-invasive ventilation were significantly higher in co-infected patients than in only SARS-CoV-2 positive patients.12 In addition Fang et al.16 found that the seroprevalence of SARS-CoV-2 and other respiratory pathogens such as C. pneumoniae was associated with severity. Meanwhile' other studies reported that less than 10 patients required ICU care2'41'51'66. There was also no statistical difference comparing death to COVID-19 mono-infected and COVID-19 co-infected individuals51. In the same way, Zhu et al. (2020)66 did not find a specific relationship between co-infection and ICU admission, as well as the occurrence of death. The median duration of hospitalization ranged from 7 to 28 days15,34,41,51.

Discussion

Although numerous studies were focused on viral and bacterial co-infections, there is scant information about human coronaviruses. In the present review we described all the reports of described patients infected with SARS-CoV-2 and Chlamydia pneumoniae published so far. This last microorganism can affect adults and children, usually causing mild infections and only occasionally could represent life-threatening conditions18.

The percentage within the total number of co-infections ranges between 1.78 and 71.4% for C. pneumoniae in the eleven analyzed studies, and this wide difference may be associated with the used diagnostic technique, since the positivity increased in the studies that used serology12. Furthermore, the reasons accounting for the discrepancies may be multifactorial, for example, different study populations, small sample sizes and high sensitivity of molecular assay detection. Moreover, the diagnosis of co-infections may mostly be performed only with serology, as the molecular analyses of respiratory samples of SARS-CoV-2 patients for the diagnosis of C. pneumoniae need especial biosafety conditions. In fact, serology might be limited by possible false positive results and another additional limitation is represented by the lack of paired samples to confirm prior serological results for the diagnosis of atypical pathogens. Also, in the analyzed studies not all the patients with SARS-CoV-2 infection were tested for C. pneumoniae; therefore the real incidence of co-infection cannot be truly established. Routine testing for pathogens other than SARS-CoV-2 will be necessary.

Despite low rates of bacterial co-infections reported in the molecular studies of COVID-19 patients, high rates of antimicrobial prescriptions were reported. For example, in a study in China, 101 patients (99%) from critical and non-critical care, received antibacterial therapy7. No bacterial co-infections were reported in this study. Guan et al.19 reported that 637 of 1099 (58%) patients admitted to critical and non-critical care settings in China, received antibacterial agents and also no bacterial pathogens were reported in this study18. Similar data was repeated in several studies25,30,40,61 . These results showed the importance of using a broad-spectrum molecular diagnostic panel for the rapid detection of the most common respiratory pathogens to improve the evaluation and clinical management of patients with a respiratory syndrome consistent with COVID-196.

Potential stewardship interventions to support reduced antimicrobial prescribing during the COVID-19 pandemic require consideration47. The traditional markers used to support antimicrobial decisions, such as vital signs; blood tests (white blood cell count and C-reactive protein); and imaging tend to be abnormal in SARS-CoV-2 infection1,65. This makes decision making surrounding the requirement for empiric antibacterial coverage challenging.

In terms of antimicrobial prescribing for bacterial coinfection of the respiratory tract; some patients presenting SARS-CoV-2 infection have a clinical picture that is not dissimilar from that of atypical bacterial pneumonia31. SARS-CoV-2 infection may also be difficult to be distinguished from hospital-acquired and ventilator-associated pneumonia in hospital inpatients54,65,66. Moreover, patients present febrile with respiratory symptoms, such as a dry cough, associated with bilateral chest X-ray changes54,65,66. Given the suggested use of broad-spectrum agents and macrolides20,49,59; it is important to prevent unintended consequences of antimicrobial therapy including toxicity, antibiotic-associated diarrhea, and the propagation of antimicrobial resistance through the increased usage of antimicrobial agents within the healthcare systems23. Finally, according to the recommendations of the National Institutes of Health, there are insufficient data to recommend the use of empiric broad-spectrum antimicrobial therapy in the absence of another indication in patients with COVID-19 and severe or critical illness40.

Several studies did not find the presence of C. penumoniae5,9,11,17,22,29,55,56,60. A clinical study assessing features of COVID-19 in more than 20000 hospitalized patients in the United Kingdom13 does not include any reference to secondary infections despite being an item included in the ISARIC World Health Organization questionnaire used by the investigators. This may reflect the fact that co-infections are largely not considered relevant during any large infectious epidemic in which the focus is set in the sole pathogen driving the outbreak and the identification of comorbidities to identify groups of patients at risk. These analyses, arising from the earliest cases of the SARS-CoV-2 pandemic, suggest that bacterial coinfections may be less prevalent in COVID-19 patients than in patients with influenza. In the 2009 influenza pandemic, 1 out 4 severe or fatal cases of influenza A (H1N1) had a bacterial infection, with an apparent association with morbidity and mortality26,28,35,43,46. The possibility exists that severe COVID-19 patients could be subsequently or co-incidentally infected by bacteria. The median hospital stage of COVID-19 patients is 7 days13 but can reach up to 28 days or even longer34,41, and the risk of hospital-associated pneumonia increases significantly with the length of the hospitalization period. Moreover, more than 80% of nosocomial pneumonia is associated with mechanical ventilation, being this intervention one of the therapeutics used in COVID-19 patients admitted to the ICU36. However, inverse association or not statistical difference were observed between bacterial co-infection and disease severity^{2,34,41,51,66}. This association indicates a lower likelihood of ICU admission with bacterial co-infection which may be attributed to the empirical use of antibiotics during the early onset of COVID-19.

Previous studies found that nearly half of patients with COVID-19 mono-infection were over the age of 50 years, and that men are more likely to be infected than women59,61,65. Also COVID-19 and C. pneumoniae co-infection were more prevalent in male patients over the age of 50 years (Table 2). The most common comorbidities of the patients with COVID-19 and co-infection were hypertension and diabetes, which is similar to the findings in the COVID-19 mono-infected patients of previous studies25,50,53.

Similarly to what has been reported in the literature, the majority of the patients presented with fever, cough and/or shortness of breath, showed bilateral infiltrates in the lung CT and were treated with azithromycin. The blood test showed mostly lymphopenia, and increased C-reactive protein, serum lactate dehydrogenase, procalcitonin, D-dimer level and troponin. In a study by Zhou et al.65 of 191 patients, 54 of whom died, authors found that D-dimer >1 mg/ml and elevated procalcitonin level >0.5 could assist in the early identification of patients who may have a poorer prognosis and were associated with a higher chance of death65. Another laboratory abnormality found in patients with bacterial co-infection was a decrease in total lymphocyte count, which is consistent with the conclusions of existing research indicating that lymphocytopenia is more often observed in non-survivors of SARS-CoV-2 infection54.

Ma et al.34 also found high IL-2, IL-4 and TNF-a levels and decreased T-cells and NK-cells. Chen et al.8 found an increased expression of IL-2 and also IL-6 in serum, proposing that it might predict the severity of COVID-19 pneumonia and bad prognosis of patients.

Bacterial co-infection in the setting of viral pneumonia is known as a major cause of mortality21. Co-infection is possible among COVID-19 patients. Clinicians can neither rule out co-infection with other respiratory pathogens when diagnosing SARS-CoV-2 infection nor rule out COVID-19 by detecting non-SARS-CoV-2 respiratory pathogens. However, those findings were based on a limited number of studies. A further large-sample and well-designed studies are warranted to investigate the prevalence of COVID-19 co-infection, risk of co-infection, microbiological distribution, and impact of co-infection on the clinical outcomes of COVID-19 patients. After obtaining more data regarding SARS-CoV-2 co-infection, empirical antimicrobial agents in suspected COVID-19 cases can be recommended.

The absence of standardized criteria to define the presence of co-infections does not allow us to estimate the problem of co-infection worldwide. The enormous heterogeneity of the results does not allow for synthesis measures. Likewise, the frequency of co-infection depends to a great extent on the country where the study is conducted. The results cannot be extrapolated between the different countries. No studies were identified in Latin America; therefore, more information is necessary at the regional level.

Co-infection may considerably inhibit the host’s immune system, increase antibacterial therapy intolerance and be detrimental to the prognosis of the disease32. To truly define the role that these co-infecting pathogens play in the pathogenesis of COVID-19 is exceedingly difficult, considering the fact that bacterial co-infections commonly occur during other viral respiratory infections. This type of co-infection is very difficult to prevent and can complicate the course and treatment of the underlying viral infection.