In 2019, the Coronavirus disease (COVID-19) rapidly spread worldwide and posed a global threat. The co-infection among COVID-19 patients was reported variable in different studies. However, it could reach 50% of non-survivor patients. Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila are responsible for respiratory infections and also can act as co-pathogens with COVID-19, making their detection challenging. These bacteria exhibit similar clinical signs to COVID-19, leading to potential oversight. Furthermore, treating these bacteria requires a different antibiotic regimen compared to typical respiratory bacterial agents. Thus, recognizing the clinical characteristics, laboratory findings, and outcomes of co-infections is crucial for improving understanding and treatment strategies.
En 2019, la enfermedad del coronavirus (COVID-19) se propagó rápidamente por todo el mundo y representó una amenaza mundial. La coinfección entre pacientes con COVID-19 se informó de forma variable en diferentes estudios. Sin embargo, podría llegar al 50% de los pacientes que no sobreviven. Chlamydia pneumoniae, Mycoplasma pneumoniae y Legionella pneumophila son responsables de infecciones respiratorias y también pueden actuar como co-patógenos con COVID-19, lo que dificulta su detección. Estas bacterias exhiben signos clínicos similares a los de COVID-19, lo que lleva a una posible supervisión. Además, el tratamiento de estas bacterias requiere un régimen antibiótico diferente en comparación con los agentes bacterianos respiratorios típicos. Por lo tanto, reconocer las características clínicas, los hallazgos de laboratorio y los resultados de las coinfecciones es crucial para mejorar la comprensión y las estrategias de tratamiento.
Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19 disease and is characterized by severe shortness of breath, cough, and fever. COVID-19 has a high mortality rate, especially among the elderly and those with pre-existing medical conditions.1 It is well-known that SARS-CoV-2 can lead to severe respiratory infections with high mortality rates. Nonetheless, there is no evidence that the virus itself causes pneumonia or acts in concert with other pathogens.2
According to World Health Organization (WHO) reports, until October 2020, 41.8 million people were diagnosed with COVID-19 and 1.13 million of of those individuals lost their lives. Seven percent of all hospitalized COVID-19 patients also suffered from secondary bacteria infections. Fourteen percent of all patients with severe COVID-19 infection and hospitalized in the ICU were infected with Mycoplasma. In addition, 50% of deceased COVID-19 patients had secondary bacterial infections.3 Up to 30% of SARS-CoV-2patients with secondary infections were diagnosed when the disease got worsened.4 In a study from China, among 191 patients, 54 died of whom 27 had secondary infections.5
Chlamydia pneumoniae is responsible for about 10% of community-acquired pneumonia and it is transmitted from human to human. C. pneumoniae is associated with multiple chronic inflammatory diseases such as atherosclerosis. Moreover, exposure to C. pneumoniae is common, and infection can happen among most people repeatedly.6,7
Mycoplasma pneumoniae is a small bacterium that commonly causes atypical pneumonia. Among the different types of pathogens associated with community-acquired pneumonia, M. pneumoniae is the primary causative agent associated with 5.2–27.4% of all cases.8,9Legionella pneumophila is a small and ubiquitous bacterium and the causative agent of Legionnaires' disease.10 The COVID-19 pandemic leading to prolonged building closures resulted in stagnation in building water systems. This phenomenon increased the risk of Legionella colonization.3,10,11
Therefore, due to the importance and challenge of co-infections and diagnosis of these pathogens with COVID-19, in the current review, we investigated the different factors and outcomes related to the co-infection of C. pneumoniae, M. pneumoniae, and L. pneumophila with COVID-19.
Symptoms and clinical characteristicsCOVID-19 can present itself with different forms, from an infection without any symptoms, to a deadly infection with Acute Respiratory Distress Syndrome (ARDS) and multiple organ failures.13 The most common symptoms of patients co-infected with COVID-19 and M. pneumoniae or C. pneumoniae are fever, coughing, and shortness of breath. According to a study conducted in India, COVID-19 patients who have co-infections of M. pneumoniae or C. pneumoniae have a higher likelihood of developing ARDS compared to those who only have COVID-19 infection.14 Pneumonia, shock, and ventilator usage were also more common in COVID-19 patients with M. pneumoniae or C. pneumoniae co-infection. Additionally, average hospitalization periods were significantly higher among COVID-19 patients with M. pneumoniae or C. pneumoniae co-infection who were likely to develop complications. In addition, mortality rates were higher among COVID-19 patients with M. pneumoniae or C. pneumoniae co-infections compared to patients with COVID-19 infection alone.14
In the majority of reported cases of L. pneumophila co-infection with COVID-19, patients exhibited symptoms such as fever, coughing, and shortness of breath with less incidence of fatigue, hypoxia, and diarrhea. Non-specific symptoms can sometimes make it difficult to suspect. In severe COVID-19, the clinical manifestation is similar to some patients involved with Legionnaires' disease (LD), showing both pulmonary and extrapulmonary manifestations.10 The signs and clinical outcomes gathered from different studies are summarized in Table 1.
The signs and clinical outcomes from different studies.
| References | Chaudhry et al14 | Amin et al16 | Zha et al19 | De Francesco et al20 | Olivia et al34 | Gayam et al15 | Ma et al35 | Pérez-Lazo et al18 |
|---|---|---|---|---|---|---|---|---|
| Signs | ||||||||
| Fever | 100% | 65% | 45% | 72% | 86% | 100% | 71% | 62% |
| Cough | 65% | - | 18% | 52% | 43% | 83% | 67% | 69% |
| Dyspnea | 65% | - | 9% | 48% | 43% | 83% | 43% | 69% |
| Chest pain | 6% | - | 0% | 2% | 14% | – | – | – |
| Fatigue/Myalgia | −/18% | – | 18%/– | −/6% | 14%/14% | 83%/67% | 5%/10% | 46%/− |
| Diarrhea | – | - | 9% | 8% | – | 33% | 19% | 7% |
| Mental change/Confusion | −/41% | – | −/4% | – | 14% /− | 17%/− | – | – |
| Hospital supports | ||||||||
| Mechanical ventilation (%) | 76% | 33% | – | 7% | – | 17% | – | 6% |
| ICU admission (%) | 88% | 37% | – | – | – | 17% | – | 10% |
| Duration of hospital stay (day) | 17 (7–30) | – | 14 (7–18) | – | 28 (13–34) | 8 (5–11) | 20 (14–27) | 10(6–21) |
| Death outcome (%) | 65% | 48% | 4.5% | 24% | 0% | 17% | 0% | 19% |
The typical chronic conditions among patients with COVID-19 and Mycoplasma or Chlamydia co-infection may aid in early identification of critical cases and adjusting treatment plans for better outcomes and potentially lowering the risk of mortality.
Hypertension and diabetes were the most common underlying conditions in patients co-infected with COVID-19 and Mycoplasma or Chlamydia. In the reviewed studies, the proportion of the infected population with hypertension varied between 18% and 83%. Diabetes was also a common underlying disease, with rate of 20–36%.14–20 Although the incidence of chronic kidney disease differs from other risk factors, it is associated with high mortality rate in patients with COVID-19.21 The incidence of kidney disease was 5–28%.14–17,19,20
Moreover, a study found 5 patients (50%) had heart failure and another reported 69 patients (28%) had cardiovascular disease.15,20 Finally, Chaudhry et al reported that neurological complications occurred in 5 cases (36%), which were significantly more common among co-infected patients than in those infected with COVID-19 alone.14
Co-infections by Legionella spp. in SARS-CoV-2 patients may be less frequent than early reports suggested.22 The case reports mentioned histories of hypertension, chronic kidney disease, bronchial asthma, chemotherapy, traveling, obesity, rheumatoid arthritis, smoking, and working on air conditioners as underlying risk factors in patients co-infected by Legionella and SARS-CoV-2.1,3,23,24 An interesting study described the co-occurrence of LD and COVID-19 in France during March 2020 with a frequency of 10.8% (7/65). Most of them had more than one underlying condition like cardiovascular diseases, smoking, and diabetes. Additionally, it is worth noting that 5 out of the 7 patients who had a co-infection were residing in a region that typically reports a high number of cases of LD.25
Diagnostic tests and laboratory findingsAll of the studies that were examined utilized chemiluminescence immunoassay and immunoenzymatic assays to detect IgM antibodies in the serum of patients to investigate M. pneumoniae co-infection. This method was also used as the primary detection method for C. pneumoniae due to its high specificity and sensitivity.
In addition, a few of the studies showed favorable outcomes for M. pneumoniae reverse transcription polymerase chain reaction (RT-PCR) tests of throat swabs. In most studies, Legionella diagnosis was confirmed through urinary antigen testing, while respiratory specimen PCR was used in some cases. However, only a few patients were positive for Legionella radiological findings from chest X-rays or CT scans that showed more bilateral infiltrations in patients with co-infection, as mentioned in Table 2.
The clinical and laboratory finding of COVID-19 co-infected patients from different studies.
| Reference | Chaudhry et al14 | Gayam et al15 | Olivia et al34 | De Francesco et al20 | Ma et al35 | Pérez-Lazo et al18 | Zha et al19 |
|---|---|---|---|---|---|---|---|
| Laboratory and radiological parameters | |||||||
| Positive chest radiography findings | 100% | 100% | 100% | 92% | – | – | 95% |
| Bilateral infiltrations | 91% | 100% | 86% | 76% | – | – | – |
| Total leukocyte count (×103 cells/μl) | 9.6 (2.9–19.4) | 7.6 (3.7–13.4) | – | 6.6 | 4.9 (4.0–5.9) | 9.01 (6.4–12.8) | 5.81 (5.13–6.84) |
| Platelet count (×103 cells/μl) | 154 (29–476) | 198 (140–271) | – | – | – | 283 (201–394) | 187 (144–250) |
| Leukocytosis | 47% | 33% | 1%7 | 25% | 0% | – | – |
| Lymphopenia | 76% | 100% | 43% | 72% | 0% | – | – |
| Thrombocytopenia | 47% | 0% | 28% | 16.5% | – | 0% | – |
| C-reactive protein (mg/dl) | 7.18 (0.17–25) | 11.9 (4.6–14.6) | – | – | 8.5 (3.2–13.4) | 8.4 (4.3–22.6) | 0.24 (0.10–2.08) |
| Elevated C-reactive protein (>10 mg/l) | 62% | 100% | 43% | 92.5% | 100% | 100% | – |
| Elevated LDH>240 u/l or average | – | 100% | 57% | – | 197 | 284 | 0% |
| Elevated D-dimer 500 ng/ml FEU or average | – | 100% | 71% | – | – | 647 | 720 |
| Abnormal IL-6 or average | 93% | 100% | – | – | 5 (3.0–12.1) | - | 0% |
| Procalcitonin (ng/ml) | 0.55 (0.01–39) | – | – | – | – | 0.15 (0.065–1.16) | 0.05 (0.03–0.07) |
| Elevated procalcitonin 0.25 ng/ml | 57% | 33% | – | – | 5% | – | – |
| Abnormal creatinine 1.3 mg/dl | 53% | 67% | – | – | – | 0% | 0% |
| Abnormal blood urea nitrogen | 53% | 67% | – | – | – | – | 0% |
| Elevated AST | 65% | 67% | – | 58% | – | – | 0% |
| Elevated ALT >36 u/l or Average | 59% | 17% | – | 29% | – | 51 | 0% |
| Direct bilirubin (μmol/l) | – | – | – | – | – | – | 19.19 ± 72.26 |
| Indirect bilirubin (μmol/l) | – | – | – | – | – | – | 14.67 ± 28.72 |
Patients co-infected with M. pneumoniae or C. pneumoniae were more likely to have an elevated white cell count and a lower level of lymphocytes, which is typical of viral infections.15 In addition, the majority of cases showed elevated levels of the inflammatory markers, including IL-6, CRP, LDH, and D-dimer. Additionally, 2 studies reported abnormal values of procalcitonin.14,15 Finally, higher AST and ALT were observed in several patients and Zha et al found a significantly higher bilirubin level in patients co-infected with M. pneumoniae.19 Liver injury in patients may be aggravated by the direct effect of viruses or the application of certain drugs such as antibiotics of macrolides or quinolone, and steroids.26 Moreover, liver injury is associated with poorer clinical outcomes and the severity of diseases; therefore, it is important to monitor for any signs of liver injury. Although, L. pneumophila may have a similar clinical symptoms and laboratory findings, certain uncommon radiological patterns and some risk factors may suggest the presence of this pathogen.3,23–25
Treatments and outcomesAccording to our current knowledge about the pathogenesis of COVID-19, the disease is driven by both virus replication and a dysregulated immune/inflammatory response to infection that may lead to further tissue damage and thrombosis. In addition, co-infections may complicate treatment and recovery. Based on National Institutes of Health (NIH) guidelines, patients should be prioritized for anti-COVID-19 therapies.27 Although, the WHO suggested that antibiotic therapy or prophylaxis in patients with mild/moderate COVID-19 should not be used unless justifiable. However, it is common for patients with COVID-19 to be prescribed broad-spectrum antibiotics.28
In one study, of the 17 patients with M. pneumoniae or C. pneumoniae co-infection, 7 (41%) patients received antimicrobial agents with atypical pneumonia coverage, including azithromycin, doxycycline, and levofloxacin. Six (35%) patients received antiviral treatment, and 7 (41%) patients received corticosteroids. They also found a higher proportion of fatal cases in the M. pneumoniae or C. pneumoniae co-infection group than in patients with only SARS-CoV-2 infection (64.7% vs. 32.8%, P=0.029).14
Another study reported more quinolone antibiotics and corticosteroids administration to patients with M. pneumoniae co-infection. In addition, ribavirin and umifenovir were the most administered antivirals in co-infected patients. Only 1 fatal case in the co-infection group was reported.19
A recent study reported a higher receive of azithromycin in co-infected cases of M. pneumoniae or C. pneumoniae (57%). In addition, M. pneumoniae and/or C. pneumoniae co-infection group had a slightly higher mortality rate compared to the other group of patients.20
A case series reported that azithromycin and hydroxychloroquine were administered to all patients, and lopinavir/ritonavir was administered to 29% of patients. In addition, 43% of patients received corticosteroids. All patients were discharged after 28 days of an average length of hospitalization and no patients died.17
In another case series, all the patients received ceftriaxone for pneumonia, and about half of them (3 patients, 50%) were treated with azithromycin or doxycycline. Two patients were administered hydroxychloroquine (33.3%), while 2 others were given steroids (33.3%). The deceased patient was treated with azithromycin, ceftriaxone, and steroids, but did not receive hydroxychloroquine.15
There was a similar antiviral treatment (umifenovir) rate of initiation between co-infected and mono-infected patients in the Ma et al study. However, the use of azithromycin was significantly higher in the group with co-infection compared to the other group (38% vs. 12%, P=0.023). Furthermore, 76% of co-infected patients were treated with interferon inhalation, and 10% received corticosteroids.29
Pérez-Lazo et al reported that 72% of patients co-infected with atypical bacteria received antibiotics (ceftriaxone, azithromycin, and imipenem), and nearly 50% of the patients who received antibiotics did not have a bacterial co-infection.18 They challenged future studies to guide the rational use of antibiotics in COVID-19 co-infections.
It is critical to prescribe the right antibiotics for patients co-infected with L. pneumophila and COVID-19. As usual, the primary medication against bacterial pneumonia is beta-lactams, which are useless against L. pneumophila. Healthcare facilities and clinicians should follow the L. pneumophila infection prevention and diagnosis protocols. In one study, 2 fatal cases suspected for bacterial infection were prescribed with amoxicillin/clavulanate and clarithromycin at admission while only clarithromycin would obstruct LD. Despite antimicrobial drugs and supportive treatments, the patients died at 5 and 20 days after admission, respectively.23 In another study, the patient received azithromycin and ceftriaxone before diagnosing LD, switching to levofloxacin after positive results. However, the patient's status was still critical, receiving mechanical ventilation and intravenous levofloxacin.1 In another study, the patient was immediately administered levofloxacin, piperacillin/tazobactam, remdesivir, vancomycin, ciclesonide, dexamethasone, and nafamostat mesilate. He was discharged on the 27th day of hospitalization.3 In another study, the case was initiated on dexamethasone, remdesivir, azithromycin, and ceftriaxone, and after 18 days, the patient was discharged.24 A systematic study shows a significant ratio of case fatalities in patients (26.3%). Moreover, co-infection cases may lead to a more unfavorable outcome, with a longer intensive care requirement and a need for intubation and mechanical ventilation (84.2%).30
ConclusionThe unknown effect of the co-infection mechanisms and rates of SARS-CoV-2 with respiratory pathogens led to the virus's rapid spread worldwide. The rates of co-infections may be higher than anticipated, which creates a challenging situation for the diagnosis and management of patients by physicians.18,31–33 Furthermore, the exact mechanisms of co-infection of SARS-CoV-2 with Legionella and other pathogens are unknown. Therefore, the admitted patients with COVID-19 infection should be carefully evaluated for possible co-infections with other respiratory pathogens. Ideally, the diagnosis should have occurred at an early stage in order for treatment to begin.3C. pneumoniae, L. pneumophila, and M. pneumoniae are difficult to culture, have complex diagnoses, and can easily be neglected. Therefore, due to the different antibiotic regimes needed for treating these bacteria, detecting them in infected patients is essential.
FundingNot applicable.
Author contributionAKH designed the study. SV, PG, and ZS contributed in research and data extraction. AKH, and FT wrote the paper and edited the manuscript. Notably, all authors have reviewed and approved the manuscript.
Ethics approval and consent to participateNot applicable.