Organ transplantation is an effective treatment for various end-organ failures, and the advent of this technique became a new milestone in the history of medicine. Subsequent developments in this and related disciplines have led to improved surgical success rates and longer patient survival times. Nevertheless, post-transplant infection remains a major problem affecting post-operative complications and mortality, especially in the lungs.
The incidence of pulmonary infections and the pathogens of infection vary due to the dosage and usage of immunosuppressive drugs and the immune function status of patients at different times after surgery, which is also known as the infection schedule. The current unified view is that there are three stages: 1. The first month after surgery. Mostly related to surgery and stay in the care unit, and secondly, related to the application of immunosuppressive drugs, so the pathogens are mostly hospital-acquired bacteria: G-bacteria, Streptococcus pneumoniae, Staphylococcus aureus and latent infections already present before surgery, such as tuberculosis infection. 2, 2-6 months after surgery. There are two categories: one is infections caused by some kind of virus with immunomodulatory function, the most common being cytomegalovirus. The other category is infections caused by various opportunistic pathogens, such as Pneumocystis, mycobacteria, etc. 3.After 6 months postoperatively. If there are no additional risk factors, such as rejection reactions requiring intensive immunosuppressive therapy, the pathogens are similar to community infections in the usual population, mostly socially transmitted influenza, Streptococcus pneumoniae pneumonia and fatal opportunistic infections that are easily complicated by long-term massive immunosuppressive therapy, such as Pneumocystis, Cryptococcus novelis, Nocardia, etc.
1 Pathogenesis
1.1 Bacterial pneumonia
Bacteria are still the main causative agents of postoperative infections in patients with various organ transplants. Bacterial pneumonia is divided into hospital-acquired pneumonia and community-acquired pneumonia according to the time of infection, causative organisms and prognosis.
1.1.1 Hospital-acquired pneumonia
Causative organisms: The main causative organisms are gram-negative bacteria, Staphylococcus aureus, sometimes Legionella, and the incidence of methicillin-resistant staphylococcal pneumonia is also on the rise.
Risk factors: Prolonged mechanical ventilation is the most important risk factor. Secondly, it is associated with severe pain after chest or upper abdominal surgery that restricts coughing. In lung transplant patients, narrowing of the bronchial anastomosis, diminished or absent cough reflex due to denervation and damage to the airway mucosa are also risk factors for increased infection. In addition, pathogenic bacteria latent in donor lung tissue are susceptible to infection when immunocompromised after transplantation. In liver transplant patients, large amounts of preoperative ascites and prolonged postoperative indwelling gastric tube are also important risk factors for pulmonary infections. Legionella pneumonia is most often seen when the disease is endemic, and its transmission is associated with inhalation of Legionella bacteria from contaminated water or air conditioning systems.
Clinical manifestations: high fever, cough, pus sputum, dyspnea, and wet rales in the lungs. Chest radiograph shows early thickening of lung texture, followed by focal pulmonary solidity and pulmonary nodular shadow.
Selection of antibiotics: The selection was based on the results of preoperative patient pharyngeal or sputum culture. Third-generation cephalosporins that are effective against gram-negative aerobic bacteria and take into account staphylococci are mostly used for empirical treatment, and antibiotics are adjusted according to bacterial culture results [8].
1.1.2 Community-acquired pneumonia
It occurs mostly at a later stage after transplantation, with a mortality rate of 0-33%.
Common causative organisms:: Haemophilus influenzae, Streptococcus pneumoniae, Legionella. Pseudomonas aeruginosa is often present in patients with bronchiectasis. Nocardia pneumonia is relatively common in the early post-transplant phase. Rhodococcus equi pneumonia has also been reported in a few cases in recent years.
Risk factors and clinical manifestations: Patients with occlusive fine bronchitis at a later postoperative stage are more likely to develop lower respiratory tract infections, manifesting as recurrent purulent bronchitis and pneumonia. The incidence of Nocardia pneumonia can be reduced with preoperative prophylactic application of sulfonamide . Nocardia pneumonia can have a subacute onset with fever, cough, pleuritic chest pain, dyspnea, hemoptysis, and weight loss, and in one-third of cases, spread to the brain, skin, and soft tissues. The typical imaging presentation is one or several nodular shadows, and sometimes cavities may be present. However, the possibility of Equisetum equi pneumonia should be considered when imaging shows cavity formation, insensitivity to conventional empirical treatment, smear staining for Gram-positive cocci, and culture of diphtheria-like bacteria suspected to be contaminated, and equi-specific PCR helps in the diagnosis.
Choice of antibiotics: for Nocardia pneumonia choose sulfonamides, and for those allergic to sulfonamides use tetracycline, amikacin, imipenem, ceftriaxone. Treatment is recommended for 3 months, and 12 months for those with spread elsewhere. A more effective treatment for equine erythrococcal pneumonia is vancomycin combined with imipenem, followed by ciprofloxacin and memantine.
1.1.3 Tuberculosis
The incidence of tuberculosis after organ transplantation is 0.5%;-2%; in Europe and the United States, and up to 15%; in developing countries (India).
The pathogenesis may be related to the proliferative immune response of the organism after occult infection.Singh and Paterson’s study found that the median time of tuberculosis onset was 9 months after surgery and 2/3 of the patients developed the disease within a year. Fever is the most common clinical manifestation, and there can be cough, hemoptysis and dyspnea. Imaging manifestations: focal infiltrates in 40%, cornified TB in 22%, pleural infiltrates in 15%, extensive interstitial infiltrates in 5%, and cavitary type in 4%.
Treatment: Treatment in the active phase is the same as anti-tuberculosis treatment in the general population, with a combination chemotherapy regimen. Because rifampicin induces hepatic P-450 microsomal enzyme system production and increases clearance of cyclosporine, thereby increasing the risk of rejection, care should be taken to monitor the blood levels of immunosuppressive drugs when administered. Preoperative PPD and prophylactic antituberculosis treatment are recommended for patients with possible occult TB infection against pre-existing hypersensitivity reactions, with 9 months of isoniazid application and 4 months of rifampicin recommended.
Currently, the morbidity and mortality rate of tuberculosis after organ transplantation is 25-40%.
1.1.4 Non-tuberculous mycobacterial pneumonia
The incidence of nontuberculous mycobacterial pneumonia is higher in lung transplant patients than in tuberculosis (6.1%;: 0.8%;), with Mycobacterium avium and M. kansasii being common in other types of organ transplantation: 1.6% in heart transplantation; [19], 0.1% in kidney transplantation; [20], and only one case of this type of pneumonia has been reported in liver transplantation.
1.2. Viral pneumonia
1.2.1 Cytomegalovirus (CMV) pneumonia
Cytomegalovirus is the most common viral pathogen in organ transplantation, with infection rates of 8%, 29%, 25%, and 39% in patients with renal, liver, heart, and combined heart-lung transplants, respectively, often occurring in weeks 2-12 after organ transplantation, generally within one year, although later onset has been reported with the application of new immunosuppressive agents.
Route of infection and risk factors: Transmission to the recipient through infected donor organs or blood products. There are three modes of recipient infection: 1. Primary infection. The risk of infection is greatest in blood CMV-negative recipients (R-) who receive cells from blood CMV-positive donors (D+) that are already potentially cytomegalovirus-infected, with resurgence of the virus leading to infection; 2. Secondary infection or reinfection, in which blood CMV-positive recipients resurrect their own latent virus after transplantation. 3. positive donor with already infected cells. In addition, the application of immunosuppressive agents against lymphocyte antibodies can increase the risk of infection and worsen the extent of infection. Early mortality can reach 70% in bone marrow transplant patients; and is often combined with other pathogenic infections, especially pneumocystis.
Clinical manifestations: CMV pneumonia after renal transplantation is highlighted by interstitial pneumonia and hypoxemia, with rapid progression and a high mortality rate, mostly starting with cough and fever discomfort, and may have arthralgia, leukopenia and thrombocytopenia, rapidly progressing to respiratory distress, which can further suppress the immune system and lead to frequent and other opportunistic pathogenic infections, thus explaining the frequent combination of CMV infection with fungal, pulmonary cysticercosis infections, etc. It is also associated with the later development of graft organ insufficiency and loss. The chest radiograph shows interstitial exudate in the lung of interstitial pneumonia.
Diagnosis: Because of the low specificity of its clinical symptoms, diagnosis is mainly based on laboratory tests. In vitro CMV virus culture of urine, blood and other body fluids as well as biopsy tissues is highly specific and is a golden indicator for the diagnosis of CMV infection, but it has low sensitivity and is time-consuming; positive serum CMV-IgM and CMV-IgG elevation >;4 times suggest active CMV infection in vivo, but CMV antibody production is often delayed due to the suppression of body immune function in organ transplant recipients using powerful immunosuppressive drugs However, CMV antibody production is often delayed or lacking due to the suppression of immune function in organ transplant recipients using strong immunosuppressive drugs, limiting the use of CMV antibody testing in transplant recipients. The qualitative CMV-DNA-PCR assay is rapid, sensitive, and early, but has a high false-positive rate; the CMVpp65 antigen blood assay is highly specific, and there is a good correlation between the number of CMVpp65 antigen-positive cells and CMV viral load, and invasive CMV infection [36], and the combination of both methods can be used for the early diagnosis of CMV infection and can be quantitatively analyzed for active early diagnosis and early treatment of CMV pneumonia provide a reliable basis.
Therapeutic drugs: CMV pneumonia symptoms appear early and clinical manifestations are heavy, while X-ray changes and pulmonary signs appear late; therefore, early diagnosis and early treatment are warranted.
1. Ganciclovir. Only clinical trials have demonstrated the effectiveness of ganciclovir in the treatment of CMV infection in organ transplant patients. 5mg/kg-10mg/kg intravenous twice daily for 2-3 weeks is recommended as the standard treatment regimen, and some believe that the combination of sodium phosphonate is more effective. Antiviral drugs can only temporarily inhibit viral replication, so the relapse rate is high. To reduce the relapse rate, it is recommended to continue oral ganciclovir, and some people reported that oral ganciclovir within 12 weeks after surgery can effectively prevent cytomegalovirus disease, but it has no significant preventive effect on the late stage (3 months~1 year after surgery).
2. Acyclovir. Oral low-dose acyclovir (600-800 mg/d) reduces viral infections and decreases the rate of CMV positivity in post-transplant patients [25]. However, the ability of acyclovir to prevent CMV infection in patients with other types of organ transplantation is unclear. Therefore, acyclovir is not generally recommended as a prophylactic agent, except for renal transplantation.
Prophylactic regimens: There is considerable evidence that prophylactic antiviral therapy can reduce the incidence of CMV infection. All blood CMV-negative recipients receiving a blood CMV-positive donor should receive prophylactic treatment with ganciclovir by the intravenous or oral route [24]. Prophylaxis is also recommended for blood CMV-positive recipients with increased blood CMV viral load [24]. Two weeks of intravenous ganciclovir (6 mg/kg.d) followed by 12 weeks of oral ganciclovir (1 g, Q8h) after transplantation is more effective in preventing cytomegalovirus disease than taking acyclovir (800 mg, Q6h) for the same duration [27]. Sodium phosphonate can be used for those who are resistant to ganciclovir, but attention should be paid to its nephrotoxicity.
1.2.2 Other respiratory viral pneumonia
Common pathogens: influenza virus, parainfluenza virus, adenovirus, respiratory syncytial virus , herpesvirus-6, 7 and others.
The manifestation is bronchitis or pneumonia, and clinical manifestations can include fever, cough, dyspnea, wheezing, etc. Imaging: the lungs can have ground glass-like changes, reticular changes, nodular shadows, etc. Diagnosis relies on finding the virus in nasopharyngeal swabs or bronchoalveolar lavage fluid, and a positive viral culture is its gold standard, but it is too time-consuming. The application of enzyme-linked immunosorbent assay or immunofluorescence test can achieve a rapid diagnosis.
There are no clear and effective treatment options.
Prevention: Because it is highly contagious, contact with the source of the disease should be reduced, hand washing should be increased, and inactivated influenza virus vaccine can be given to organ transplant patients. During an influenza epidemic, transplant patients who have had contact with patients with confirmed influenza may be given amantadine or ceramidase inhibitors for prophylaxis.
1.3 Fungal pneumonia
1.3.1 Pulmonary aspergillosis: It is the most common fungal infection of the lungs in organ transplant patients. The incidence of invasive pulmonary aspergillosis is 5% in transplant patients with liver, heart and lung. It mostly appears within 3 months after transplantation, and the massive application of glucocorticoids after transplantation causing neutrophil and megalophil hypofunction is the main cause of Aspergillus infection. Clinical manifestations can be dry cough, chest pain, dyspnea, low fever, coughing green or green granular sputum, lesions are mostly located in the middle and lower lobe of the lung, typical X present as dense shadows with smooth round edges, a few spheres with fine sparse areas and a crescent-shaped transparent area above the sphere.
Diagnosis: sputum culture positive rate of 8-34%, alveolar lavage fluid 45%-62%; sputum detection of Aspergillus is not significant, should be repeatedly isolated Aspergillus or smear detection of Aspergillus mycelium before diagnosis, if necessary, puncture biopsy to clarify the diagnosis.
1.3.2 Pulmonary candidiasis
It usually occurs within two months after surgery. Immunosuppression leading to low cellular immune function is the main cause of Candida opportunistic disease. Clinical manifestations are fever, irritating cough, coughing white mucus-like sputum or small gelatinous lumps, even shortness of breath, hemoptysis, wet rales in both lungs, X-ray shows uniform shadows of variable size and shape with unclear borders, lesions are often patchy or nodular, lesion sites often change, and usually do not involve the lung apices.
1.3.3 Fungal pneumonia due to other pathogens, such as pulmonary cryptococcosis, pulmonary trichococcal infection, etc.
Treatment: 1. Amphotericin B: In the past, it was the main drug used in the treatment of severe fungal infections, but its application was limited by its interaction with cyclosporine and its nephrotoxicity. The liposomal amphotericin developed in recent years is less nephrotoxic and can be used simultaneously with cyclosporine, etc. 2. Triazoles voriconazole (voriconazole), fluconazole and itraconazole. Voriconazole is available in two dosage forms: oral and injectable. It is well absorbed orally and is effective in the treatment of Aspergillus infections, and is effective in invasive fungal infections resistant to other conventional antifungal drugs with low toxic side effects. Fluconazole also has two dosage forms, effective for Candida and Cryptococcus, but ineffective for Aspergillus infection, and in recent years with its wide application of drug-resistant fungal beads increased significantly. Itraconazole only oral formulation, and the amount of absorption is uncertain, but well tolerated, can be used for long-term maintenance treatment, post-transplant prophylaxis can be the same as fluconazole to reduce fungal colonization and reduce the incidence of serious fungal infections. 3. caspofungin is the first formulation of the new drug echinocandins, and triazoles and polyenes act on the cell membrane ergosterol, it acts on the cell wall dextran, and clinical trials have confirmed that its antifungal effect is comparable to that of amphotericin B, its tolerability is comparable to that of triazoles, and it does not have cross-resistance to these two classes of drugs [1], and will be increasingly used in clinical practice in the future.
1.4 Pneumocystis carinii pneumonia (PCP)
Pneumocystis carinii is an opportunistic pathogen with an incidence of 11% in liver transplant patients, 4% in kidney transplant patients, and 33% in lung transplants without prophylactic medication, and is associated with drug doses for anti-rejection therapy, with an increased incidence of Pneumocystis carinii pneumonia in patients with CMV infection [33]. The disease is most likely to present 2-6 months after transplantation. Clinical manifestations include cough, fever, dyspnea, and interstitial or alveolar exudative changes in both lungs. 90% of cases can be diagnosed by bronchoalveolar lavage, and transbronchoscopic lung biopsy is also feasible. The first-line drug is still high-dose sulfamethoxazole (60-70 mg/kg.d, 12-14 mg/kg.d), and pentamidine is the second-line drug, administered intravenously. Prophylactic application of small doses of potentiated sulfamethoxazole (480 mg) in liver transplant patients significantly reduces the incidence of PCP [34]. Low-dose methimazole-sulfamethoxazole is recommended for the prophylaxis of PCP in patients with intractable acute or chronic rejection with intensive immunosuppressive therapy and in patients with lung transplantation [35].
1.5 Pulmonary helminthiasis
In endemic areas, fecal round nematodes can sometimes cause severe pulmonary infections, which can be diagnosed by finding the pathogen in sputum or stool, along with elevated blood eosinophils. Treatment options are albendazole and ivermectin.
2 Laboratory tests and ancillary investigations
Due to the special immunopathophysiological status of post-transplant patients, pneumonia can have an insidious or acute onset, but the general characteristic is that the disease progresses rapidly, and if it is not controlled in a timely and effective manner, it will soon progress to acute respiratory distress and become life-threatening. The poor specificity of clinical symptoms in various types of pneumonia makes pathogenic diagnosis particularly important.
2.1 Non-invasive examination means
Routine blood, sputum, pharyngeal swab culture, PPD test, sputum for antacid bacilli, blood TB-PCR, CMV-IgG, IgM and leukocyte CMV antigen tests, and if Legionella infection is suspected, urine for Legionella antigen. If the chest X-ray is not clear or if there are clinical symptoms and the X-ray is normal, further CT scan of the chest should be performed. Nodular or cavernous lesions are more common in fungal, Mycobacterium tuberculosis, and Actinomyces infections, and diffuse interstitial lesions are more often seen in those with viral and Pneumocystis infections. Lesions in unilateral or bilateral lobes of the lung are more often seen in bacterial infections [38].
2.2 Invasive examination means
If positive results are not obtained by the above tests, further transbronchoscopic bronchoalveolar lavage fluid culture, lung biopsy examination and, if necessary, open lung biopsy can be performed. Wilcox et al. found that transbronchoscopy or open lung biopsy altered the course of disease in 61% of patients and affected the prognosis of 57% of patients with positive results. Alveolar lavage (BAL) without lung biopsy and fibrinoscopy with protective brushing (PSB) are safe, and both are comparable in bacterial detection, but BAL is superior for cytomegalovirus and Pneumocystis. Moreover, bilateral BAL examination has a higher positive rate than unilateral. Trans-fiberoptic lung biopsy (TBLB) can increase the pathogen detection rate from 36.3% in BAL alone to 67.5%; TBLB has a higher positive rate for the diagnosis of tuberculosis, Kaposi’s sarcoma, fungal infections, and malignant hematologic tumors [There is no significant difference between TBLB and BAL for the diagnosis of pneumocystis, but BAL is more effective for the diagnosis of cytomegalovirus pneumonia However, for the diagnosis of cytomegalovirus pneumonia, BAL was more effective . IL-6 and plasma C-reactive protein levels in BALF can be measured to evaluate the inflammatory response and provide appropriate interventions for the treatment of pulmonary complications. an IL-6 >;40 pg/ml in BALF is an independent predictor of mortality and usually indicates the need for mechanical ventilation therapy.
The following issues should be considered in the comparison and selection of TBLB and open lung biopsy (OLB): the advantage of TBLB is that it does not require general anesthesia and surgery and is less invasive, but the selection of indications is relatively strict, and patients with bleeding tendency and severe airway injury are not suitable, and the test is not considered in critically ill patients. On the contrary, OLB requires general anesthesia and surgical procedures, therefore, it can be selected for seriously ill patients and has a high incidence of postoperative complications (10-20%). Nevertheless, OLB is higher than TBLB in terms of pathogen detection rate, which may be related to the fact that OLB is a biopsy taken under direct vision and more tissue is obtained.
3 Summary
Post-transplantation pneumonia is one of the important causes of death in transplantation patients, and early diagnosis and treatment is the key to improve the prognosis of patients, so the monitoring of the pathogenesis of pulmonary infection in post-transplantation patients must be further strengthened. Preventive medication and strengthening of comprehensive treatment: oxygenation, correction of acid-base imbalance electrolyte disorders, correction of hypoproteinemia, adjustment of the dosage of immunosuppressants, discontinuation if necessary, and application of gammaglobulin may be considered for severe cytomegalovirus pneumonia. For those with respiratory distress and partial pressure of oxygen below 60 mmHg, non-invasive mechanical ventilation is given, and if necessary, it is changed to invasive ventilation. Only in this way can the morbidity and mortality of pneumonia in organ transplant patients be reduced and the prognosis of transplant patients be improved.