Authors: Liang Rui, Zhang Zhu, Liu Dong, Wang Jinzhi, Huang Qiang, Xie Wanmu, Zhai Zhenguo
First author's affiliation: National Key Laboratory of Respiratory and Comorbidity of National Center for Respiratory Medicine, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Diseases, Chinese Academy of Medical Sciences, Department of Respiratory and Critical Care Medicine, Respiratory Center, China-Japan Friendship Hospital, Beijing University of Chinese Medicine
Corresponding authors: Zhai Zhenguo, National Key Laboratory of Respiratory and Comorbidities, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Diseases, Chinese Academy of Medical Sciences, Department of Respiratory and Critical Care Medicine, Respiratory Center, China-Japan Friendship Hospital
Cite this article: LIANG Rui, ZHANG Zhu, LIU Dong, et al. One case of "pneumonia" that did not heal[J]. Chinese Journal of Tuberculosis and Respiration, 2024, 47(9): 845-850. DOI: 10.3760/cma.j.cn112147-20231017-00242.
summary
大动脉炎肺动脉受累（Takayasu′s arteritis-pulmonary artery involvement，TA-PAI）是一种累及肺动脉及其分支的慢性进行性炎性疾病，多数患者早期表现为发热、呼吸困难、胸痛等非特异性呼吸系统症状，误诊率较高。
At present, the diagnosis of TA-PAI is mainly based on the diagnostic criteria of Takayasu's artery and imaging evidence of pulmonary artery involvement, but pulmonary artery involvement has not been included in the commonly used diagnostic criteria for Takayasu's arteritis, resulting in the diagnostic rate of TA-PAI, especially solitary pulmonary artery involvement, may be seriously underestimated.
This article reports a 26-year-old female patient with recurrent chest pain and fever, diagnosed with "pneumonia" in the hospital, and did not show significant improvement after 4 months of treatment. By analyzing the clinical characteristics and diagnosis and treatment ideas of this case, and reviewing relevant literature, clinicians could improve their understanding of pulmonary artery involvement in Takayasu's artery.
body
The patient, a 26-year-old female, was admitted to the emergency department of China-Japan Friendship Hospital on January 17, 2023 due to hemoptysis for 1 day.
More than 4 months ago (August 29, 2023), the patient had fever and chest pain without obvious causes, chest CT showed multiple subpleural patchy hyperdensities in the right lung (no original film was seen), and was diagnosed with "pneumonia" by the hospital and treated with anti-infective treatment (specifics unknown), intermittent low-grade fever with dyspnea after discharge, no medical treatment, and self-intermittent oral antibiotic therapy, but no obvious improvement.
Three months ago (October 10, 2023), the patient was hospitalized again in an outpatient hospital for fever and chest pain, and chest CT showed obvious patchy and flocculent hyperdensity opacities in the middle lobe of the right lung and lower right lung, and the extent of the lesion was smaller than before (Figs. 1 and 2), and he was discharged after anti-infective therapy with moxifloxacin, cefdinir, piperacillin sulbactam sodium, azithromycin and diclofenac sodium analgesic therapy.
After being discharged from the hospital, he continued to have intermittent low-grade fever with cough and sputum production, and was repeatedly treated with antibiotics in the outpatient department of the hospital until he was treated in the emergency department of our hospital due to hemoptysis. During the chest CT examination in the emergency department of our hospital, the patient coughed up bright red blood again, the amount was about 100 ml, and the chest CT showed ground-glass opacities in the upper lobe of the right lung and the lower lobes of both lungs, and compared with the front, the nodular opacity of the right upper lung and the consolidation of the right lower lung were partially absorbed, and the new ground-glass opacities of both lungs, the upper right lung and the right lower lung were the main ones (Figs. 3 and 4).
The patient was given nasal cannula oxygen inhalation 6 L/min, ceftriaxone anti-infective therapy, caroxine sodium, and posterior pituitary lobe hemostatic therapy, and the patient coughed up about 200 ml of bright red blood again in the morning of the next day, and was admitted to the respiratory department of our hospital for further diagnosis and treatment.
After admission, the patient's vital signs: body temperature 36.5 °C, heart rate 100 beats/min, respiration 18 times/min, blood pressure 94/60 mmHg (1 mmHg=0.133 kPa), SpO2 98% (FiO2 0.33), BMI 19.2 kg/m 2, pale eyelid color, and no other special positive signs were found. Some of the patient's medical records from other hospitals and some of the results of our hospital are shown in Table 1.
In order to stop the bleeding as soon as possible and make a clear diagnosis, bronchial arteriography was performed immediately, and gelatin sponge embolization was given to the right intercostal bronchial artery trunk, left and right co-trunk, and right intercostal artery through catheter, and the patient did not bleed again. The patient is unmarried and childless, and there is no special past medical history, personal history, or family history.
Figs. 1,2 Chest CT on October 10, 2022: obvious patchy and flocculent hyperdensity opacities in the middle lobe of the right lung and lower lung (original report); Both the lung window and the mediastinal window suggest a cuneiform with the base in the pleura and the tip pointing to the hilum under the pleura in the right lower lobe, as indicated by the arrow. This finding may indicate "pulmonary infarction"
Figs. 3,4 Chest CT on January 17, 2023: ground-glass opacities in the upper lobes of the right lung and lower lobes of both lungs, compared with the anterior stage, the nodular opacities of the right upper lung and the consolidation of the right lower lung were partially absorbed, and the new ground-glass opacities of both lungs were developed, with the upper right lung and the lower right lung being the highlights
Table 1
According to the diagnostic criteria for pneumonia in mainland China, the patient had a community onset accompanied by fever, elevated peripheral blood leukocytes, and new reality changes on imaging examination, and was considered to have a high possibility of community-acquired pneumonia (CAP) at the initial diagnosis and empiric anti-infective therapy was initiated. However, after empiric antibiotic therapy, the patient still had intermittent fever, so he was readmitted to the hospital, and the other hospital gave multiple antibiotic therapy again without identifying the pathogen.
The reasons for the misdiagnosis in other hospitals may be as follows: (1) the patient is not alert to the infection of special pathogens, the patient has intermittent fever, has failed to search for conventional pathogens for many times, and has failed to treat multiple antibiotics, so bronchoscopy should be further improved or transferred to a higher-level hospital, rather than continuous empirical antibiotic treatment. (2) The identification of non-infectious diseases was insufficient, the patient was a young woman, had no special contact history, "pneumonia" recurred, the patient's chest CT showed ground-glass opacity and subpleural cuneiform in the lower lobe of the right lung, and there were characteristics of alveolar hemorrhage and vascular infarction, so further identification was needed.
First of all, infectious factors should be considered: the patient was diagnosed with pneumonia in other hospitals for many times due to fever and cough and sputum, empirical anti-infective therapy failed, and no evidence of bacterial, fungal, tuberculosis, virus and other infections was found in routine pathogenic examination (Table 1), considering that the possibility of infection with conventional pathogens is small, and it is necessary to be vigilant for special pathogen infection, such as leptospira, tuberculosis, actinomycosis, etc. The patient's blood glucose and urine glucose are abnormal, and the increase in blood glucose may lead to metabolic disorders and decreased immune function, thereby increasing the possibility of colonization of the respiratory tract by rare pathogens such as actinomycosis.
The clinical manifestations and imaging of actinomycosis are not specific, and the clinical misdiagnosis and missed diagnosis rate can be as high as 74.5%, and actinomycosis can only be diagnosed by clearly isolating it from lung tissue or alveolar lavage fluid. Because the patient was admitted with less sputum and was in the stage of massive hemoptysis, sputum culture and bronchoscopy were not performed. The patient's blood glucose and urine glucose were normal after repeated re-examination after admission, and the patient was a young woman with no special contact history, and it was considered that the abnormal index at the time of admission may be a stress reaction, and there was no long-term glucose metabolism disorder, so the possibility of special infection was small.
Among non-infectious factors, we consider immunological factors first. (1) Primary pulmonary capillaritis: the most common is ANCA-related vasculitis, which is mostly middle-aged and elderly, usually accompanied by extrapulmonary organ involvement, and mostly accompanied by ANCA positive, the image is mostly patchy shadow of both lungs, ground-glass opacity, etc., the patient is a young woman, there is no clinical manifestations of other organ involvement, ground-glass is heavy on the right side, and the vasculitis antibody spectrum is negative, so it is less likely. (2) Pulmonary vasculitis secondary to connective tissue disease: the patient has recurrent fever, elevated ESR, positive ANA, and suspected connective tissue disease. The patient had no positive signs such as rash and ulcer, no clinical manifestations of extrapulmonary organ involvement such as heart and kidney, and asymmetrical lung lesions on CT scan, so pulmonary vasculitis secondary to connective tissue disease was less likely.
Secondly, non-immune factors should be considered: (1) pulmonary vascular disease: the patient had chest pain, hemoptysis, and elevated D-dimer, and chest CT on October 10, 2022 showed that the upper and lower lobes of the right lung were suspected to be subpleural wedges (Figs. 1 and 2), which may be pulmonary vascular infarction, pulmonary embolism and Takayasu's arteritis may be suspected, and pulmonary artery CTA should be further performed. (2) Left heart failure: the patient is a young woman, no underlying disease, no symptoms such as palpitation, shortness of breath, edema, etc., normal myocardial injury markers, CT does not show abnormal heart size, acute left heart failure is unlikely, and there is no obvious abnormality in the heart confirmed by bedside echocardiography. (3) Coagulation dysfunction: the patient's APTT was still mildly prolonged under hemostatic therapy, indicating the possibility of abnormal coagulation function, the patient did not have hemoptysis after hemostasis, and there were no other bleeding points such as skin petechiae and ecchymosis, and the subsequent re-examination showed that the patient's coagulation function was normal, and the APTT was 40.9 s, so it was not considered for the time being. (4) Others: The patient is a young woman, with no obvious abnormalities in tumor markers, no obvious mass lesions on chest CT, no history of transplantation, and no history of drug and poison exposure, so tumor, transplantation, drugs/poisons and other reasons are not considered for the time being.
In summary, in order to further rule out pulmonary embolism and Takayasu's artery, CTA examination of the aorta and pulmonary artery was completed on January 20, 2023 (Figs. 5 and 6), and the results suggested that Takayasu'arteritis may involve the right pulmonary artery trunk and the middle and lower lobe pulmonary arteries. The patient, a female of childbearing age, was unmarried and childless, and had fever on January 23, with a maximum body temperature of 38.3 °C, a blood routine white blood cell count of 8.28×10 9 cells/L, a C-reactive protein of 33.53 mg/L, an ESR of 88 mm/1 h, and an IL-6 of 7.33 pg/ml.
According to the 1996 revised Ishikawa Takayasu's arteritis diagnostic criteria, the patient met one of the main criteria (intermittent fever time > 1 month) and two minor criteria (ESR>20 mm/1 hour and imaging diagnosis of pulmonary artery injury), so the diagnosis of Takayasu's artery pulmonary artery involvement (defined as the corresponding manifestation of pulmonary artery Takayasu's artery disease) was met.
We further discussed with the Department of Rheumatology and Immunology that according to the Kerr score, the patient was currently in the active stage of Takayasu's arteritis, so according to the 2022 mainland Takayasu's arteritis diagnosis and treatment standards, methylprednisolone 40 mg was given once a day on January 23, and tocilizumab 320 mg was added on January 30 once a month, and mycophenolate mofetil 0.5 g was added on February 2 twice a day, and the hormone dose was gradually reduced. The patient was at high risk of bleeding and was not treated with anticoagulation.
After 3 months of anti-inflammatory and immunosuppressive therapy, the patient did not have hemoptysis, fever, or cough and sputum production, but the patient developed post-activity chest tightness, and the WHO cardiac function class was II.-III. On April 6, 2023, a follow-up CTPA (Figs. 9 and 10) showed that the pulmonary artery involvement of Takayasu's artery was similar to that on January 20, 2023, with basic absorption of alveolar hemorrhage in both lungs, and no mural nodules in the aortic wall of the T7 segment were not shown. The patient was a young female with high quality of life requirements, so she was readmitted to the hospital on May 9, 2023 for the evaluation of balloon pulmonary angioplasty (BPA).
The patient's artery in the middle and lower lobes of the right lung was completely occluded, and the CTPA was re-examined after 3 months of regular drug treatment (Figs. 9, 10), and the stenosis did not improve, and the Takayasu's arteritis was in a stable stage, with a 605 m walk test in 6 minutes, and the inflammatory indicators were normal. Therefore, the patient received BPA treatment on May 15 (Figs. 11, 12, 13, 14), and the dorsal artery, the main trunk of the lower lobe artery, and the main trunk of the posterior basal segment of the lower lobe artery in the right lung were opened, and the blood flow was restored after surgery. After BPA therapy, rivaroxaban 10 mg once daily was given to prevent thrombosis. Two weeks later (May 29), the patient was readmitted to the hospital for re-examination, and the WHO cardiac function grade I.~II., 623 m on the 6-minute walk test, and the re-examination of CTPA showed partial recanalization of the pulmonary artery in the lower lobe of the right lung (Figs. 15, 16).
Figs. 5 and 6 CTA of the aorta and pulmonary artery on January 20, 2023: the right pulmonary artery trunk is slender, the pulmonary artery trunk occlusion of the right middle and lower lobes is occluded, and the pulmonary artery branch contrast medium in the basal segment of the right lower lobe is light; The aorta and branches are clearly shown, the wall is smooth without thickening, and the T7 segment is an aortic wall with a mural nodule, as indicated by the arrow
Figs. 7,8 PET-CT on January 22, 2023: increased metabolism of the artery branch of the right lower lobe artery and the artery of the right upper lobe as shown by the arrows
Fig. 9,10 CTPA on April 6, 2023: right pulmonary artery slender, posterior upper lobe of the right lung, middle lobe, and lower lobe of the right lung occluded, similar to the January 20, 2023 film, as shown in the arrows
Fig. 11~14 Pulmonary angiography + balloon pulmonary angioplasty on May 15, 2023, where Figure 11 shows complete occlusion of the middle and lower lobe artery in the right lung, mild stenosis of the upper lobe artery and irregularity of the wall, as shown by the arrow; Figure 12 shows the contrast showing complete occlusion of the middle and lower lobes of the right lung, as shown by the arrows; Figure 13 shows the balloon dilation of the main trunk of the posterior basal segment of the right lower lobe artery, as shown by the arrows; Figure 14 shows a significant improvement in pulmonary artery blood flow after contrast compared with before balloon dilation, as shown by the arrows
Figs. 15,16 CT pulmonary angiography on August 9, 2023 showed partial recanalization of the pulmonary artery in the lower lobe of the right lung, as shown by the arrows
discuss
The patient was diagnosed with "pneumonia" several times in other hospitals, and it was not until the condition worsened that hemoptysis was diagnosed with Takayasu's artery pulmonary artery involvement (TA-PAI) in our hospital, and he was treated in a standardized manner after multidisciplinary discussion.
The patient's "pneumonia" did not heal, and he was admitted to our hospital due to hemoptysis after 4 months of anti-infective therapy, and there were still consolidations on chest CT, indicating that empirical anti-infective therapy may have failed, but the patient was a young woman, with no underlying disease and no evidence of infection, why did the "pneumonia" not heal? Are there any other causes of intermittent low-grade fever and dyspnea that progress to hemoptysis during anti-infective therapy?
Therefore, the diagnosis of CAP is doubtful, and hemostasis and etiology should be stopped in time to exclude pulmonary embolism, pulmonary vasculitis, pulmonary interstitial disease, etc., rather than empiric anti-infective therapy.
For patients with non-specific respiratory symptoms, chest CT is a common choice in clinical practice, and all the information displayed on chest CT is the key to finding the cause, and possible clues should be grasped on the basis of clinical information. For example, the Hampton hump (wedge-shaped consolidation, with a raised medial border, always arranged along the periphery of the visceral pleural surface) on chest CT is a common manifestation of pulmonary vascular lesions on chest CT and is an important hint in the investigation, but the sensitivity (24%) and specificity (82%) of the Hampton hump are not high, and it should be comprehensively judged in combination with other features or radiomics analysis.
Takayasu's arteritis often has an insidious onset and is chronically progressive, and is clinically divided into brachiocephalic arterial type, thoraco-abdominal aortic type, aortic-renal artery type, mixed type and pulmonary artery type according to the location of the lesion.
Depending on the site of the lesion, patients will have different clinical manifestations, and the involvement of the ascending aorta may lead to aortic regurgitation, and a diastolic blowing murmur may be heard in the aortic auscultation area; Ischemic symptoms such as vertigo and headache may occur when the carotid and vertebral arteries are involved, and arterial bruits can be heard on auscultation; Subclavian artery involvement, asymmetry of blood pressure in both upper extremities, systolic blood pressure difference of >10 mmHg, decreased or pulseless pulse on palpation or pulselessness, systolic murmur audible on auscultation; Involvement of the thoracic aorta and abdominal aorta may manifest as chest pain, abdominal pain, hypertension, etc.; Iliac artery involvement may manifest as intermittent claudication, weakened or absent arterial pulses in the lower extremities, etc.; Renal artery involvement can lead to renovascular hypertension, renal atrophy, and renal function decline. Pulmonary artery involvement may present with shortness of breath, hemoptysis, and systolic murmur and hypersecond tone in the pulmonary valve area.
However, no specific autoantibodies have been found in Takayasu's arteritis, and studies have found that some patients are positive for anti-endothelial cell antibodies and anticardiolipin antibodies. Therefore, the current diagnostic criteria for Takayasu's arteritis are still mainly based on clinical manifestations and imaging, and the diagnostic criteria formulated by the United States Society of Rheumatology in 1990 are commonly used in clinical practice: (1) age of onset< 40 years old; (2) intermittent limb claudication; (3) decreased brachial artery pulses on one or both sides; (4) The difference in systolic blood pressure between the two upper limbs > 10 mmHg; (5) Murmur in one or both subclavian arteries or abdominal aorta; (6) Imaging including CTA, angiography, etc.: found that the first-level branches of the aorta or the proximal aortic arteries of the upper and lower limbs were stenosis or occlusion; Lesions are often focal or segmental, with the exception of arteriosclerosis, fibromuscular dysplasia, or similar causes.
10%~50% of Takayasu's artery patients will involve pulmonary arteries, Takayasu's artery pulmonary artery involvement was first reported in the literature in 1940, and later studies found that pulmonary artery involvement is not uncommon in Takayasu's arteritis patients, and pulmonary artery involvement can be the first or only manifestation of Takayasu's arteritis. Clinical studies have shown that the incidence of pulmonary artery involvement in Takayasu's artery is less than 20%, but autopsy data show that the incidence of pulmonary artery involvement in Takayasu's artery can reach 20%~83%, and the huge difference between the two suggests that the incidence of TA-PAI is seriously underestimated clinically.
The incidence of TA-PAI is significantly underestimated and is not easily diagnosed, and current diagnostic criteria for Takayasu's arteritis include the 1996 modified Ishikawa criteria and the 1990 and 2022 United States College of Rheumatology/European League Against Rheumatism (ACR) classification criteria.
According to the 1996 modified Ishikawa Takayasu's arteritis diagnostic criteria, the diagnosis of Takayasu'artitis was clear, but according to the latest 2022 ACR classification criteria for Takayasu's arteritis, although the patient met the access criteria (age of diagnosis≤60 years, evidence of vasculitis on imaging) and scored 3 points (1 point for women, 2 points for 2 arterial involvement), but could not diagnose Takayasu'eritis, and the patient also did not meet the 1990 ACR classification criteria. It can be seen that the existing diagnostic criteria for Takayasu's arteritis are not of high diagnostic value in patients with TA with pulmonary artery involvement as the main manifestation.
The 1990 and 2022 ACR criteria are based on the presence of aortic and branch involvement, and patients with TA with PAI alone or PAI as the main manifestation may not be diagnosed due to insufficient evidence of aortic involvement. One of the differences in the Ishikawa criteria is the addition of the "pulmonary artery involvement" item to the secondary criteria, which can be used to confirm the diagnosis in patients with TA-PAI as the presenting symptom and aortic system involvement, but PAI alone cannot be diagnosed.
If the existing diagnostic criteria for Takayasu's arteritis are rigidly applied, it will be very difficult to make a clinical diagnosis of TA-PAI, and imaging examination is the main means to confirm TA-PAI at present, among which pulmonary artery CTA is the most commonly used, so it is urgent to explore the diagnostic criteria suitable for TA-PAI in combination with imaging examination! TA-PAI is more likely to have complications such as pulmonary hypertension, ischemic heart disease, and lung infection than TA without pulmonary artery involvement, and once complications occur, the clinical symptoms are more serious, the treatment effect and prognosis are poor, and most patients have complications when TA-PAI is diagnosed.
Multidisciplinary discussion and formulation of standardized treatment plans in respiratory, rheumatology and immunology, and vascular intervention are equally important for the prognosis of patients with pulmonary artery involvement in Takayasu's artery.
Takayasu's arteritis is a type of systemic vasculitis, and hormones and immunosuppressants are the cornerstones of its treatment. Patients with newly diagnosed Takayasu's arteritis need adequate hormone therapy, which is gradually reduced to ≤5 mg/d after 4~8 weeks of continuous treatment, and a small number of patients with persistent remission can consider discontinuation. Patients with mild to moderate disease may be treated with oral antirheumatic drugs, and biologic agents such as the IL-6 blocker tocilizumab should be considered in patients with severe disease.
At present, there is also an expert consensus that mycophenolate mofetil can be used for the induction and maintenance of remission treatment of systemic vasculitis such as Takayasu's arteritis and ANCA-associated vasculitis. The meta-analysis of two observational studies abroad showed that the combination of corticosteroids and mycophenolate mofetil in the treatment of Takayasu's arteritis can significantly improve the clinical condition of patients, and the prospective observational study in mainland China also showed that the overall effective rate of mycophenolate mofetil in the treatment of active Takayasu's arteritis was 90%.
In addition to pharmacotherapy, invasive procedures (balloon dilation or stenting) have been reported to be considered in Takayasu's arteritis with severe pulmonary artery stenosis, but they are rarely used. Combined with this patient, we believe that BPA may also be a potential treatment for pulmonary artery involvement in Takayasu's artery based on a variety of factors such as the patient's lesion location, lesion extent, potential risk, and systemic condition, as well as the patient's wishes.
The choice of subsequent anticoagulant and antiplate therapy should first be evaluated for risk factors for cardiovascular disease and venous thromboembolism. Risk factors include male sex, advanced age, smoking, obesity, diabetes, hyperlipidemia, hormone use, etc. There is a lack of high-quality evidence for anticoagulant antiplate therapy in this population, and anticoagulant antiplate therapy should be evaluated with adequate control of disease activity and risk factors for cardiovascular disease and venous thromboembolism. References (omitted)