60-Year-Old Man with Non-resolving Pneumonia

A 60 year-old man with a past medical history for coronary artery disease requiring four vessel coronary artery bypass grafting, hypertension, hyperlipidemia, nephrolithiasis and cirrhosis related to alcohol abuse was deemed a liver transplant candidate after complications of several episodes of hepatic encephalopathy and esophageal variceal bleeding. He remained abstinent from alcohol.

一名60岁男性患者曾因冠心病接受冠脉搭桥手术（4根血管），此外，既往史包括高血压，高脂血症，肾结石及酒精性肝硬化。患者还曾数次发生肝性脑病及食道静脉曲张出血，因而等待肝移植。

He underwent a living donor liver transplant using the right hepatic lobe graft donated by his son. His immunosuppression regimen included sirolimus, mycophenolate, and prednisone. Valgancyclovir and trimethoprim/sulfamethoxazole included his prophylactic therapy. There were no peri-operative complications noted. Post-operatively, the patient noted mild dyspnea and a non-productive cough. His postoperative course was complicated by cholangitis secondary to biliary stricture necessitating percutaneous trans-hepatic cholangiography (PTC) and biliary dilation.  Work up for his cholangitis included an abdominal CT that incidentally demonstrated a dense pulmonary infiltrate of the right middle lobe (RML) (Figure 1). He also developed acute renal insufficiency, but did not require renal replacement therapy. It was determined by the surgical team that the patient had pneumonia and was treated amoxicillin/clavulanate. His respiratory symptoms resolved and followed up in clinic.

患者接受了活体肝移植（儿子捐献的肝脏右叶）。免疫抑制剂包括西罗莫司，麦考酚酯和强的松。同时预防性使用缬更昔洛韦和复方新诺明。术后，患者出现轻度呼吸困难及干咳。术后患者因胆道狭窄继发胆管炎行经皮经肝胆管造影(PTC)及胆管扩张。有关胆管炎的诊断检查包括腹部CT，CT检查意外发现右中叶(RML)致密性浸润影（图1）。患者还发生急性肾脏功能不全，但无需接受肾脏替代治疗。外科医生认为患者发生肺炎，并使用阿莫西林／克拉维酸治疗。患者呼吸道症状缓解，随后在门诊随访。

As an outpatient, the patient required one additional biliary dilation procedure for biliary stricture. A follow up chest CT (Figure 2) 7 weeks after initial imaging demonstrated a persistent RML infiltrate. The patient was completely without respiratory complaint at the time.  A pulmonary consultation is requested.

门诊随访期间，患者因胆道狭窄再次进行胆道扩张。7周后复查胸部CT（图2）显示RML浸润影持续存在。此时患者没有任何呼吸道主诉，遂请呼吸科医生会诊。

Physical examination revealed the patient to be afebrile with an oxygen saturation of 99% on room air. The remaining vitals were also unremarkable. The patient was not in acute distress and could talk in complete sentences.  Auscultation of the lungs was clear throughout and cardiac examination revealed a 3/6 systolic murmur. The extremities were void of edema and there was no clubbing.

体格检查显示患者不发热，吸入空气时氧饱和度99%。其余生命体征无明显异常。患者没有急性呼吸窘迫的症状，且能够说出完整的话。肺部听诊呼吸音清晰，心脏检查发现有3/6级收缩期杂音。四肢没有水肿，没有杵状指。

Figure 1: CT chest showing right middle lobe dense consolidation with associated ground glass opacities

图1：胸部CT显示右中叶致密实变影伴磨玻璃影

Figure 2: Persistent, more consolidated right middle lobe infiltrate with increased ground glass opacities

图2：右中叶浸润影持续存在且实变更明显，磨玻璃影加重

Question 1 问题1

What would be the next best diagnostic approach for this patient’s non-resolving opacity?

对于肺部病变，下一步应选择以下哪种诊断措施？

正确答案1

Flexible bronchoscopy with bronchoalveolar lavage (BAL) and trans-bronchial biopsies

纤支镜下行肺泡支气管灌洗(BAL)及经支气管活检

Identification of potentially treatable pulmonary complications is important in patients who are immunosuppressed. The differential diagnosis of non-resolving pulmonary infiltrates includes both infectious and non-infectious etiologies. Recent advances in urine antigen testing, induced sputum analysis, and other rapid non-invasive studies have aided in the diagnosis of pulmonary infiltrates in immunosuppressed patients¹.

In patients who are not severely ill with pulmonary infiltrates, an empiric course of antibiotics can be considered.  Persistent pulmonary infiltrates commonly represent bacterial or opportunistic infections, such as fungal pneumonia or Pneumocystis jerovecii pneumonia.  Common bacterial pathogens include methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aureuginosa.  Legionella pneumonia remains a challenging infection in solid organ transplant recipients as major outbreaks can be seen with water or inhaled aerosol contamination².  Viral infections are also common post-transplant, and are well described by the length of time since transplant.  Cytomegalovirus (CMV), Herpes simplex viruses (HSV) and Ebstein-Barr virus (EBV) are among the most commonly encountered.  Immunusuppressive medications have led to reactivation of Mycobacterium tuberculosis following solid organ transplantation.

Malignancy may also represent non-resolving pulmonary infiltrates.  Post-transplant lymphoproliferative disorder (PTLD) is an example of a lymphoproliferative disorder related to immunosuppression following solid organ transplantation as well as hematopoetic stem cell transplantation.  The pathophysiology is related to B-cell proliferation induced by Ebstein-Barr virus.  Clinically, patients present with constitutional symptoms such as fever, malaise and weight loss.  More than half of patients with this disorder develop extra-nodal masses in the GI tract, lungs, skin, or central nervous system.  Diagnosis is made by high clinical suspicion followed by biopsy.  Full excisional biopsy is preferred; however, needle biopsy is an acceptable alternative in certain situations.  Treatment of PTLD necessitates a reduction in immunosuppressive medications transplant recipients receive^2,3. Typically chemotherapy is given for the treatment of PTLD as well.  Chemotherapy regimens are similar to treating non-Hodgkin’s lymphoma with CHOP and rituximab, a monoclonal antibody to CD20 expressed on mature and immature B lymphocytes.  Alternative non-infectious etiologies include atelectasis from airway obstruction, cryptogenic organizing pneumonia, or pulmonary vasculitides, such as granulomatosis with polyangiitis.

Bronchoscopy with alveolar lavage remains an essential component of the diagnostic algorithm.  A 1990 study evaluated a diagnostic team to rapidly diagnose pulmonary infections in solid organ transplant recipients.  Fiberoptic bronchoscopy was performed on patients with clinical and radiographic evidence of pneumonia that could not readily expectorate an adequate sputum sample.  Bronchoscopy with lavage and brushing was done within 24-hours if deemed necessary.  A diagnosis was made in 92% of patients, the overwhelming majority related to infectious processes³. In immunocompromised hosts, non-invasive and bronchoscopic procedures early in the course of pulmonary infiltrates related to infectious etiologies had significantly lower mortality if therapy was tailored within seven days⁴.

While all of the listed diagnostic procedures are feasible, bronchoscopy is a semi-invasive, well-tolerated procedure with acceptable risks.  Bronchoscopy allows for bronchoalveolar lavage, protected brush sampling, endobronchial biopsy and transbronchial biopsy, depending on the specific patient characteristics.  Infection in transplant recipients is common.  Recognition is often difficult with advances in immunosuppression to prevent allograft rejection.

A sputum culture may not provide the diagnostic yield in this patient and therefore, choice A is incorrect.  A VATS biopsy (choice B) will most likely make a diagnosis; however, this would not be optimal next step in this patient.  VATS procedures are more invasive and inherently have higher complication rates than flexible bronchoscopy.

In this patient, bronchoscopy with BAL, brushing, and trans-bronchial lung biopsy were performed.  Cultures including bacterial, viral, and fungal were negative.  Legionella, nocardia, AFB and pneumocystis were negative as well.  Cytology examination of the BAL and bronchial brush samples revealed no evidence of malignancy.  Transbronchial biopsies were taken and these also did not show malignant cells.  Pathologic examination of the transbronchial biopsies revealed normal alveolar structures with crush artifact, mildly atypical cells, and submucosal calcifications.  Specimens stained for AFB and fungus were negative as well.

此例患者在纤支镜下进行BAL，毛刷和经支气管肺活检。细菌、病毒和真菌培养均阴性。有关军团菌、奴卡菌、抗酸杆菌和肺孢子虫的检查也为阴性。BAL及支气管毛刷标本的细胞学检查未发现恶性肿瘤迹象。经支气管活检也未发现恶性肿瘤细胞，病理检查显示正常肺泡结构，轻度非典型细胞，粘膜下钙化。活检标本抗酸杆菌及真菌染色阴性。

There has been persistence to this pulmonary infiltrate over during a seven week follow up already and following up with an additional CT scan of the chest in 3 months would not be appropriate at this time, and thus choice A is incorrect.

Trans-thoracic needled aspiration (TTNA) has become a well-established and widely utilized procedure for the diagnosis of peripheral lung nodules.  A recent study has demonstrated a sensitivity of 92% and 100% in malignant and benign disease, respectively⁵.  Although there the sensitivity for diagnosis of both benign and malignant disease is high, there are certainly associated complications from CT-guided TTNA.  Severe complications such as hemorrhage (1%), pneumothorax (15%) and pneumothorax requiring a chest tube (6.6%) are reported⁶.  In this case, the fact remains that this dense, consolidated, peripheral pulmonary nodule persisted over many weeks despite antibiotic therapy.  Furthermore, there was no evidence for spread to other organs or the mediastinum.  At this point, referral for surgical lung biopsy is warranted, making answer choice D correct.

Pneumocystis jerovecii (formerly carinii) pneumonia (PJP/PCP) is widely regarded as an opportunistic infection in those afflicted with the human immunodeficiency virus (HIV).  There has been a paradigm shift as the number of patients receiving solid organ transplants and immunosuppression increases. A 1996 study of 116 non-AIDS patients revealed that solid organ transplant was associated with PJP/PCP in 25% of the cases⁷.  In this study, the median corticosteroid dose was 30 mg daily; however, 25% of patients received only 16 mg daily.  As such, patients on prolonged corticosteroid treatment should have consideration for prophylaxis against Pneumocystis, as our patient did.  Prophylaxis is associated with a 91% observed reduction in Pneumocystis pneumonia in a meta-analysis⁸.  The number needed to treat to prevent one was fifteen in that meta-analysis of twelve randomized controlled trials in patients with autologous bone marrow or solid organ transplant or who had hematologic malignancy⁹.  Acute infection with Pneumocystis is typically associated with fever, shortness or breath and cough¹⁰, which can result in acute respiratory failure.  Diagnosis has relied on direct visualization of the organisms by microscopy in BAL fluid or induced sputum.  Non-HIV patients typically are infected with lower parasite burden than those infected with HIV, and microscopic evaluation may be falsely negative¹¹.  Our patient did not have any of the typical clinical signs or symptoms of PJP/PCP infection and similarly the BAL and trans-bronchial biopsies were negative for the organism.  As such, empiric therapy for PJP/PCP would not be warranted.

History Continued 病史继续...

The patient undergoes a VATS biopsy without any complications. The pathology slides include

患者接受胸腔镜下肺活检，过程顺利。病理片显示

Question 3

Based on the VATS biopsy shown, what is the most likely diagnosis?

根据VATS活检结果，最可能的诊断是什么？

正确答案3

Pulmonary calcinosis 肺钙化

The pathology from the right middle lobe wedge resection is consistent with pulmonary calcinosis.  The biopsy shows dystrophic calcifications of the lung interstitium and blood vessels.  The term dystrophic refers to calcium deposition in previously injury tissue, as opposed to metastatic calcification, which occurs in non-injured tissue.

Diffuse, nodular calcification can be observed following Varicella pneumonia.  Acutely, Varicella pneumonia radiographically appears as scattered, ill-defined pulmonary nodules.  These infiltrates typically resolve over time.  In some cases, however, calcification occurs three to five years later¹².  The pattern of calcification is typically punctate or miliary, resembling initial injury patterns. Thus, choice A is incorrect.

Pulmonary infarcts are typically wedge-shaped, peripheral pulmonary lesions with the broad base abutting the pleural surface as was seen with our patient.  Histopathologically, pulmonary infarction is characterized by basophilic necrosis.  Granulomatous changes have been noted as well¹³.The majority of specimens have vascular inflammation, however calcification in the lung parenchyma and vasculature has not been reported, making answer choice B incorrect.

Pneumocystis jerovecii pneumonia (PJP, formerly Pneumocystis carinii pneumonia, PCP) is historically regarded as the most common AIDS-defining illness, typically when the CD4⁺ count falls below 200 cells/mm³. With the routine use of chemoprophylaxis and the emergence of highly active anti-retroviral therapy, the incidence in HIV positive patients has declined¹⁴.  However, the incidence of PJP in non-HIV immunocompromised patients is increasing, including those who receiving transplants.  The radiologic appearance of PJP varies, but common features include ground glass opacities in a perihilar distribution on high resolution computed tomography.  Pneumatoceles are common as is septal thickening.  Consolidation, lymphadenopathy and pleural effusions are rare.  Pathologically, PJP proliferates as a trophozoiote and associates with type I pneumocytes¹⁵, which has been demonstrated by electron microscopy.  Rarely, calcification of the lung can be seen with PJP and other parasitic infections, however, the clinical history, radiographic appearance, pathologic specimen and chemoproprohylaxis eliminate answer choice C.

References

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10. Ewig, S, Bauer, T, Schneider C, Pickenhain, A et al. Clinical characteristic and outcome of Pneumocystis carinii pneumonia in HIV-infected and otherwise immunosuppressed patients. Eur Respir J. 1995;8: 1548-1553.

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12. Chan, ED, Morales, DV, Welsh, CH, et al. Calcium Deposition with or without Bone Formation in the Lung. Am J Respir Crit Care Med. 2002; 165:1654-69.

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15. Bartlett, MD and Smith, JW. Pneumocystis carinii, and Opportunist in Immunocompromised Patients. Clin Microbiol Rev. 1991;4(2):137-49.

16. Bein, ME, Lee, DBN, Mink, JH, et al. Unusual Case of Metastatic Pulmonary Calcification. AJR. 1979;132:812-816.

17. Wechsler, RJ, Feld, R, Munoz, SJ, et al. Suprahepatic Circumcaval Ring: CT Finding After Orthotopic Liver Transplantation. AJR. 1992; 183:545-48.