key: cord-0037493-7cmupd6r
authors: Grannis, Frederic W.; Ito, James; Sandoval, Argelia Jossie; Wilczynski, Sharon P.; Hogan, John Martin; Erhunmwunsee, Loretta
title: Diagnostic Approach to Life-Threatening Pulmonary Infiltrates
date: 2016-11-19
journal: Surgical Emergencies in the Cancer Patient
DOI: 10.1007/978-3-319-44025-5_10
sha: 177d94f7eabe6c2523e56355947c72e0c35fa589
doc_id: 37493
cord_uid: 7cmupd6r

Diagnosis of pulmonary disease is typically based upon consideration of presenting symptoms, physical examination, and pulmonary function testing in combination with classification of radiographic features, to guide diagnostic tests and initiate empiric treatment. When diagnostic efforts and/or empiric treatment fails, thoracic surgeons have traditionally been called upon to perform surgical biopsy of the lung to aid in the diagnosis of indeterminate, life-threatening pulmonary disease. Such biopsy has been requested specifically in the case of diffuse lung disease among patients receiving treatment for solid-organ or hematologic cancers, particularly when symptoms of respiratory failure progress and when noninvasive diagnostic tests and empiric treatments fail to halt progression. In such circumstances, radiologists, pulmonologists, and thoracic surgeons may be consulted and asked to provide tissue specimens that will allow rapid, accurate diagnosis leading to specific treatment. It is imperative that biopsy take place before respiratory failure supervenes [1], and that the specimens provided to clinical laboratories, pathologists, and microbiologists are comprehensive and properly preserved.

Diagnosis of pulmonary disease is typically based upon consideration of presenting symptoms, physical examination, and pulmonary function testing in combination with classifi cation of radiographic features, to guide diagnostic tests and initiate empiric treatment. When diagnostic efforts and/or empiric treatment fails, thoracic surgeons have traditionally been called upon to perform surgical biopsy of the lung to aid in the diagnosis of indeterminate, life-threatening pulmonary disease. Such biopsy has been requested specifi cally in the case of diffuse lung disease among patients receiving treatment for solid-organ or hematologic cancers, particularly when symptoms of respiratory failure progress and when noninvasive diagnostic tests and empiric treatments fail to halt progression. In such circumstances, radiologists, pulmonologists, and thoracic surgeons may be consulted and asked to provide tissue specimens that will allow rapid, accurate diagnosis leading to specifi c treatment. It is imperative that biopsy take place before respiratory failure supervenes [ 1 ] , and that the specimens provided to clinical laboratories, pathologists, and microbiologists are comprehensive and properly preserved.

In his review of the subject, Grant attributed priority for pulmonary biopsy, using open thoracotomy in the diagnosis of diffuse lung disease , to Klassen of Columbus, Ohio, circa 1949 [ 2 ] .

There is a diminishing need for surgical biopsy of pulmonary lesions as we apply modern diagnostic procedures as a cooperative effort of the internist, radiologist and pathologist. Most patients with diffuse pulmonary disease can have an accurate diagnosis made without a direct biopsy of the lung. When this cannot be established in a relatively short time, thoracotomy and biopsy should be carried out without hesitation. [ 3 ] This statement is as cogent today as it was 46 years ago, but from the perspective of the thoracic surgeon, consults on patients during and following treatment of solid-organ and hematopoietic neoplasms in whom it was early recognized that "virtually any infectious agent can cause pulmonary disease in any immunocompromised host" [ 4 ] are increasingly complex. In such patients, the ratio of risk to benefi t is often substantial. For a successful outcome, the biopsy must provide defi nitive identifi cation of a specifi c etiology. That disease, in turn, must be amenable to successful treatment. Finally, intervention will prove futile if the patient's cancer recurs or progresses.

Differential diagnosis is expansive and sometimes bewildering. The cancer patient is also subject to a wide range of diffuse lung diseases unrelated to infection or malignancy [ 5 , 6 ] . Lung infi ltrates or nodules may represent progression or spread of the primary (or new) neoplasm to the lungs [ 7 , 8 ] . There are literally thousands of drugs and drug combinations used in the treatment of cancer, and new agents and combinations are added on a frequent basis. Many of these agents have inherent lung toxicity, and most impair the immune response, fostering infection with a wide spectrum of organisms that are seldom, if ever, pathogenic in healthy individuals [ 9 ] . These considerations are further amplifi ed in patients who undergo stem-cell transplantation. Profound and prolonged immunosuppression allows an even broader range of infectious pathogens and adds lung damage secondary to other mechanisms (e.g., diffuse alveolar hemorrhage, radiation pneumonitis, and graft-versus-host disease [GVHD] ) [ 10 ] . Adding further complexity, the entities in the expanded differential diagnosis list are addressed using a plethora of new diagnostic methods which, in their turn, have morphed over time. The risk of individual infectious organisms has also changed in response to the adoption of new prophylactic regimens [ 11 -14 ] .

Time can be of the essence. If the patient's condition is stable and anesthesia with singlelung ventilation is possible, minimally invasive methods ( VATS ) foster more comfortable and rapid patient recovery. Accordingly, biopsy is optimally performed early, before progressive loss of pulmonary function prohibits single-lung anesthesia and increases the risk of postoperative complications, including the requirement for ventilator support or even death.

Psychological factors may also prove diffi cult to manage. Patients are often young and have endured multiple, prolonged, and highly stressful treatment regimens and may have experienced distressing complications. Malignant disease may have recurred following initial treatment or salvage regimens. Patients managed with hematopoietic stem-cell transplantation (HSCT) may be subject to manifestations of GVHD . Patients, family members, and primary physicians are frequently frustrated, frightened, and desperate when faced with recurring complications of treatment and deteriorating health status. In such circumstances sympathy may overwhelm sober clinical judgement. Will biopsy provide a meaningful chance of treatment to alleviate suffering or prolong life? The oncologist, patient, or family may desire to continue diagnostic and therapy options even when potential benefi t appears minimal. Should surgical biopsy be performed when the patient has little or no chance of survival?

In selected circumstances, e.g., localized fungal infection, second primary lung cancer, or limited lung metastasis, the surgeon must be prepared not just to biopsy, but to try to resect all detectable disease, adding a potential curative benefi t [ 15 , 16 ] .

For all of these reasons, it has become increasingly diffi cult for the busy thoracic surgeon to stay current. There are no formal published guidelines established for management of these situations [ 17 ] . There is no randomized controlled study addressing the issue. Results of published series are inconsistent and recommendations vary [ 18 -20 ] .

The surgeon must rely heavily on colleagues in hematology-oncology, pulmonary medicine, infectious disease, radiology, and pathology for guidance and support. It is imperative that such consultation take place before frank discussion of potential risks and benefi ts with the patient and family and subsequent surgical biopsy. In the case of a major divergence of professional opinion or if the family demands, consultation with a multispecialty ethics committee may be in order.

In order to craft a chapter that will assist surgeons to make the diffi cult decision as to whether and when surgical biopsy is indicated, decide upon the optimal technique for the biopsy, and ensure that collection of tissue and microbiological specimens is suffi ciently comprehensive to allow defi nitive diagnosis, a group of clinicians and scientists with long and extensive experience in the treatment of solid and hematological malignancies has crafted a coherent, evidencebased diagnostic algorithm for management of the diffi cult problem of life-threatening diffuse lung disease in the cancer patient. Experience in the management of more than 10,000 patients undergoing HSCT uniquely qualifi es them to do so [ 21 ] . Their opinions are supplemented by a review of the literature.

We approach this task with humility, in the clear understanding that the advice provided in this chapter may rapidly become obsolete.

The clinical presentation of pulmonary problems does not vary signifi cantly between an oncologic patient, a hematologic patient, and an HSCT patient. The most common presentations the pulmonologist sees in these patient populations are shortness of breath, wheeze, cough, sputum production, and hemoptysis . The differential diagnosis, on the other hand, can vary greatly.

In a cancer patient presenting with shortness of breath, the differential diagnosis includes obstruction of the central airway secondary to intraluminal tumor or extrinsic compression, lymphangitic spread, a reaction to either chemotherapy or radiation therapy, or infection. Pulmonary edema , emboli, or tumor emboli can also present as shortness of breath in the oncologic patient, as well as pleural and pericardial effusions.

Infections are especially common after treatment with chemotherapy agents that cause neutropenia. Patients treated with prolonged steroids may be more prone to Pneumocystis pneumonias.

When an asymptomatic or a symptomatic patient shows radiographic pulmonary infi ltrates the primary consideration is whether it is caused by infection.

The most common Gram-positive bacteria that cause pulmonary infections in the cancer patient are Staphylococcus aureus (including methicillinresistant S. aureus or MRSA), Group A, B, and G streptococci, anaerobic streptococci, Streptococcus pneumonia , and enterococci (including vancomycin-resistant enterococci or VRE). Gram-negative causes include Pseudomonas aeruginosa , Escherichia coli , Acinetobacter spp., Enterobacter spp., Klebsiella pneumonia and K. oxytoca , Stenotrophomonas maltophilia , and anaerobic bacteria ( Bacteroides spp., Porphyromonas spp., 

The most common causes of fungal pneumonias in the severely immunocompromised patient, i.e., those with hematologic malignancies (HM) or hematopoietic cell transplant (HSCT) recipients, are the molds. The most common of these is Aspergillus spp., primarily Aspergillus fumigatus . The Aspergillus spp. are followed in frequency by the Mucorales spp., Fusarium spp., and Scedosporium spp. (Fig. 10.1 ). Before trimethoprim-sulfamethoxazole (TMP/SMT) prophylaxis became a standard of care in HSCT, Pneumocystis jiroveci was one of the most common fungal pneumonias. Candida spp., while a common cause of mucous membrane infection and candidemia, rarely cause pulmonary infection , except for the rare pulmonary septic embolus caused by Candida spp. Finally, the endemic fungi can cause severe pulmonary infection and disseminated disease: Coccidiodes immitis , Histoplasma capsulatum , and Blastomyces dermatitidis .

The most common causes of viral pneumonias in the most severely immunocompromised cancer patient, the HSCT recipient, are the herpes viruses. These include cytomegalovirus (CMV), herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), and human herpes virus 6 (HHV6). All of these viruses share a number of characteristics including universal exposure/ infection before adulthood, latency, and reactivation during immunosuppression. Other viruses that can cause pneumonia are the respiratory viruses including infl uenza A and B, respiratory syncytial virus (RSV), parainfl uenza virus (PIV), metapneumovirus (MPV), and adenovirus.

Toxoplasma gondii can cause pulmonary lesions, but is uncommon since TMP/SMT has been used as prophylaxis. Strongyloides stercoralis can cause a disseminated form of pulmonary hyperinfection which is usually lethal.

The presentation of immunocompromised cancer patients with pneumonia is quite varied. The cancer patient with pneumonia or pulmonary nodules may be afebrile and without any signs of infection, but may also be febrile, with productive cough, dyspnea on exertion, pleuritic chest pain, and hemoptysis. Patients may present in septic shock with multiorgan system failure if the causative organism disseminates via the bloodstream.

Certain symptoms are more specifi c to certain infections. The classic presentation of a patient with invasive pulmonary mold (e.g., aspergillosis, mucormycosis) infection is cough, fever, pleuritic chest pain, and hemoptysis, but alternatively, such patients may be afebrile and asymptomatic. Although bronchitis is the most common cause of hemoptysis , bleeding can also be caused by tumor invading the airway, necrotic cavitary lesions, pulmonary embolism, or thrombocytopenia. Major hemoptysis can lead to shortness of breath, and if not treated quickly, total airway obstruction, asphyxia, and death. Pulmonary fi brosis , as a reaction to chemotherapy, can cause shortness of breath; the best known example is bleomycin toxicity. Wheezing can be due to partial airway obstruction, heart failure secondary to fl uid overload, reactive airway disease as a result of chemotherapy, or pneumonitis secondary to immunosuppression. Cough can be due to infection, hemoptysis, or reaction to treatment. Cough can also be caused by obstruction by endobronchial tumor, pneumonia, or bronchitis secondary to neutropenia following chemotherapy or radiation. Bronchorrhea (cough productive of copious amounts of thin mucous) is sometimes encountered in patients with mucinous adenocarcinoma. Cough secondary to bronchiectasis is usually seen in patients with slowly growing tumors (neuroendocrine tumors) that obstruct a lobar orifi ce, but is uncommon in most rapidly growing lung cancers. Chest pain can present due to tumor invasion or metastasis to chest wall, pulmonary embolism, pleural or pericardial effusion, and infection (pneumonia with parapneumonic effusion and empyema).

In non-transplant HM patients, shortness of breath can be due to infection, airway obstruction (usually in lymphoma), pneumonitis from chemotherapy, radiation or other treatment, or ARDS secondary to sepsis. More uncommon mechanisms include hyperleukocytosis and leukostasis causing sluggish fl ow through the lungs. Treatment for hyperleukocytosis can lead to tumor lysis syndrome that can also result in dyspnea secondary to capillary leak syndrome and fl uid overload. Certain HM (e.g., acute myelogenous leukemia) can cause hypercoagulation and pulmonary emboli. Other pathophysiologic mechanisms that can combine in causing respiratory failure in hematology patients include DIC and thrombocytopenia with alveolar hemorrhage and hemoptysis . Thrombocytopenia secondary to chemotherapy alone (without DIC) can cause hemoptysis and diffuse alveolar hemorrhage. Prolonged neutropenia can lead to infection with invasive molds, which, in turn, frequently result in hemoptysis, especially in combination with thrombocytopenia.

Differential diagnosis assumes further complexity following HSCT . Shortness of breath and hemoptysis can be due to diffuse alveolar hemorrhage (DAH) either as a result of previous treatment, conditioning regimens, or thrombocytopenia. Most commonly dyspnea is caused by infection. Transplant patients with prolonged (>21 days) neutropenia are especially susceptible to fungal infections and may present with high fever, dyspnea, and occasionally hemoptysis. Pneumocystis jiroveci is often seen when steroids are tapered during treatment of GVHD.

When an infectious organism cannot be isolated with sputum culture, bronchoscopy, or invasive biopsy, a number of noninfectious causes must be considered (Table 10 .1 ).

Dyspnea can result from pulmonary fi brosis secondary to chemotherapy. A few examples from a long list of agents that may cause such fi brosis are busulfan, and chlorambucil. Pulmonary fi brosis can also result from radiation received as treatment of lymphoma or as part of conditioning regimens for HSCT. GVHD can also present with shortness of breath. DAH can present as subtle shortness of breath which can become severe if not recognized. Hemoptysis is seen with DAH but the amount is usually not great. If massive hemoptysis is seen in the transplant patient one must seriously consider fungal infection as the cause. Thrombocytopenia alone, in the absence of other disease, can lead to hemoptysis. DIC as a result of [ 58 , 59 ] Pulmonary edema Damage due to chemotherapy or radiation Diffuse alveolar hemorrhage (DAH) [ 60 ] Adult respiratory distress syndrome (ARDS) Bronchiolitis obliterans obstructive pneumonia (BOOP) [ 61 ] Cytolytic thrombi Idiopathic pneumonitis syndrome [ 62 , 63 ] Graft-versus-host disease (GVHD) [ 64 ] Second malignant neoplasms [ 65 , 66 ] infection or secondary to the hematologic malignancy itself can cause hemoptysis. Cough in the HCT patient is often due to infection but can also be due to GVHD or pneumonitis caused by chemotherapeutic agents and/or radiation pneumonitis. Wheezing in the transplant patient may be due to reactive airway disease from chemotherapy or GVHD .

The workup for the clinical presentations described above should always start with a comprehensive history and physical followed by a chest X-ray or CT of the chest. The CT scan can be done without contrast unless evaluation of the mediastinum is necessary. If shortness of breath, cough, or wheezing is being evaluated in a non-emergent setting, pulmonary function testing with and without bronchodilators is indicated.

The radiologic fi ndings of pneumonia in cancer patients can be quite varied [ 22 ] . Although radiologists can assist clinicians in differential diagnosis, specifi c etiological diagnosis is diffi cult [ 23 ] . The radiologist can however assist the clinician to narrow down the differential diagnosis by combining radiologic and clinical factors [ 24 ] . Classically, viral pneumonias demonstrate bilateral, diffuse, and interstitial infi ltrates, while bacterial pneumonias present with more localized, lobular, and segmental infi ltrates or consolidations [ 25 ] . Invasive pulmonary mold infections usually present as multiple nodular, pleural-based consolidations (refl ecting pulmonary infarction secondary to obstruction of peripheral pulmonary arteries by fungal hyphae) (Fig. 10.2 ) .

The classic early lesion is the " halo sign " where a consolidation is surrounded by a "halo" of hemorrhage [ 26 ] . A later lesion evolves into a "crescent sign" lesion that represents early peripheral necrosis, with separation of necrotic lung away from the wall of the cavity (Fig. 10.3 ) .

Classic radiologic fi ndings are not always present. When pathognomonic fi ndings of invasive pulmonary mold infection are found, CT scans of the sinuses and brain should be ordered since these are other sites to which molds frequently spread.

A review of radiographic fi ndings in patients with diffuse lung disease not being treated for cancer is outside the scope of this chapter [ 27 ] . 

Pulmonary complications in BMT patients present an enormous problem, as 40-60 % of HSCT patients develop this complication and 90 % of deaths following HCST are caused by respiratory complications [ 28 ] .

The fi rst and most important determination to be made in the approach to diagnosis of pulmonary infi ltrates in the cancer patient is that of urgency. Urgency is determined primarily by the degree of the immunosuppression. At the top of the list of immunocompromised patients and those at highest risk for devastating opportunistic infection and diseases of the lungs with the highest mortality rates are those patients with HM suffering from prolonged neutropenia due to chemotherapy, particularly in the case of HM, and patients during and after HSCT. Patients with solid organ cancers, whether undergoing short courses of chemotherapy or not, are less immunosuppressed and, therefore, at lower risk for rapidly progressive, devastating pulmonary infection or disease. Immune-compromised patients form the primary focus of our approach below.

When a severely immunosuppressed patient presents with respiratory symptoms (e.g., cough, shortness of breath) a chest radiograph ( CXR ) is usually ordered. It can be argued that a chest CT scan should be performed because of the lower sensitivity of CXR. The nature of the pulmonary infi ltrates can be helpful in making a diagnosis, for example, the halo and crescent signs referenced above.

The following tests should be drawn immediately upon presentation of a cancer patient, especially patients with HM or HSCT recipients, with suspected pneumonia: (1) blood cultures;

(2) sputum for (a) culture (Gram stain) and sensitivity testing, (b) AFB stains and culture × 3, and (c) fungal culture and KOH examination; (3) nasopharyngeal washings for respiratory virus PCR; (4) serum/plasma testing for (a) Aspergillus galactomannan EIA, (b) 1,3 β-D -glucan, and (c) cryptococcal antigen; (d) Coccidioides immitis antibodies; (e) Histoplasma capsulatum antigen (also in urine); and (f) Quantiferon Tb gold assay.

At this stage of the workup empiric therapy for infectious diseases and other noninfectious diseases should be initiated, and should continue, with appropriate modifi cations, based on test results, throughout each stage of the diagnostic workup (Table 10 .2 ).

When a cancer patient presents with radiographic pulmonary infi ltrates, a number of factors will determine which antibiotics should be administered. For example, neutropenic febrile patients with pneumonia should be started on empiric cefepime. In addition, if the patient is a known carrier of MRSA, vancomycin should be added. If the patient acquired the pneumonia as an outpatient, coverage of community-acquired pneumonia with azithromycin should be added. If the patient is suspected of having aspirated, anaerobic coverage should be added or, alternatively, piperacillin/tazobactam can be substituted for the cefepime. In the high-risk patient, i.e., the neutropenic patient with HM or the HSCT recipient with GVHD , a broad-spectrum anti-mold agent, i.e., isavuconazonium or an amphotericin B lipid formulation , should be initiated empirically.

Because even pathognomonic radiographic fi ndings are not 100 % specifi c, regardless of the type of lesions or infi ltrates present, the patient should proceed to bronchoscopy with bronchial lavage [ 29 ] . Prior to bronchoscopy, certain serologies and tests should be performed (see above).

In the oncologic patient with a low platelet count, bronchoscopy with lavage will often yield an etiologic diagnosis leading to change in treatment, clinical response, and survival ( Fig. 10.4 ) [ 30 -33 ] . The bronchoalveolar lavage (BAL) fl uid specimen should be sent to cytology and microbiology (see Table 10 .3 ).

If the initial bronchoscopy and lavage are nondiagnostic, then the next step should be to decide the best way to obtain a biopsy specimen for pathologic and microbiologic studies. Repeat bronchoscopy and BAL have a low yield [ 34 ] . Although transbronchial lung biopsy (TBLBx) has been shown to supplement diagnosis by BAL , because HSCT patients typically have low platelet counts and accordingly higher risk of hemoptysis and pneumothorax , TBLBx is seldom utilized today [ 35 , 36 ] .

If the prior workup (including cytologic examination) and culture of the BAL fl uid do not result in a diagnosis, one may proceed to percutaneous biopsy of a lung nodule or focal infi ltrate. Yield is lower for diffuse infi ltrates [ 37 -39 ] .

"Fine-needle" biopsy with single 22-gauge needles has largely been replaced by a coaxial needle biopsy approach. Typically an 18-gauge coaxial guide needle is placed percutaneously into the target area under CT guidance. Then a 20-gauge spring-powered needle is inserted through the 18-gauge needle to obtain 3-5 core samples for pathology and microbiology. This has the advantage of obtaining much better samples and generally requires one puncture of the pleura, and it also eliminates delays for making cytology smears to evaluate for adequacy of the sample. This is most often done under light sedation and local anesthesia. After the needle is removed, a rapid CT scan survey of the chest is done to evaluate for early pneumothorax, significant bleeding, and air embolization (a rare but potentially devastating complication, especially if not recognized before the patient is allowed to get off the CT table). A follow-up inspirationexpiration CXR is generally obtained 2 h after the procedure to check for delayed pneumothorax or bleeding. If all is stable, the patient can then be discharged home with post-procedure instructions.

Finally, if there is no diagnosis forthcoming after sputum cultures, bronchoscopy , BAL , and//or CT-guided biopsy , surgical lung biopsy for both diagnostic and possibly therapeutic reasons may be indicated [ 40 , 41 ] . None of the prior studies are suffi ciently sensitive to exclude infectious disease [ 42 ] . Additionally, if the patient is deteriorating rapidly, recourse to surgical biopsy may need to precede bronchoscopy or needle biopsy [ 43 , 44 ] .

Surgical biopsy may be performed thoracoscopically ( VATS ) or via limited thoracotomy.

Most published material on surgical lung biopsy is from series of patients with nonmalignant disease. Ooi et al. found that VATS diagnostic biopsy had a low perioperative mortality (1.8 %) and morbidity (9 %) [ 45 ] . 100 % of the patients ( n = 55) who underwent VATS biopsy had suffi cient diagnostic tissue obtained and a median hospital stay of only 2 days. Importantly, this group found that a difference between preoperative clinico-radiological and fi nal histological diagnosis suffi cient to change prognosis and defi nitive management was made in 27.1 % of patients. Kreider and colleagues found that complications in patients who underwent VATS diagnostic biopsy were higher in those who were dependent on oxygen and those who have pulmonary hypertension [ 46 ] . Utz et al. found that a DLCO of <35 % predicted and a diagnosis of idiopathic usual interstitial pneumonia were predictors of mortality as well [ 47 ] . Preoperative ventilator dependence and an immunocompromised status were the only predictors of mortality [ 67 ] in Lettieri's analysis [ 48 ] . Unfortunately, many patients who have life-threatening pulmonary infi ltrates will have one or more of the above risk factors and thus worse survival. Those who are acutely ill or are in a late stage of the disease have decreased pulmonary compliance and decreased DLCO and a limited ability to tolerate general anesthesia, particularly with single-lung ventilation. Such patients may require open lung biopsy through a mini-thoracotomy [ 49 ] .

For many surgeons, open lung biopsy is only performed when VATS is impossible (e.g., extensive adhesions) or if patients are too compromised to tolerate one-lung ventilation. Risks and potential benefi ts must be carefully weighed when sick patients are being evaluated for surgical biopsy.

Utz and colleagues found that open lung biopsy was associated with mortality in the range of 16-20 % in patients with suspected diffuse interstitial lung disease . Morbidity and mortality associated with surgical lung biopsy may be due to progression of disease or secondary to the surgery itself, which may trigger an exacerbation of the disease. It is imperative that risks of respiratory decline, prolonged ventilation, need for tracheostomy, and even death are discussed with patients and their families before undergoing surgical biopsy, especially if patients have an oxygen requirement, are nonambulatory, or possess other signifi cant comorbidities.

Although some have argued against open lung biopsy in patients receiving ventilator support, in carefully selected patients surgical biopsy may be benefi cial. Wong conducted a meta-analysis of 14 series involving more than 500 patients and reported that therapeutic changes ensued in 78 % with 29 % procedure-related complications and mortality of 54 %. Most common diagnoses were fi brosis/pneumonitis and viral pneumonia [ 50 ] .

Results of surgical lung biopsy (SLB) in immunosuppressed patients have been reported in a limited number of series. Snyder reported the experience at the University of Minnesota with SLB following HSCT in children from 1975 to 1986. A specifi c diagnosis was obtained in 60 %, but mortality at 30 days was 45 % [ 51 ] . Wang et al. performed 35 SLB following HSCT and reported fi ndings leading to change in therapy in 63 % and clinical improvement in 46 %. Findings included idiopathic interstitial pneumonitis (40 %) , CMV (20 %), and miliary tuberculosis (9 %). Patients with respiratory failure or GVHD had a worse prognosis [ 52 ] . Hayes-Jordan of St. Judes Children's Hospital reported on 19 SLB among pediatric patients following HSCT and failed diagnosis by BAL . There were six infections, fi ve cases of BOOP , four interstitial pneumonias, and other specifi c diagnoses, with change in treatment in 90 % of patients and improved outcome in 47 %. Mortality was 47 %. No patient with a surgical complication or ventilator status survived [ 53 ] . Qualter et al. reported on 16 patients with SLB following failed attempt at diagnosis with BAL in 193 HSCT recipients. 94 % of SLB provided an etiologic diagnosis. The probability of 2-year overall survival was 17.5 % for patients who underwent biopsy [ 54 ] .

General anesthesia is induced and either a bronchial blocker or a dual-lumen tube is placed to achieve one-lung ventilation. If both sides are equally diseased, then the right side is generally chosen for biopsy. The patient is placed in the lateral decubitus position with the operative side up. A camera port is placed in the eighth intercostal space in line with the mid to posterior axillary line. A small utility incision is made typically in the fi fth interspace more anteriorly and is the site where thoracoscopic instruments enter the chest. The thoracic space is explored and typically two small wedge resections of two distinct disease sites are performed with endoscopic stapler. Thicker lung parenchyma will require thicker staple loads. Biopsies are taken of the upper and the lower lobe along the major fi ssure. If there is an obvious abnormality within the lung, pleura, or diaphragm, consideration of further biopsy is imperative. Because the differential diagnosis is so broad, it is imperative that the surgeon not omit important studies. Comprehensive informa-tion on this topic is provided in the section on pathologic workup below.

A chest tube is typically left in place through the camera port. Frequently the tube can be maintained on water seal overnight and removed on the following morning if there is no air leak or persistent drainage. Pleural effusions should be drained and sent for culture and cytology as well. If effusion is recurrent, consideration of placement of an indwelling pleural catheter is reasonable.

When open biopsy is necessary, a small posterolateral incision can be made in the fi fth intercostal space and the procedure performed as above.

Although some have questioned the appropriateness of surgical biopsy, it may represent the last and only chance of appropriate diagnosis in patients with life-threatening infi ltrates. Although morbidity and mortality can be sizable in sick patients who undergo SLB , in many patients the procedure alters management and offers a chance of cure. Specifi c potential benefi ts include identifi cation of occult infection not detected by endoscopic or needle biopsy methods and diagnosis of various noninfectious lung diseases . Although it must be understood that the long-term results of treatment of such entities as BOOP , GVHD , and idiopathic pneumonia syndrome are poor, biopsy results provide an accurate diagnosis to allow assessment of new treatments [ 55 ] .

In cases where lesions are nodular in character, various methods have been described to allow precise identifi cation of the location of the nodule during thoracoscopic resection. Where nodular or cavitary lesions are multiple and limited in scope, and might represent separate lung cancer, lung metastasis, local recurrence of lymphoma, lung abscess, mycobacterial cavity, fungus ball, or invasive mold infection, consideration of resection of all identifi able disease may mandate open thoracotomy with wedge and/or anatomic segmental or lobar resections.

The pathologic diagnosis of pulmonary infi ltrates in patients with and without cancer can be very challenging. The differential is usually extensive and includes infectious organisms (many of which are unusual and rarely seen in immunocompetent patients), reactive processes related to cancer therapy, and recurrence of malignancy.

Obtaining the appropriate tissue sample is critical and it is equally important that the clinician communicates to the laboratory/pathologist the pertinent clinical information, radiographic fi ndings, and working differential diagnosis so that interpretation and testing on the specimen are expeditious and meaningful (Table 10 .4 ). Table 10 .5 lists lung specimen types that are commonly used to evaluate pulmonary processes and general information on the fi xation as well as handling. Guidelines for handling and reporting pulmonary specimens have been published [ 56 ] . In specifi c settings, the successful identification of the underlying pathologic process will depend on the pulmonary physician's ability to target the diagnostic area of the lesion. In general, the more invasive procedures yield more specifi c diagnosis.

When recurrent lymphoma or leukemia is suspected, fl ow cytometry studies can be useful particularly on fl uid specimens such as pleural fl uids or BAL . The specimen is sent fresh to the pathology lab with instructions to use a portion for fl ow cytometry. If the specimen is suffi ciently cellular, routine analysis is then also done. CT-guided percutaneous lung biopsies have a high diagnostic yield for documenting recurrent malignancy as well as identifi cation of specifi c infections (Figs. 10.5 and 10.6 ) [ 57 ] . 

We have published our results in the surgical resection of 50 patients with presumed invasive mold infection (IMI) in immunocompromised patients ( Fig. 10.7 ) [ 16 ] . Although there was substantial morbidity and 30-day mortality (12 %), and while the majority of patients died from recurrent malignancy or recurrent fungal infection, 19 % of patients survived longer than 5 years ( Fig. 10.8 ).

When the surgeon is asked to provide lung biopsy in the workup and/or treatment of patients with life-threatening lung disease in immunosuppressed patients during or following treatment of hematologic and solid cancers with chemotherapy or HSCT , it is important that consultation with colleagues from multiple disciplines take place. While time pressure favors biopsy as soon as possible, unnecessary biopsy can be avoided by ensuring that all reasonable nonsurgical modalities have been tried. Moving forward to minimally invasive surgical biopsy with reasonable dispatch before deteriorating lung function forces open biopsy is clearly in the patient's best interest.

Open Lung Biopsy among critically ill, mechanically ventilated patients: a meta-analysis

Open lung biopsy for diffuse pulmonary lesions

Open lung biopsy: a strong stand

Pulmonary disease in the immunocompromised host (2)

Noninfectious lung disease in the immunocompromised host

Noninfectious lung disease in immunocompromised patients

Thoracic presentations of posttransplant lymphoproliferative disorders

Post-transplant lymphoproliferative disease in children

Survival after surgical resection of invasive mold infection

Drug-induced pulmonary disease

Diffuse alveolar hemorrhage in pediatric hematopoietic cell transplant patients

Prophylaxis of cytomegalovirus infection after bone marrow transplantation

Preemptive ganciclovir administration based solely on asymptomatic pulmonary cytomegalovirus infection in allogeneic bone marrow transplant recipients: long-term followup

Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, European Blood and Marrow Transplant Group, American Ad Society of Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Disease Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Diseases Canada

Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients

Pulmonary resection for fungal infection in children undergoing bone marrow transplantation

Survival following lung resection in immunocompromised patients with pulmonary invasive fungal infection

Survey of academic pulmonologists, oncologists, and infectious disease physicians on the role of bronchoscopy in managing hematopoietic stem cell transplantation patients with pulmonary infi ltrates

Open lung biopsy in bone marrow transplant recipients has a poor diagnostic yield for a specifi c diagnosis

Use of fi rst line bronchoalveolar lavage in the immunosuppressed oncology patient

Evaluation of persistent pulmonary infi ltrates in pediatric oncology patients

Bone marrow transplantation: the City of Hope experience

Diffuse lung disease in the immunocompromised non-HIV patient

Pulmonary infections in immunocompromised hosts: the importance of correlating the conventional radiologic appearance with the clinical setting

An approach to the diagnosis of pulmonary infections in immunosuppressed patients

Viral and Pneumocystis carinii infections of the lung in the immunocompromised host

Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia

A retrospective analysis of computed tomography fi ndings in patients with pulmonary complications after allogeneic hematopoietic stem cell transplantation

Pulmonary complications in bone marrow transplantation: a practical approach to diagnosis and treatment

Clinical application of bronchoscopy and bronchoalveolar lavage in the immunocompromised host

Safety, diagnostic yield, and therapeutic implications of fl exible bronchoscopy in patients with febrile neutropenia and pulmonary infi ltrates

Role of bronchoalveolar lavage in immunocompromised patients with pneumonia treated with a broad spectrum antibiotic and antifungal regimen

To bronch or not to bronch? A recurring challenge in neutropenic patients with pulmonary infi ltrates

Utility of bronchoscopy with bronchoalveolar lavage in diagnosing pulmonary infection in hospitalized patients with underlying malignancy

Value of repeat fi beroptic bronchoscopies and signifi cance of nondiagnostic bronchoscopic results in patients with the acquired immunodefi ciency syndrome

Transbronchial biopsy in the thrombocytopenic patient

Utility of fl exible bronchoscopy in the evaluation of pulmonary infi ltrates in the hematopoietic stem cell transplant population-a single center fourteen year experience

The value and safety of percutaneous lung aspiration for children with serious pulmonary infections

Biopsy diagnosis and clinical outcome of persistent focal pulmonary lesions after marrow transplantation

Role of fi neneedle aspirates of focal lung lesions in patients with hematologic malignancies

Use of fi beroptic bronchoscopy in bone marrow transplant recipients

Role of open lung biopsy in diagnosing pulmonary complications of AIDS

Role of fl exible bronchoscopy in the diagnosis of pulmonary infi ltrates in pediatric patients with cancer

Does every patient with enigmatic lung disease deserve a lung biopsy? The continuing dilemma

The impact of open lung biopsy on diffuse pulmonary infi ltrates in patients with AIDS

VATS lung biopsy in suspected, diffuse interstitial lung disease provides diagnosis, and alters management strategies

Complications of video-assisted thoracoscopic lung biosy in patients with interstitial lung disease

High short-term mortality following lung biopsy for usual interstitial pneumonia

Outcomes and safety of surgical lung biopsy for interstitial lung disease

Sabiston and Spencer's surgery of the chest, 2 vols

Open lung biopsy among critically ill, mechanically ventilated patients. A metaanalysis

Diagnostic open-lung biopsy after bone marrow transplantation

Diffuse pulmonary infi ltrates after bone marrow transplantation: the role of open lung biopsy

Open lung biopsy in pediatric bone marrow transplant patients

A comparison of bronchoalveolar lavage versus lung biopsy in pediatric recipients after stem cell transplantation

Biopsy-verifi ed bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation

Examination of lung specimens

GT-guided percutaneous lung biopsies in patients with hematologic malignancies and undiagnosed pulmonary lesions

Clinical presentation, outcome and risk factors of late-onset non-infectious pulmonary complications after allogeneic stem cell transplantation

Therapy-related noninfectious complications in patients with hematologic malignancies: high-resolution computed tomography fi ndings

Differential diagnosis of diffuse alveolar haemorrhage in immunocompromised patients

Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease

Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation

Non-specifi c interstitial pneumonia as a manifestation of graft-versushost disease following pediatric allogeneic hematopoietic stem cell transplantation

Chronic graft-versus-host disease and late effects after hematopoietic stem cell transplantation

Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies