result from ongoing exposure to the culprit drug or chemical or to a background of constitutional NADPH de ciency, especially in the newborn and in infants. Exchange transfusion and ECMO can be required. Ready availability of methylene blue should be monitored in all appropriate care settings, as immediate administration of the drug may be life-saving.

An important and often overlooked area is the pulmonary toxicity of molecular oxygen. In particular, elevated and FiO2 on a previously drugor radiation-exposed lung for even a short period of surgery may be damaging. Undeniable acute postoperative ILD and ARDS has been reported in patients previously exposed to amiodarone, bleomycin, chemotherapeutic drugs or radiation with no preoperative evidence for ILD [177]. “Whitening” of the single lung that had been ventilated using 100% oxygen during the surgical procedure in an amiodarone-exposed patient is consistent with this view [127]. Maintaining the intraoperative FiO2 at the lowest level required to ensure an adequate SaO2 is indicated in any patient who has a history of exposure to pneumotoxic drugs, particularly amiodarone, bleomycin, nitrosoureas, chemotherapeutic agents, or radiation.

Cases of negative pressure pulmonary edema (NPPE) have increased since the 1980s [178]. This form of pulmonary edema appears to be related to the barotrauma of forceful inspirations against a closed extrathoracic airway. Markedly negative swings of intrathoracic pressure can cause exudation of fuid or blood [178] from damaged or stress-fractured capillaries toward the interstitium and alveolar spaces [179]. Causes of airway closure have included biting or obstruction of the endotracheal or laryngeal tube, goiter, trauma, amygdalitis, oropharyngeal surgery, tonsillectomy, vocal cord adduction, peri-anesthetic laryngospasm, laryngeal edema, septoplasty, foreign body (including throat packs) inhalation or aspiration and any type of rapid-­ onset upper-airway obstruction including rheumatoid arthritis-­associated airway closure, or ACEI-induced upper airway obstruction [180]. The diagnosis is suggested with the sudden onset of dyspnea and hypoxemia in the appropriate, often postoperative clinical setting, accompanied by bilateral batwing pulmonary shadowing. Severe cases can be complicated by full-blown pulmonary edema, froth at the mouth, and/or alveolar hemorrhage. Although pneumomediastinum and hemoptysis can be part of the clinical manifestations of NPPE, these manifestations require examination of the upper airway and/or esophagus for possible laceration. The treatment of NPPE is mainly supportive and directed at reversing hypoxemia and restoring airway patency. Diuretic administration can result in hypovolemic shock requiring fuid resuscitation. NPPE is best prevented if maintenance of a patent airway is ensured in the perioperative setting at all times.

Other Rare Presentations

Pulmonary Nodules and Masses

Pulmonary reactions to 18 discreet drugs or radiation can be in the form of a pulmonary a nodule, nodules or a mass [3, 4]. The reverse halo sign has also been described [3, 4]. Amiodarone, bleomycin, and ICI toxicity have all been reported to present as pulmonary nodules or masses [3, 4]. The main differential in these cases such as these is typically malignancy or an infection. Nodules with ill-de ned borders are a classic complication of chest radiation therapy, particularly with the novel stereotactic body radiation therapy techniques [3, 4] in which the gantry rotates around the patient’s body. Areas of radiation-induced lung injury may assume a whorled or convoluted appearance and are densest in the areas that have received the greatest doses of radiation. Uptake values on PET scan tend to decrease with time, as opposed to recurrence of the underlying malignancy in which SUV tends to increase with time on serial PET scan examination.

Although a bilateral diffuse pattern of involvement is more common, a solitary lung nodule or a mass also is a classic manifestation of mineral oil aspiration, and the name paraf noma is appropriate [3, 4] [181]. Paraf noma may be tracer-avid on PET scan and mimic pulmonary malignancy [3, 4].

Multiple nodules can develop in children or in adults during or following therapy with carbamazepine, minocycline, hydralazine, and antineoplastic agents including bleomycin and ICI [3, 4]. The main issue is ruling out progression in those patients with an underlying malignant condition. Review of pretherapy chest imaging, response of the underlying disease to treatment, 18F-PET imaging, watchful fol- low-­up or a lung biopsy can be indicated. Nonneoplastic nodules, when examined on pathology, may correspond to areas of organizing or eosinophilic pneumonia [3, 4].

Disease-modifying antirheumatic drugs (DMARDs) including methotrexate, lefunomide, and anti-TNF agents have been temporally associated with the development or progression of pulmonary rheumatoid nodules. This is known as pulmonary nodulosis and occurs mainly in patients with rheumatoid arthritis but not exclusively so [3, 4]. Nodules are moderately tracer-avid on 18F-PET-scan examination. The main issues are eliminating an infection (e.g., tuberculosis or histoplasmosis), particularly in patients exposed to TNF antagonists, and malignancy as rheumatoid arthritis is more prevalent in smokers or former smokers. Drug discontinuation, maintenance of therapy with DMARDs, or rituximab have met with some success. The mechanism(s) of nodule formation induced by these drugs is unclear.

Amiodarone pulmonary toxicity may manifest as a mass or multiple round-shaped opacities or masses in about 10%

of the cases. Large masses are coined amiodaronoma [3, 4]. The nodules and masses in amiodarone pulmonary toxicity tend to exhibit indistinct, ill-de ned borders and can be surrounded by a halo of decreasing attenuation peripherally [182]. Nodules can be deep-seated in the lung, or they are noted peripherally abutting the pleura, causing localized pleural thickening and/or pleuritic chest pain. Nodules may be discovered incidentally on CT and may exhibit high attenuation on CT due to the bi-iodinated chemical structure of amiodarone [3, 4]. On pathology, nodular APT shows the classic features of APT including chronic interstitial infammation, in ltration by myo broblasts, and the presence of organizing pneumonia and foam cells, which are most intense in the center of the lesion and decrease peripherally. Other patients present which one or more rounded or indented masses up to several centimeters in their largest dimension [3, 4, 183]. There may be decreased attenuation in the center of the mass consistent with aseptic necrosis. Ruangchira-Urai et al. described the pathologic features of four such nodular APT cases [183]. Three had received a high maintenance dose of 800 mg amiodarone daily for 7 months or more. None of the four patients had a preoperative diagnosis of APT and the indication for excision was the suspicion of malignancy. The 18F-PET-scan was positive in the single patient so tested [183]. Histopathology in all four patients showed “vacuolated histiocytes massed within alveoli to form macroscopic nodules with tissue breakdown,” smudged geographic necrosis and purulent abscesses. On electron microscopy, the characteristic cytoplasmic inclusions were present in histiocytes and macrophages. Awareness of these types of unusual, yet distinctive APT presentations may obviate the need for resectional lung biopsy in some cases. Also, the drug history should be given to the pathologist, it is notable that this information was unavailable to the pathologist at the time of examination in the four cases above [183].

Pleuroparenchymal Fibroelastosis

This distinctive syndrome has been better delineated and named [184–186] in the past few years [3, 4]. Clinical presentation is with shortness of breath exaggerated on exercise, tachypnea, chest pain on inspiration, restrictive physiology, biapical pleural thickening on imaging [186], and a downhill disease course that is often complicated by spontaneous dif cult-­to-treat pneumothorax or pneumomediastinum. The pathologic features include dense subpleural brosis with a prominent mesh of elastin bers and intervening collagen [184, 185], and there is abrupt transition to a normal architecture in the deeper lung underneath the pleura [186]. Although most such cases are deemed to be idiopathic, a few were followed exposure to chemotherapeutic agents [187] (notably cyclophosphamide [188]) or occurred in recipients of stem cell or lung transplant [186].

Late Radiation-Induced Injury

Beside classic radiation-induced pneumonitis, a subset of atypical distressing, sometimes devastating radiation-­ induced injuries to the chest, heart, mediastinum, neck or esophagus may occur. Clinical presentations include painful myositis of intercostal muscles, constrictive pericarditis, coronaryor valvular heart disease, brosing mediastinitis, phenic nerve injury, chronic compressive pleuropericardial effusion or thickening, neck musculature problems and the “dropped-head syndrome,” or swallowing disorders causing aspiration and chronic aspiration pneumonia and lung destruction.

Chest Pain

Drug-induced acute trans xing chest pain can be a cause for presentation for emergency care [3, 4]. The condition can result from drug-induced pleuritis, or subpleural drug-­ induced pulmonary involvement, acute coronary artery disease or spasm, pulmonary vasoconstriction, pericarditis or without association to clinically demonstrable disease [3, 4]. Drug-induced acute chest pain has been reported with the use of nitrofurantoin, lowand high-dose methotrexate, statins, lupus-inducing drugs including beta-blockers, interferons, carbamazepine, hydralazine, sulfasalazine, mesalazine, bleomycin, 5-fuorouracil, vindesine, adenosine 5′-triphosphate, triptans, cocaine, crack cocaine, and blood transfusion [3, 4]. Failure to identify the drug etiology exposes the subject to the risk of future distressing relapses and readmissions. Acute transient chest pain has also been reported following sclerotherapy of esophageal varices, arteriovenous closure of brain arteriovenous malformations, kyphoplasty, and cryoablation for atrial brillation or in the context of drug-induced esophageal erosion [3, 4].

Rebound Phenomenon

Rebound consists in a fare of the underlying disease that may occur upon withdrawal of a vital therapy drug and can be life-threatening. Examples include rebound pulmonary hypertension upon cessation of prostacyclin or nitric oxide, relapse of amiodarone pulmonary toxicity or DRESS or the development of acute radiation pneumonitis after tapering or abrupt removal of corticosteroid therapy, early relapse of ACEI-associated angioedema or of methemoglobinemia despite removal of speci c therapy or antidote, recurrence of the clinical manifestations of opioid toxicity following too early termination of naloxone, and the ruxolitinib withdrawal syndrome [3, 4].

Recall Pneumonitis

Recall is the fare that follows the administration of small amounts of a drug or agent in a patient with a history of exposure to pneumotoxic drugs or radiation [3, 4]. Recall pneumonitis can develop in the previously irradiated area