A 18-year-old male after trauma: when time and free will challenge the rules| Rassegna di Patologia dell'Apparato Respiratorio

CLINICAL HISTORY

1. 18 YEAR-OLD MALE, NEVER SMOKER, NO KNOWN ALLERGIES
2. WORKER AT A PIG BREEDING FACILITY
3. FAMILIAL CLINICAL HISTORY: not relevant
4. PAST MEDICAL HISTORY: not relevant
5. PHARMACOLOGICAL THERAPY: none
6. CLINICAL ONSET: subacute onset of polyarthralgia, fever and dyspnea

Fourteen days prior to admission to the Emergency Department the patient was involved in a motorcycle accident resulting in abrasions to the right thigh. One week later, he developed left hip pain and fever, associated to neutrophils leukocytosis, without evidence of fractures on Computed Tomography (CT) of the pelvis and lower limbs or Chest X-Ray abnormalities.

On physical examination he was febrile, with low oxygen saturation, mild tachycardia and no signs of hemodynamic instability.

Arterial blood gas analysis on room air (Tab. I) revealed type I respiratory failure and elevated lactate levels laboratory tests results (Tab. I) showed mild neutrophilic leukocytosis and significant rise in inflammatory markers, with no impairment of liver or kidney function and normal electrolytes.

Chest X-ray demonstrated numerous disseminated nodular opacities in both lungs and no pleural effusion (Fig.1).

Urinary antigen tests for Streptococcus pneumoniae and Legionella pneumophila serotype I were negative.

CT angiography was performed to exclude pulmonary embolism.

In the MEDIASTINAL WINDOW, normal opacification of the pulmonary arteries was observed and the main pulmonary artery was normal in size. No pericardial or pleural effusion was present (Fig. 2).

The PARENCHYMAL WINDOW revealed multiple nodular lesions, ranging in diameter from a few millimeters to 3 cm. The largest lesions were in the peripheral and subpleural regions and exhibited a halo sign. Some nodules showed ground-glass attenuation with a peripheral rim of consolidation. Several tiny nodules displayed a vascular tree-in-bud pattern (Fig. 3).

The clinical course was marked by rapid deterioration with progressive respiratory failure. The decision of proceed urgently, along with blood cultures, with bronchoscopy [including Bronchoalveolar Lavage (BAL) and Transbronchial Lung Cryobiopsies (TBLC)] was based on the following considerations:

1. The clinical aspects suggested an infection. He had a motorcycle accident resulting in abrasions to the right thigh two week earlier, and developed fever, leukocytosis, with pan in the left hip. A slight increase of plasma lactate was suggestive of incipient sepsis.
2. Procalcitonin has poor sensitivity, but better specificity, in diagnosing sepsis in suspected infection.
3. The CT findings were not per se diagnostic. The lesions were suggestive of hematogenous dissemination, with infection considered the primary differential diagnosis. However, fat embolism could not be excluded, even in the absence of fractures and diffuse ground-glass opacities. Metastatic disease (e.g., angiosarcoma) was considered less likely.
4. Choice of the most appropriate ventilatory support strategy. Documentation of the histopathological findings could help determine the most suitable strategy in the highly probable event of further rapid deterioration in respiratory function.

A blood culture and rigid bronchoscopy with BAL and TBLC was carried out.

BAL

BAL cytology and flow cytometry (Tab. II) revealed an increase in total cellularity, predominantly composed of neutrophils CD3 + and CD8+T cells. Extensive microbiological investigations on BAL fluid including Bacteria, Mycobacteria, Nocardia, Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis, Pneumocystis jirovecii and other fungi, SARS-CoV-2, other coronaviruses, Influenza and parainfluenza, Syncytial Respiratory Virus, Enteroviruses, Metapneumovirus, Adenovirus, Herpes viruses, Cytomegalovirus, Epstein-Barr Virus: were all negative except for methicillin-susceptible Staphylococcus aureus (MSSA).

The Whole Genomic sequencing (WGS) (16SrRNA-Illumina platform) on BAL documented Staphylococcus aureus with luk S-PV and luk F-PV genes coding for Panton-Valentine leukocidin.

Histological examination with hematoxylin-eosin staining (Fig. 4) of lung parenchyma samples obtained by transbronchial cryobiopsy demonstrated alveolar spaces filled with fibrin and necrotic material rich in nuclear debris, associated with necrosis of the alveolar septa. In addition, intralobular pulmonary artery branches showed lumina occlusion by fibrin, nuclear debris, and inflammatory (mainly neutrophils) cells.

TBLC

Transesophageal echocardiography was carried out and it excluded myocardial dysfunction or valvular vegetations.

DIAGNOSIS

A few hours after bronchoscopy the patient was intubated and mechanically ventilated for severe hypoxemia.

Intravenous infusion therapy with and piperacillin-tazobactam was promptly initiated.

In the meantime, blood cultures confirmed the growth of methicillin-susceptible Staphilococcus aureus (MSSA) and on the basis of the antibiogram results, antibiotic therapy was replaced with linezolid and meropenem.

A concurrently marked increase in procalcitonin level (38 μg/L) supported the infectious hypothesis, while autoimmune tests, including autoantibodies against beta-2 glycoprotein I and those for idiopathic inflammatory myopathies, excluded an autoimmune etiology.

Laboratory tests results on BAL and peripheral blood samples, combined with the histological evaluation of the lung biopsy, allowed the diagnosis of Sepsis due to Panton-Valentine leukocidin producing Staphilococcus aureus (MSSA) and guided the subsequent therapeutic management of the patient.

Discussion

The presence of infected thrombi in the centrilobular pulmonary arteries and alveolar septal necrosis as documented by histopathologic features on TBLC samples led to cannulate the patient and initiate an Extracorporeal Membrane Oxygenation (ECMO). The patient was sent home three months after admission with normal blood gas analysis values.

Staphilococcus aureus (S. aureus) is a coagulase-positive, Gram+ micro-organism. Virulence in Staphylococcus aureus is driven by numerous factors that enable tissue adherence, immune evasion, inflammation, and cellular injury. The expression of these factors is tightly regulated by complex genetic systems, notably the accessory gene regulator (agr). Strain variability in virulence determinants underlies the organism’s adaptability and its broad spectrum of clinical manifestations. Genes encoding virulence factors may be located on the chromosome as part of the core genome or within mobile genetic elements (or their remnants), including bacteriophages, pathogenicity islands, cassettes, or plasmids. Alpha-toxin, Panton-Valentine leukocidin (PVL), and phenol-soluble modulins appear to be particularly important virulence factors mediating disease severity. PVL is a toxin that forms pore-forming heptamers on neutrophil membranes, leading to neutrophil lysis. Invasive community-onset PVL-producing Staphylococcus aureus infections have emerged worldwide; however, their incidence varies and is strongly influenced by strain types and lineages. Although PVL is produced by fewer than 5% of S. aureus strains, it is detected in a large proportion of isolates causing necrotic skin lesions and severe necrotizing pneumonia. Diagnostic microbiology laboratories do not routinely test for PVL. Methicillin-sensitive S. aureus (MSSA) can cause aggressive, rapidly progressive infections even in immunocompetent individuals. Approximately 20-40% of healthy individuals are colonized with S. aureus, with a smaller proportion (around 10%) persistently colonized by the same strain. Colonization rates are higher among patients with type 1 diabetes, HIV infection, those undergoing hemodialysis, injection drug users, and individuals with damaged skin. For these microorganisms to invade the host and cause infection, some or all of the following steps are required: contamination and colonization of host tissue surfaces, breach of cutaneous or mucosal barriers, establishment of localized infection, evasion of host immune responses, and metastatic spread. S. aureus is the most common cause of osteomyelitis, both acute and chronic. The primary mode of infection is hematogenous seeding. Up to one-quarter of bacteremia cases are complicated by osteomyelitis, and concurrent bacteremia is present in 50% or more of osteomyelitis cases. Acute osteomyelitis – defined as an initial episode with a clinical course lasting days to weeks but not months – typically presents with fever and localized pain. Long bones are more commonly affected in children, whereas vertebral involvement (most commonly lumbar and cervical) predominates in adults.

In the present case, the clinical profile and laboratory findings at disease onset suggested that sepsis with acute hip osteomyelitis and pulmonary hematogenous dissemination was the most likely diagnosis. Nevertheless, although less probable, alternative diagnoses had to be considered. The clinical decision therefore lay between obtaining maximal diagnostic information through an invasive procedure, such as TBLC, within the most favorable temporal window, or relying on non-invasive investigations such as blood cultures. Blood cultures rapidly provided both the diagnosis and the antibiogram, offering clear guidance for antibiotic therapy. Conversely, identification of the pathological pattern on TBLC samples contributed to the decision to pursue extracorporeal membrane oxygenation (ECMO) as the most effective form of respiratory support. ECMO is selected as a respiratory support option based on a combination of clinical severity, failure of conventional therapies, and patient-specific factors. The main criteria include severe hypoxemia, refractory hypercapnia with severe respiratory acidosis, acute, potentially reversible lung injury (e.g., ARDS, severe pneumonia). ECMO is considered only after failure of lung-protective mechanical ventilation, high PEEP strategies, prone positioning, neuromuscular blockade and optimization of fluid balance and hemodynamics. Finally, ECMO is strongly suggested when lung compliance and injury pattern suggesting that further mechanical ventilation would cause ventilator-induced lung injury. Early consideration (usually within 7 days of mechanical ventilation) is associated with better outcomes. Histopathologic aspects of PVL producing S. Aureus pneumonia are not extensively described. Diffuse microthromboembolism associated to necrosis of alveolar septa as highlighted by TBLC were considered criterion for pursuing ECMO as the preferred respiratory support from the outset. Indeed, thromboembolism lies at the extreme of the alveolar-capillary ventilation-perfusion mismatch, characterized by ineffective alveolar ventilation, and the necrosis of the alveolar septa renders the pulmonary parenchyma particularly susceptible to barotrauma. The adoption of a personalized approach was neither considered nor implemented. A recent study has shown that among patients with sepsis, precision immunotherapy targeting macrophage activation-like syndrome (blood ferritin > 4,420 ng/mL) or sepsis-induced immunoparalysis (< 5,000 human leukocyte antigen DR receptors on CD45/CD14 monocytes) using anakinra intravenously or subcutaneous recombinant human interferon gamma respectively improved organ dysfunction by day 9 compared with placebo.

The decision to perform bronchoscopy with BAL and TBLC immediately before the anticipated marked deterioration in respiratory conditions, and utilization of ECMO as respiratory support soon after it, is clearly debatable, and explicitly not recommended by current guidelines. In this case however TBLC made it possible to obtain an accurate depiction of the pulmonary histopathologic damage and provided valuable information to optimize the management of similar cases in the future.

Interestingly, from a philosophical perspective, the case described here raises the question of whether-and if so, when- it is appropriate to go beyond established rules or “guidelines’ recommendations”. Several major philosophical traditions concur that a rule may be broken when adherence to it would betray the very rationality, truth, or ethical responsibility that originally justified the rule’s existence. Henri Bergson had a peculiar interpretation of that question, suggesting that rule belongs to the realm of what has already been done, whereas life-and with it, authentic thought and freedom- is essentially the producer of novelty (“la vie est creation d’imprevisible nouveauté; le concept est fait pour immobilizer ce qui, par nature, est mobile”).

Figure e tabelle

Figure 1.Chest X Ray: numerous disseminated nodular opacities in both lungs; no pleural effusion.

Figure 2.(a-d) CT scan mediastinal window: (a) main pulmonary artery normal in size; (b) normal opacification of the pulmonary arteries; (c-d) no pericardial or pleural effusion.

Figure 3.(a-f) CT scan-parenchymal window: (a-f) nodular lesions ranging in diameter from a few millimeters to 3 cm; (b) vascular tree-in-bud pattern ()(c)lesion in the peripheral and subpleural regions exhibiting halo sign () (f) ground-glass attenuation with peripheral rim of consolidation ).

Figure 4.TBLC: Alveolar spaces contain, focally, fibrin and necrotic material rich in nuclear debris, scattered neutrophils. Some alveolar septa are necrotic () (H&E, low power). The lumen of the intralobular pulmonary artery branches contains fibrin, nuclear debris, inflammatory cells, neutrophils () (H&E, mid power).

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