An acute onset dyspnea with the clinical presentation of pneumonia, often associated with respiratory insufficiency, is a relatively common clinical presentation in childhood. Most such cases are caused by the infection of an otherwise healthy respiratory system, and usually, such patients respond well to standard therapy with antibiotics and corticosteroids. However, this clinical presentation can also be a secondary complication of an underlying chronic disease, such as bronchial asthma, cystic fibrosis, primary ciliary dyskinesia, or an immunodeficiency, which may represent a diagnostic conundrum. A timely recognition of these conditions enables customized management and often alters the course of the disease. The authors of this manuscript have been granted ethical committee approval by the Ethics Committee of the General University Hospital in Prague, for the publication of this article, approval number 132/24 S-IV. A 7-year-old Caucasian patient arrived at the pediatric emergency room with symptoms of acute dyspnea. His parents reported that he had been quite well the previous day and that during the night he had suddenly woken up with shortness of breath. Apart from abnormal growth at the third percentile, this was a healthy patient with no significant past medical history. The patient was born to a primigravida mother at 38 weeks of gestation, with normal postnatal adaptation and up-to-date vaccinations (Figure 1a). On arrival, he was febrile (38.1°C) tachypneic (60 breaths/min), and dyspneic, with a dry cough and marked tachycardia (144 beats/min). The peripheral blood oxygen saturation (SpO2) was 83% on room air without apparent cyanosis. The physical examination revealed a shallow breathing pattern, and prolonged active expiration with apparent retractions of subcostal and jugular regions. On auscultation, there were both expiratory wheezing and rhonchi. An intensive bronchodilation therapy with short-acting β agonist (SABA) was started and the patient was admitted to the inpatient department where, on oxygen therapy (3 L/min via a face mask) his SpO2 normalized. The physician then ordered a C-reactive protein (CRP), full blood count (CBC), chest radiograph, and an antigen panel for common respiratory viruses. The CRP was elevated (77.8 mg/L, reference range: 0–5 mg/L), and the CBC showed marked leukocytosis with neutrophil predominance (33.0 × 109/L, reference range: 4.5–14.5 × 109/L). The chest radiograph (Figure 1b) revealed bilateral pulmonary infiltrates, while the left middle and left lower fields showed a marked increase in opacity. After obtaining nasal swabs, oral swabs, and sputum samples for microbiology cultures, antibiotic treatment was administered with ampicillin 300 mg/kg/day divided into three doses, repeated bronchodilation therapy (salbutamol, 100 µg/dose) and intravenous methylprednisolone for 5 days (1.1 mg/kg/day). The patient had no notable past medical history and had been fully vaccinated according to the Czech national schedule (including the pneumococcal vaccine), yet experienced an uncommonly rapid progression of respiratory insufficiency, and fever His chest radiograph showed an alarming image of markedly increased opacity. What is the most likely diagnosis? Which infectious agents should be suspected? Which tests would you order to help achieve the correct diagnosis? For more information, see Podcast 1. Despite receiving broad-spectrum antibiotics (ampicillin and clarithromycin), steroids, and inhaled bronchodilators for 7 days, there was minimal clinical improvement. The patient remained febrile, required oxygen therapy, and started to have night sweats. Repeated CBCs revealed persistent leukocytosis (25.0 × 109/L) and a new onset of eosinophilia (26%, reference value:< 7%), a CRP value of 58 mg/L, the blood cultures, as well as sputum, urine, and rectum swabs were negative. In addition, vesiculopapular skin lesions began to appear on the patient's right arm and left cheek (Figure 2a); where a fixation tape was previously attached (i.v. catheter and oxygen mask). Initially, the lesions appeared as red indurations, which eventually developed white tips and coalesced. The dermatologist ordered swabs of the lesions for the detection of various infectious etiologies (aerobic and anaerobic bacteria, viral and fungal pathogens), which were all negative. The lesions were treated with topical fusidic acid and a corticosteroid cream. At the same time, the result of the PCR from the sputum sample came back positive for Aspergillus species antigen; however, both the Aspergillus antigen in serum and the sputum culture for Aspergillus were negative. In addition, a rheumatology consultation was requested to evaluate a possible vasculitis, because marked eosinophilia, vesiculopapular skin lesions, and respiratory insufficiency could be indicative of eosinophilic granulomatosis with polyangiitis (EGPA). Due to these new findings and the alarming clinical state of the patient, a chest computed tomography (CT) scan was indicated, which showed an extensive interstitial lung process with marked mediastinal lymphadenopathy (Figure 2b). Despite receiving broad-spectrum antibiotics, the patient showed minimal clinical improvement. Additionally, new skin lesions and new-onset eosinophilia were detected. What is the potential differential diagnosis? What would be the next most rational diagnostic step(s)? How would you treat the skin lesions? For more information, see Podcast 2. Without any improvement of the clinical state, the patient still required oxygen and suffered from spiking fever throughout the day, with extensive sweating at night. Repeated CBCs showed persistent leukocytosis (23.0 × 109/L) and eosinophilia, as well as a new increase in CRP (106 mg/L). As part of a vasculitis work-up, the tests for autoantibodies (antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti-Saccharomyces cerevisiae antibodies) and serum calprotectin were normal, screening for renal involvement detected no proteinuria or hematuria. Due to the lymphadenopathy, the Mantoux test and the interferon gamma release assay (IGRA) test were performed to exclude tuberculosis, both of which were negative. Furthermore, the angiotensin converting enzyme (ACE) levels and chitotriosidase levels for the diagnosis of sarcoidosis were normal for the age. Lung function tests uncovered a severe reduction of lung vital capacity at 30% of the predicted value. At this point, a bronchoscopy was scheduled to visualize the airways, obtain samples by bronchoalveolar lavage (BAL), and to perform an endobronchial biopsy for detailed tissue analysis. Simultaneously, a skin biopsy from one of the lesions on the arm was carried out. On bronchoscopy, the macroscopic airway anatomy was normal, with the airway mucosa showing signs of discrete inflammatory changes and viscous secretions throughout the bronchial tree (Figure 3a). The differential leukocyte count from the BAL showed 10% eosinophils (physiological value: < 1%), 6% lymphocytes (physiological value: < 10%), 76% macrophages (physiological value: > 90%) and 8% neutrophils (physiological value: < 3%). Importantly, microbiology investigations from the BAL revealed a high number of Cytomegalovirus (CMV) copies (38,000 IU/L). Also, an elevated Candida species antigen (157 pg/mL, physiological values: < 62.4 pg/mL), yet normal value of the Aspergillus galactomannan (0.12, physiological index < 0.49) was found in the BAL. Later, fungal culture from the BAL was also found to be negative. Elevated BAL CMV copies with normal values in blood were suggestive of CMV lung infection, possibly CMV pneumonia. Serologically, IgG levels for CMV were elevated (71 U/mL, reference range 0–13 U/mL) but IgM levels were low (14 U/mL, reference range 0–17 U/mL), which was not suggestive of a recent CMV primoinfection. Valganciclovir therapy was initiated at a dose of 5 mg/kg/day as a precaution. CMV pneumonia in an otherwise immunocompetent child seemed very unlikely; however, the CMV viral load in the BAL was very high. What is the potential differential diagnosis given the bronchoscopy findings? What would be the next most rational diagnostic step(s)? Additional information, see Podcast number 3. After 5 days of intravenous valganciclovir, the patient showed little improvement. Fever spikes continued, along with night sweats. Repeated laboratory tests demonstrated a reduction of leukocytosis (17.0 × 109/L); but the CRP remained unchanged (110 mg/L). The rheumatology consultant ordered computed tomography positron emission tomography (PET-CT) and flow cytometry assessment of peripheral blood leukocytes to exclude hematopoietic malignancy. On the PET-CT, no extrapulmonary pathology was evident. An extensive interstitial process with multiple diffuse nodules was described in both lungs (Figure 4). The flow cytometry screening was not suggestive of a malignant lymphoproliferative etiology. Meanwhile, the results of the skin and transbronchial biopsies became available. The transbronchial biopsy showed nonspecific inflammatory changes and no infectious agent was found (particularly focusing on CMV). The skin biopsy revealed unspecific hyphae (Figure 4c), prompting the reconsideration of the fungal etiology, although a secondary contamination would also be possible, according to the histopathologist. After a targeted query, the parents reported a brief contact of the patient with mulch 24 h before the development of the symptoms (he had played with mulch on an animal farm) and the patient's exposure to household molds. At this point, blood and BAL were sent for the pan-fungal antigen beta-D-glucan test in search of a fungal agent. The PET-CT scan showed an extensive interstitial lung process. Usually, corticosteroids are administered to prevent permanent changes, however, with the suspicion of fungal infection, the immunosuppressive treatment might have been harmful. Which disease could explain these findings? Which test/consultation would you suggest to confirm your suspicion? Additional information is available on the podcast 4. An immunological investigation including IgG, IgG subclasses, IgA, IgM, and lymphocyte differential count was not suggestive of a cellular or humoral immunodeficiency. Additionally, the granulocytes' ability to produce reactive oxygen species was tested with the oxidative burst test, or dihydrorhodamine test and was found to be markedly abnormal. This was consistent with chronic granulomatous disease (CGD), an inborn error of phagocyte function that renders patients susceptible to infections, particularly fungal and bacterial. At the same time, the results of the beta-D-glucan test from the BAL showed borderline levels (96 µg/mL, confirmatory result > 100 µg/mL) and an extensive mold-derived antigen-specific IgG panel returned strongly positive for numerous types of molds. Therefore, treatment with antifungal voriconazole was initiated (20 mg/kg/day), as well as trimethoprim/sulfamethoxazole prophylaxis, which is the standard care for patients with CGD. Genetic testing was requested to confirm the diagnosis. A potential diagnosis of primary immunodeficiency in an otherwise healthy 7-year-old patient, without a history of repeated chronic infections, is not very intuitive. Does the diagnosis of primary immunodeficiency explain the specific lung involvement in this patient? Additional information is available in the podcast 5. On the 34th day of hospitalization, the genetic results confirmed the suspected diagnosis of X-linked CGD (pathogenic variant in CYBB gene encoding for gp91-phox protein, a component of NADPH oxidase). The patient's mother is a healthy carrier of the pathogenic variant and his younger brother and father carried healthy wild-type variants. Trimethoprim/sulfamethoxazole, voriconazole, and valgancyclovir were continued in prophylactic doses. To reverse the interstitial lung process and prevent pulmonary fibrosis, corticosteroid therapy was reintroduced with prednisone 5 mg/day. The clinical status of the patient improved rapidly, as did the lung function tests performed shortly before discharge, 41 days from admission (Figure 5). The patient remained under close monitoring by a pneumologist and was referred to tertiary immunology center. A 7-year-old patient with no history of severe infections presented with sudden onset of dyspnea, fever, and acute respiratory insufficiency. Although this clinical condition is usually associated with an acute respiratory infection, a rare primary immunodeficiency was eventually diagnosed. The borderline growth represented the only finding indicative of possible chronicity. Because the respiratory failure did not respond to first-line therapeutic approaches, a detailed pulmonary evaluation was performed, revealing acute diffuse lung parenchymal disease. While the chest CT pattern can usually narrow the otherwise extensive differential diagnoses [1], in our case the lung involvement combined with skin involvement, required an extensive workup to exclude a range of diagnoses, such as sarcoidosis, tuberculosis, and vasculitis. The diffuse nodular pattern with hilar lymphadenopathy also warranted an oncologic screening in search of possible malignancy [2]. Finally, the history of mold and mulch exposure, high levels of specific IgG antibodies against molds together with the corresponding CT pattern suggested the diagnosis of hypersensitivity pneumonitis (HP) [3]. However, at the initial stage, several aspects were unclear. First, the association of HP with skin lesions was elusive. Second, an ongoing fungal lung infection had to be thoroughly assessed, particularly as the targeted examinations were inconclusive. Third, although the CMV positivity in BAL did not match the short history of symptoms, CMV infection may, in rare cases, present as diffuse parenchymal pattern on CT scan [4] and, as such, CMV pneumonia had to be considered in the differential diagnosis. Eventually, given the atypical combination of symptoms and pathogens, an underlying immune pathology was considered and confirmed to be CGD, altering the course of the child's management. Primary immunodeficiencies are often present with pulmonary symptoms. Besides infections with common and opportunistic pathogens, they can manifest with noninfectious complications of immune dysregulation, ranging from individual lung lesions to a diffuse lung involvement [5, 6]. Perhaps the best-known example is the granulomatous and lymphocytic interstitial lung disease (GLILD) that occurs most typically in predominantly antibody immunodeficiencies, such as common variable immunodeficiency [7]. CGD is a rare primary immunodeficiency (prevalence ~1 in 250,000) typically manifesting within the 1st years of life, although late-onset cases have been recorded. The underlying immune pathology resides with the impaired ability of phagocytes to eradicate the internalized pathogens inside the phagosome. This is due to the aberrant function of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex which fails to transfer electrons from NADPH to molecular oxygen. This precludes the generation of reactive oxygen species (ROS) in a process called respiratory/oxidative burst. ROS, such as superoxide anion, hydrogen peroxide, and hydroxyl radicals, are directly toxic to microbes, including various bacteria (e.g., Staphylococcus, Nocardia, Serratia, Burkholderia, Pseudomonas) and yeast (particularly Candida spp., Aspergillus, and other opportunistic yeast). Additionally, ROS trigger signaling pathways that enhance antiviral immune responses [8-10]. Correspondingly, the characteristic symptoms of CGD are recurrent bacterial and fungal infections. Additionally, noninfectious inflammatory events are common in CGD, hallmarked by granuloma formation in various organs [11, 12]; Lungs are the most frequently affected organ in CGD [8, 13]. The radiologic patterns encompass a variety of findings, such as single or diffuse nodules, ground-grass opacities, focal consolidations and masses with cavities and abscesses, interstitial pneumonia with tree-in-bud opacities, interlobular septal thickening, fibrosis, and emphysema [13, 14]. When managing patients with CGD, it is essential to consider the presence of active infections, sterile inflammation, and a combination of both. Regarding the yeast-related pathologies, fulminant mulch pneumonitis or invasive pulmonary aspergillosis can be a life-threatening emergency in CGD patients exposed to aerosolized organic material (mulch, hay, wood chips) [15] and must be treated appropriately with antifungal compounds. On the other hand, an acute worsening of lung disease mimicking noninfectious hypersensitivity pneumonitis has been described in CGD patients with a history of corresponding exposure [16]. These patients initially responded to systemic corticosteroid therapy (3 weeks), the first-line therapy for HP, however, they consequently developed invasive pulmonary aspergillosis. Our patient had a recent history of mulch exposure preceding the onset of prolonged, severe pulmonary symptoms, with radiological findings indicative of HP. Furthermore, elevated levels of specific antifungal IgG antibodies provided supportive evidence of HP. Despite negative fungal cultures, the possibility of invasive pulmonary aspergillosis had to be rigorously considered. The patient's clinical condition began to improve following the administration of systemic antifungal therapy, underscoring the pivotal role of fungal infection. This was supported by positive sputum PCR results and the presence of hyphae in the skin biopsy. Concurrently, it is postulated that the clinical presentation partly reflected HP, as this condition is documented in individuals with chronic granulomatous disease [14, 17], likely due to their aberrant immune response. The patient received adjunctive systemic corticosteroid therapy for HP only after therapeutic antifungal drug concentrations were attained in the serum. As for the CMV, the lung infection is rather rare yet reported complication in CGD patients [18]. In our case, we suspect that the immune defect together with the diffuse inflammatory lung damage might have allowed the multiplication of CMV in the lungs. Taken together, this patient with CGD probably suffered from inflammatory lung disease, caused by hypersensitive reaction to the inhaled yeast parallel to fungal colonization and subsequent CMV reactivation. The therapeutic benefit was achieved with combination of antifungal and steroid treatment, alongside the cessation of exposure to mold, and possibly aided with antiviral medication. Going forward, the patient will receive regular antifungal and antibacterial prophylaxis and is offered a hematopoietic stem cell transplantation, which represents a curative option for patients with CGD [19]. This case emphasizes the need to maintain a high index of suspicion of primary immunodeficiencies in patients with atypical symptoms, pathogens, and treatment failures, even in previously healthy children. The knowledge of underlying immune pathology has critical implications for the therapeutic strategies and follow-up management. We suggest incorporating immunologic evaluations, including the oxidative burst test, in the diagnostic workup for children presenting with otherwise unexplained diffuse parenchymal disease. Yotam Ophir: writing–original draft, writing–review and editing, investigation, validation, visualization, supervision, methodology, data curation, resources. Marketa Bloomfield: conceptualization, investigation, writing–original draft, methodology, validation, writing–review and editing, data curation, supervision, resources. Jana Tukova: conceptualization, investigation, writing–original draft, methodology, validation, writing–review and editing, project administration, data curation, supervision, resources. We express our deep gratitude to our patients and their families for both their courage in sharing their medical journey and their strength during uncertain times. We also wish to acknowledge our multidisciplinary team, composed of specialists from various hospitals and medical fields, for their invaluable contributions to the patient's care. All Podcast AI voices were generated by PlayHT. We thank Zachary Harold Kane Kendall for the English proofreading. This article was supported by the General University Hospital in Prague, MH CZ-DRO-VFN64165—General University Hospital in Prague, Czech Republic. Open access publishing facilitated by Univerzita Karlova, as part of the Wiley - CzechELib agreement. The authors of this manuscript confirm that they have received a signed informed consent from the legal guardian of the patient to use the patient's data in this paper. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Paediatrician: A viral or bacterial infection is the most probable cause of acute dyspnoea in a healthy boy with fever, cough, and increased inflammatory parameters. However, we should also keep in mind that an infection-triggered asthma exacerbation could lead to a similar clinical picture, so in this case, I would consider following both as potential causes. Pulmonologist: The manifestation is hyperacute, without any previous period of fever or cough, so if we are thinking of infectious agents, we should search for more aggressive agents such as Influenza virus, Human metapneumovirus, Mycoplasma pneumoniae, Streptococcus pneumoniae, or methicillin-resistant Staphylococcus aureus. Radiologist: The chest radiograph shows severe diffuse lung involvement. Paediatrician: It is also worth mentioning that the patient's growth charts, while stable, are on the lowest normal centile, so we should also consider this as a manifestation of an underlying chronic disease. Pulmonologist: When considering all parameters, it would make the most sense to test for potential microbiological infectious agents and in the meantime start with symptomatic therapy, such as short-acting beta-agonist inhalers and systemic corticosteroids; we should also start broad-spectrum antibiotic therapy until the causative agent is verified/excluded. Radiologist: There is an extensive image of diffuse nodular opacities throughout the parenchyma on chest CT with apparent bilateral hilar lymphadenopathy. When considering the potential differential diagnosis of this finding, we must include an inflammatory process with granuloma formation, such as sarcoidosis or Mycobacterium tuberculosis infection; however, a similar interstitial process can also be seen in hypersensitivity pneumonitis or in other diffuse lung diseases. Pulmonologist: Exactly, this is an acute diffuse parenchymal lung disease image. Importantly, the patient worsens clinically and requires constant oxygen therapy. To ascertain the diagnosis, we should perform lung function tests and bronchoscopy with bronchoalveolar lavage. These examinations can provide additional important diagnostic clues, help assess the extent and character of tissue damage, as well as find the infectious agent. Dermatologists: These skin lesions are not typical and have a broad differential diagnosis, may be a sign of contact allergy, which would also explain blood eosinophilia, but could resemble some skin manifestation of TB or sarcoidosis. To verify this, we should perform a skin biopsy of one of the lesions. Rheumatologists: From a rheumatological point of view, most of the combined symptoms would suggest vasculitis, the skin biopsy proposed by the dermatology team will help us confirm if this is the case. We would like to exclude EGPA, which although very rare in this age group, could explain the description of the symptoms the patient presents. In case of EGPA, the biopsy should revealing granulomas and ANCA autoantibodies should be positive. Pneumologist: With PCR tests suggesting acute cytomegalovirus lung infection, I think it would be very reasonable to start antiviral therapy due to the high viral load. However, we know that the CT scan is more consistent with hypersensitivity pneumonitis or other diffuse parenchymal lung process. Although severe cytomegalovirus infection can cause diffuse parenchymal disease, it is an extremely rare manifestation, which has been documented only in a few cases worldwide. Therefore, I think we should start treatment for cytomegalovirus, while at the same time look for other possible causes. It can still be hypersensitivity pneumonitis. So, we should ask the family about a possible exposition of the boy to Mold-contaminated organic materials or hot tubs. Dermatologist: In addition, these skin lesions cannot be explained by cytomegalovirus infection, they likely originated from a different source. The results of the skin biopsy take some time; in the meantime, we should continue the application of broad-spectrum antimicrobial topical treatment, such as Fusidic acid cream. Rheumatologist: The tests we performed make the diagnosis of vasculitis entities less likely, as well as TB and sarcoidosis. But because of the diffuse centrilobular involvement on chest CT, we must also consider hematopoietic malignancies, particularly lymphoma. To assess this, we should perform a PET/CT to screen for extrapulmonary manifestations. Another high-yielding test would be flow-cytometry, which is assessment of peripheral blood, particularly lymphocytes cell counts and their cell surface markers. Pneumologist: Hypersensitivity pneumonitis is now highly suspected given the chronic exposure to molds and to mulch shortly before onset which could have exacerbated a pre-existing subclinical process. The specific immunoglobulin G for moulds should be tested and if not positive, we should consider a video-assisted thoracoscopy -navigated lung tissue biopsy. Additionally, if we suspect that our patient is immunocompromised, the fungal etiology is much more likely due to the skin biopsy findings, and it is important to note that the current treatment does not systemically cover fungal pathogens. Radiologist: PET-CT does not suggest lymphoma or other malignancies and confirmed that the inflammatory process is restricted to the lungs only. Additionally, PET -CT strengthens the notion that this is not a typical CMV pneumonia despite the CMV loads. Paediatrician: It is alarming that the child still requires oxygen therapy and neither his clinical state nor the parenchymal lung involvement are improving. Should we readminister systemic corticosteroids? A therapeutic test would be highly informative and could improve his condition. Pneumologist: Although systemic corticosteroids might improve lung function, it will also cause immunosuppression in our patient. Given two opportunistic pathogens found in our patient, regardless of their role in the disease, we should consult an immunologist to assess underlying immunodeficiency before reintroducing corticosteroids, which could potentially weaken the patient's immune system even more. Dermatologist: The skin biopsy revealed an extremely interesting finding, hyphae of unknown origin; we did not yet identify the specific agent, but a fungal infection should be considered; To try to identify the agent, we should test pertinent samples for various fungal antigens. Immunologist: Lung involvement and fungal infections combined with an abnormal oxidative burst are highly suggestive of CGD. Genetic tests should be performed to map specific CGD mutations and appropriate antimicrobial treatment followed by long-term prophylaxis must be initiated promptly. Although a new onset of increased infectious susceptibility in an older child should primarily raise suspicion of secondary immunodeficiency, late-onset symptoms are not uncommon amongst primary immunodeficiencies and should not discourage a diagnostic work-up towards inborn errors of immunity in selected patients. Pulmonologist: Let us start with prophylactic voriconazole. Hypersensitivity pneumonitis has been described as a rare, yet possible primary manifestation of CGD according to the literature. Monotherapy with corticoids could lead to a progression of respiratory failure should the pneumopathy be at least in part due to infection with opportunistic pathogens. This means that if corticosteroids were to be given, they should only be started in combination with an effective systemic antifungal regimen. Paediatrician: CGD could be a rational explanation even for the borderline growth.
