Successful management of Legionella pneumonia in an immunocompromised infant presenting with generalized pustular rash: A case report

Abstract

Legionella infection is rare in children, and extrapulmonary manifestations are even less commonly reported. Cutaneous involvement, particularly in the form of generalized pustular eruptions, may present significant diagnostic and therapeutic challenges, especially in immunocompromised patients. We report a male infant under 6 months with X-linked severe combined immunodeficiency (XL-SCID) who presented with a disseminated pustular rash as the predominant clinical feature. Initial blood and pus cultures were negative, and empirical antimicrobial therapy showed limited clinical response. Metagenomic next-generation sequencing (mNGS) was subsequently performed and identified Legionella as the causative pathogen. Based on this finding, the antimicrobial regimen was adjusted to include a macrolide antibiotic combined with trimethoprim-sulfamethoxazole (TMP-SMX), resulting in significant clinical improvement and eventual recovery. This case highlights the atypical presentation of Legionella infection with predominant cutaneous manifestations in children, particularly in the context of primary immunodeficiency, and underscores the diagnostic value of mNGS in cases with inconclusive conventional testing. Early application of advanced molecular diagnostics and timely optimization of targeted antimicrobial therapy are crucial for improving outcomes in rare and complex pediatric infections.

Introduction

Legionella species are aerobic, gram-negative intracellular pathogens transmitted through inhalation of contaminated aerosols. Although Legionella infection is well recognized in adults, it remains rare in children, particularly in immunocompromised populations. Legionella pneumonia, caused predominantly by Legionella pneumophila, is an uncommon but potentially life-threatening infection characterized by a wide spectrum of clinical severity, ranging from mild febrile illness to respiratory failure and multiorgan dysfunction. ¹ Extrapulmonary manifestations are uncommon^2–5 and may occur either as complications of Legionella pneumonia or as isolated presentations, most often in immunocompromised patients. ⁶ Cutaneous involvement, including pustular eruptions and soft tissue infections, ⁵ is particularly rare and may obscure the diagnosis.

Microbiological confirmation of Legionella remains challenging. Although culture of lower respiratory tract specimens is still regarded as the diagnostic gold standard, its low sensitivity and demanding technical requirements limit clinical utility. ⁷ In recent years, metagenomic next-generation sequencing (mNGS) has emerged as a rapid and unbiased diagnostic tool, enabling early identification of atypical and rare pathogens, and thereby facilitating timely targeted therapy.

Empirical antimicrobial therapy is typically initiated based on common community-acquired pathogens. Once Legionella infection is identified, targeted therapy should be promptly administered. Inadequate or delayed antibiotic treatment in Legionella pneumonia has been associated with a worse prognosis. Macrolides and fluoroquinolones are recommended as first-line agents. However, the use of fluoroquinolone in pediatric patients is restricted due to potential adverse effects on cartilage development, making macrolides the preferred treatment option in children.^8,9

Herein, we report a case of Legionella pneumonia in a pediatric patient presenting predominantly with disseminated pustular rash. This case highlights the diagnostic challenges associated with atypical cutaneous manifestations and underscores the critical role of mNGS in guiding early diagnosis and individualized treatment in immunocompromised children.

Case description

A male infant under 6 months weighing 6.6 kg was admitted to Children’s Hospital of Nanjing Medical University with a 4-day history of fever and pustular rash, after referral from a local community hospital on October 2024.

Written informed consent was obtained from the patient’s guardians for publication of this case report, and the patient information has been fully de-identified to ensure confidentiality. The reporting of this case report conforms to the CARE guidelines. ¹⁰ This case report was approved by the Ethics Committee of the Children’s Hospital of Nanjing Medical University, China, on April 17, 2026 (Approval number: 202603055-1).

On admission, vital signs were within normal limits except for fever (38.8 °C) and occasional dry cough. His heart rate was 164 beats per minute, respiratory rate 36 breaths per minute, and blood pressure 96/53 mmHg. Physical examination revealed scattered pustular rashes distributed across the body, predominantly on the forehead.

Initial laboratory investigations showed elevated inflammatory markers and hematological abnormalities: C-reactive protein (CRP) 37.98 mg/L (reference 0-10 mg/L), lymphocyte percentage (L%) 9.9% (reference 34-81%), monocyte percentage (MONO%) 21.0% (reference 3-18%), neutrophil percentage (N%) 68.9% (reference 7-51%), absolute lymphocyte count (ALC) 0.89 × 10^9/L (reference 3.2-10.7 × 10^9/L), erythrocyte sedimentation rate (ESR) 40 mm/h (reference <20 mm/h), and procalcitonin (PCT) 0.502 ng/mL (reference <0.05 ng/mL). Based on these findings, impetigo was initially suspected. Chest radiography revealed flocculent hyperdense opacities in both lung fields, supporting a diagnosis of bronchopneumonia (Figure 1). Liver function was impaired, with alanine aminotransferase (ALT) 104 U/L (reference 8-71 U/L) and γ-glutamyl transpeptidase (GGT) 275 U/L (reference 9-150 U/L). The patient had a history of two prior hospitalizations at 1 and 2 months of age for suspected influenza, with no remarkable family history of hereditary or infectious diseases.

Figure 1.

Chest radiograph on admission.

Empirical therapy with intravenous vancomycin 0.06g every 6 hours was initiated, along with hepatoprotective ademetionine 0.25g every 24 hours, paracetamol for antipyresis 0.7ml once, and topical fusidic acid ointment twice daily for skin lesions. Blood cultures were obtained prior to antibiotic administration. On hospital day (HD) 2, the infant remained febrile with a maximum temperature of 39.8 °C. Further immunological evaluation demonstrated markedly reduced lymphocyte subsets, raising concern for immunodeficiency given the history of recurrent respiratory infections. Subsequent genetic analysis confirmed the diagnosis of X-linked severe combined immunodeficiency (XL-SCID), providing an explanation for the patient’s increased susceptibility to opportunistic infections. From HD 3 to HD 7, fever persisted and CRP further increased to 50.88 mg/L; however, blood cultures remained negative. On HD 8, fever persisted (up to 39 °C) with new pustular eruptions on the forehead and lower extremities. The patient was transferred to the Pediatric Intensive Care Unit (PICU) on HD 9. Cerebrospinal fluid (CSF) analysis was unremarkable, excluding central nervous system infection. Despite 10 days of vancomycin therapy, fever persisted. Extensive evaluation for malignancy, rheumatologic disease, autoimmune antibodies, and metabolic disorders yielded no abnormalities. On HD 11, fever reached 39.8 °C and the rash progressed, with new lesions showing erythematous bases, yellow purulent centers, and partial clustering. Older lesions became dry without exudation. Pus cultures were obtained but remained negative. A multidisciplinary team (MDT) consultation recommended high-throughput pathogen detection and therapeutic drug monitoring. On HD 12, mNGS performed on a sputum specimen identified 1,387 sequences of Legionella spp., with no evidence of fungal, viral, mycobacterial, or atypical bacterial infection. Vancomycin was discontinued, and targeted therapy was initiated with oral trimethoprim-sulfamethoxazole (TMP-SMX) (0.16 g every 12 h) and intravenous erythromycin (0.1 g every 8 h). Clinical improvement was observed rapidly. By HD 13, fever decreased to 37.8 °C and skin lesions began to regress. On HD 14, body temperature normalized (Figure 2), the rash resolved significantly, CRP declined to 7.47 mg/L, and liver function improved. On HD 15, TMP-SMX was discontinued, while erythromycin was continued. The patient was transferred back to the general pediatric ward. From HD 16 to HD 18, he remained afebrile with no new rash formation. Repeat laboratory tests and chest computed tomography (CT) were unremarkable. He was discharged on HD 18 with a prescription for oral erythromycin to complete the course of therapy. A summary of the clinical course, laboratory trends, and therapeutic interventions is presented in Table 1.

Figure 2.

Trends in body temperature during hospitalization.

Table 1.

Timeline of clinical course, laboratory findings, and treatment during hospitalization.

Hospital day	Clinical features	Laboratory findings	Treatment
HD 1	Fever (38.8 °C), pustular rash	CRP 37.98 mg/L, L% 9.9%, MONO% 21.0%, N% 68.9%, ALC 0.89 × 10^9/L, ESR 40 mm/h, PCT 0.502 ng/mL, ALT 104 U/L and GGT 275 U/L	Vancomycin started
HD 2	Persistent fever (39.8 °C)	Lymphocyte subsets reduced	Continued vancomycin
HD 3-7	Persistent fever	CRP further increased to 50.88 mg/L, blood cultures remained negative	Continued vancomycin
HD 8	Persistent fever (39.0 °C), new rash lesions	-	Continued vancomycin
HD 9	Transferred to PICU (39.8 °C)	CSF normal	Continued treatment
HD 10-11	Persistent fever (39.8 °C), rash progressed	Culture’s negative	MDT consultation
HD 12	Persistent fever (39.0 °C)	mNGS: Legionella detected	Switched to erythromycin + TMP-SMX
HD 13	Fever improved (37.8 °C), rash reduced	-	Continued targeted treatment
HD 14	Afebrile (36.7 °C), rash improved	CRP declined to 7.47 mg/L, liver function improved	Continued treatment
HD 15	Transferred back to the general pediatric ward	-	TMP-SMX stopped
HD 16-18	No fever, no new rash	Laboratory tests and CT normal	Discharged with erythromycin

(Chest radiography revealed bilateral flocculent hyperdense opacities in both lung fields, supporting a diagnosis of bronchopneumonia. No obvious pleural effusion or pneumothorax was observed).

(The figure illustrates dynamic changes in body temperature over the course of hospitalization. A marked decline in temperature is observed following the initiation of targeted anti-Legionella therapy, indicating a favorable clinical response).

Discussion

Legionella is a globally distributed pathogen that thrives in warm and humid environments. More than 60 species and 70 serogroups have been identified, of which approximately 30 are known to cause human disease. With climate change and increasing urbanization of rural areas, the severity of Legionella-related diseases is rising. Legionella pneumonia is rare but associated with high mortality. The primary mechanism of lung injury is invasion of alveolar macrophages via aerosol inhalation of L. pneumophila. Through a specialized type IV secretion system, the bacterium creates a protective vacuole to evade lysosomal degradation and replicate intracellularly.^11,12 In addition, type II secretion of degradative enzymes further damages host cells, ¹³ resulting in severe pulmonary infection that may extend to multiple organs and systems. ¹⁴

The clinical presentation of Legionella pneumonia is nonspecific and often indistinguishable from other forms of community-acquired pneumonia, making early diagnosis challenging. Traditional microbiological techniques lack sensitivity and specificity. mNGS offers an important diagnostic advantage for rare pathogens, guiding early targeted treatment. ¹⁵ However, its high-cost limits widespread application. To overcome this, the Winthrop-University Hospital (WUH) scoring system has been proposed to assess the likelihood of Legionella infection in the absence of mNGS.^16,17 The system considers the following ¹ : temperature >38.9 °C with relative bradycardia ² ; ESR >90 mm/h or CRP >180 mg/L ³ ; serum ferritin >2× normal ⁴ ; hypophosphatemia ⁵ ; creatine kinase >2× normal; and ⁶ microscopic hematuria. A score of three or more criteria strongly suggests Legionella infection. In our case, the infant presented with fever of 38.8 °C, CRP of 37.98 mg/L, ESR of 40 mm/h, ferritin of 169.3 ng/mL, serum phosphate of 1.40 mmol/L (low), creatine kinase of 51 U/L, and no microscopic hematuria. Only hypophosphatemia met the criteria, and therefore early suspicion for Legionella pneumonia was insufficient.

The infant was admitted with generalized pustular rash, initially considered to be impetigo. Empirical therapy with vancomycin and topical fusidic acid was initiated. Despite 10 days of vancomycin, the patient remained febrile with progressively rising CRP, while blood and pus cultures remained negative. By hospital day (HD) 11, new pustular lesions had developed, prompting a multidisciplinary consultation. High-throughput sequencing was recommended, and mNGS subsequently identified Legionella with 1,387 reads. However, the NGS report cannot be shared because it contains the patient’s personal information. Vancomycin was discontinued, and targeted therapy with erythromycin and TMP-SMX was initiated. The pathophysiological significance of the disseminated pustular rash remains unclear. Although its resolution following targeted anti-Legionella therapy suggests a potential association, it may also represent an immune-mediated response or a secondary inflammatory phenomenon rather than direct bacterial involvement.

Macrolides are the first-line therapy for pediatric Legionella pneumonia, with erythromycin recommended at 30-50 mg/kg/day in 3-4 divided doses for a total duration of approximately 3 weeks. In severe cases or in patients with significant immunosuppression, combination therapy with rifampicin or TMP-SMX has been suggested. Our patient (6.6 kg) received intravenous erythromycin 0.1 g every 8 hours (approximately 45 mg/kg/day) combined with oral TMP-SMX, given the suspicion of underlying immunodeficiency. Although macrolides are considered the standard first-line therapy, TMP-SMX is not routinely recommended for Legionella infection. In this case, TMP-SMX was added empirically due to the patient’s underlying immunodeficiency and the severity of the clinical presentation. Immunocompromised patients are at increased risk for atypical or mixed infections, and adjunctive or combination antimicrobial therapy was considered to provide broader antimicrobial coverage and address potential co-infection during the early phase of treatment.^18,19 However, evidence supporting such strategies remains limited.

Notably, fever improved within 24 hours after initiation of targeted therapy, while CRP and liver function normalized within 3 days, accompanied by regression of skin lesions, indicating a favorable clinical response. TMP-SMX was subsequently discontinued after 3 days based on this rapid improvement. This de-escalation strategy was adopted to reduce potential drug-related toxicity and avoid unnecessary prolonged combination therapy, while continuing erythromycin as targeted treatment for Legionella. The patient was discharged on HD 18, and follow-up at one month confirmed complete recovery after completion of the erythromycin course. The confirmed diagnosis of XL-SCID provides an important explanation for the patient’s increased susceptibility to Legionella infection and has significant clinical implications. ²⁰ Profound impairment of cellular and humoral immunity predisposes patients to opportunistic infections, may necessitate prolonged or intensified antimicrobial therapy, and is associated with an increased risk of recurrence. In addition, long-term management should include consideration of antimicrobial prophylaxis and definitive treatment strategies, such as hematopoietic stem cell transplantation.

Most pediatric cases of Legionella pneumonia present with fever, respiratory symptoms, and elevated inflammatory markers. ²¹ Our patient, however, had atypical extrapulmonary features, including disseminated pustular rash. In this case, differential diagnosis of the cutaneous manifestations should be carefully considered. Kawasaki disease was initially included in the differential diagnosis due to the presence of persistent fever and scattered pustular rash, predominantly involving the forehead. However, there was no evidence of bilateral non-exudative conjunctival injection, oral mucosal changes such as lip cracking or strawberry tongue, or extremity changes including erythema or indurative edema of the hands and feet. The diagnosis was considered unlikely as the patient did not fulfill the established clinical criteria for Kawasaki disease.

In addition, the WUH score was applied retrospectively to illustrate the low initial clinical suspicion for Legionella infection. However, it should be noted that the WUH scoring system has been primarily developed and validated in adult populations, and its applicability in infants remains limited. ²² Age-related differences in clinical presentation and laboratory parameters may reduce its diagnostic accuracy in this population, and therefore the results should be interpreted with caution. In our case, the WUH score did not indicate a high risk for Legionella infection, and conventional cultures failed to identify the pathogen. Because the initial clinical presentation was dominated by atypical extrapulmonary manifestations rather than the classic features of Legionella pneumonia, the index of suspicion for Legionella infection was low at an early stage. Consequently, urinary antigen testing (UAT), one of the most used diagnostic methods for Legionella, was not performed. Ultimately, mNGS provided a rapid and accurate diagnosis, allowing timely adjustment of therapy, shortened hospitalization, and improved prognosis. This case emphasizes the clinical value of mNGS in diagnosing rare pathogens and highlights the importance of personalized therapy, particularly in immunocompromised children.

Limitations

Several limitations should be acknowledged. First, microbiological confirmation in this case relied solely on m NGS, without validation by conventional methods such as respiratory cultures, serology, or urinary antigen testing (UAT), which are commonly used for the diagnosis of Legionella. This was mainly due to the atypical clinical presentation and the low initial suspicion, and may limit the robustness and completeness of microbiological confirmation. Second, the identification of Legionella by mNGS was limited to the genus level, without species or serogroup differentiation. This restricts direct comparison with conventional diagnostic methods, particularly UAT, which primarily detects Legionella pneumophila serogroup 1. Third, although combination therapy was applied in this immunocompromised patient, evidence supporting such strategies remains limited, and further studies are required to establish their efficacy. Fourth, the pathophysiological basis of the disseminated pustular rash remains uncertain. Although its resolution following targeted therapy suggests a possible association with Legionella infection, it may also represent an immune-mediated or secondary inflammatory phenomenon. Fifth, the WUH scoring system applied in this case has been primarily validated in adult populations, and its diagnostic performance in infants remains uncertain, which may limit its applicability in this age group. Finally, as this is a single case report, the generalizability of the findings is inherently limited. Further studies are warranted to validate the diagnostic and therapeutic strategies in similar patient populations.

Conclusion

This report describes the successful anti-infective management of an immunodeficient child with Legionella infection presenting with generalized pustular rash. It highlights the critical role of mNGS in detecting rare pathogens in clinical practice and underscores the necessity of individualized treatment strategies. In particular, the combination of erythromycin and TMP-SMX proved essential for managing Legionella infection in immunocompromised pediatric patients.

Supplemental material

Supplemental material - Successful management of Legionella pneumonia in an immunocompromised infant presenting with generalized pustular rash: A case report

Supplemental material for Successful management of Legionella pneumonia in an immunocompromised infant presenting with generalized pustular rash: A case report by Yuanyuan Zeng, Shanshan Wang, Qin Zhang, Hongjun Miao, Jin Xu and Wenjing Li in Science Progress.

Supplemental material

Supplemental material - Successful management of Legionella pneumonia in an immunocompromised infant presenting with generalized pustular rash: A case report

Supplemental material for Successful management of Legionella pneumonia in an immunocompromised infant presenting with generalized pustular rash: A case report by Yuanyuan Zeng, Shanshan Wang, Qin Zhang, Hongjun Miao, Jin Xu and Wenjing Li in Science Progress.