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Abstract

The threat of viral epidemics to long-standing diseases, such as mycobacterial infection, is constantly evolving. Enterovirus D68 (EV-D68) is an emerging cause of respiratory infection and has raised great interest since its first outbreak in 2014. Very few studies have been done to describe the clinical aspects of the coinfection of EV-D68 and mycobacteria, so this study was conducted to help round out the understanding of this coinfection pattern. We observed three adult cases of EV-D68 and mycobacteria, who were admitted to the first affiliated hospital of Zhejiang University in August/September 2024. Only one case had a definite past history of immunodeficient disease and received long-term corticosteroid treatment, and the other two were previously healthy. The diagnoses of EV-D68 and mycobacterial infection were all simultaneously confirmed through the metagenomic Next—Generation Sequencing in bronchoalveolar lavage fluid specimens. All three patients were presented with severe respiratory symptoms, such as fever, cough, dyspnea and tachypnea, without any manifestations of central nervous system involvement. The radiological findings in chest CT scans varied from patchy opacity to massive consolidation. The individualized anti-mycobacterium treatment showed little therapeutic effect, while the improvement of symptoms and pulmonary lesions in chest CT was observed after starting or intensifying the administration of corticosteroid. All patients had a marked clinical improvement when discharged from hospital, and it took about 6–9 months for the lung lesions of mycobacterial infections to nearly resolve. These cases illustrate the potential for EV-D68 coinfection to exacerbate pulmonary inflammation in patients with mycobacterial disease, highlighting the need for vigilance regarding possible viral coinfections in settings with a high tuberculosis burden, such as China.

Keywords

coinfection enterovirus D68 mycobacterium

Introduction

Tuberculosis and nontuberculous mycobacteria (NTM) disease are chronic wasting conditions that primarily cause structural destruction and persistent immune dysregulation in the lungs, thereby increasing susceptibility to secondary respiratory infections.¹ In clinical practice, coinfections of Mycobacterium tuberculosis (MTB) with bacterial or fungal pathogens in the lower respiratory tract are frequently observed and are associated with more extensive lung damage and poorer clinical outcomes when both conditions occur concurrently.^2,3 These observations highlight the substantial clinical challenge posed by coinfection in patients with underlying mycobacterial disease, particularly in terms of disease progression, diagnostic complexity, and therapeutic management.

Beyond bacterial and fungal pathogens, accumulating evidence suggests that respiratory viruses may also exacerbate mycobacterial diseases. Highly pathogenic respiratory viruses, such as influenza viruses and coronaviruses, have been linked to unfavorable clinical outcomes in MTB-infected individuals.^4,5 For example, mortality from pulmonary TB reportedly increased during influenza pandemics,⁶ and influenza may promote the progression from latent to active MTB infection in susceptible individuals through disruption of host immune defenses.⁷ Similarly, coinfection with SARS-CoV-2 and MTB has been hypothesized to aggravate pulmonary disease because both pathogens interfere with protective immune responses.⁸ From an immunopathological perspective, viral infections may impair macrophage antimicrobial functions, modulate cytokine responses such as type I interferon and IL-10 signaling, and disrupt protective T-cell immunity, thereby weakening host control of mycobacterial infection and contributing to adverse clinical outcomes.^9,10 Therefore, understanding the interaction between respiratory viruses and mycobacterial diseases is important for improving clinical management and prognostic assessment.

However, apart from influenza and COVID-19, little is known regarding the interaction of the viral epidemics/pandemics with mycobacteria, and thus we describe three patients who were infected with enterovirus D68 (EV-D68), an emerging cause of severe respiratory infection, and who were also confirmed to have active mycobacterial infections (Supplemental Material).

Case 1

A 33-year-old man was admitted on August 22, 2024, because of repeated fever, chest tightness, shortness of breath, and non-productive cough during the previous 4 months. This patient was diagnosed with GATA2 syndrome 8 years ago due to cytopenia and recurrent pneumonia, following exome sequencing. He was prescribed oral methylprednisolone therapy for several years. Intracellular mycobacterial infection was confirmed by metagenomic next-generation sequencing (mNGS) using a bronchoalveolar lavage fluid (BALF) sample at another hospital, 20 days ago. The physical examination upon admission revealed a high body temperature (38.3°C) and increased pulse rate (128/min). His respiratory system examination showed bilateral inspiratory crackles with no wheezing noted. Laboratory findings were as follows: white blood cells (WBC), 2140/mm³; neutrophils, 1850/mm³ (86.4%); lymphocytes, 250/mm³ (11.7%); hemoglobin, 8.2 g/dL; C-reactive protein (CRP), 65.01 mg/L; and erythrocyte sedimentation rate (ESR), 58 mm/h, ferritin, 1266.5 ng/mL, the 1,3-β-D-glucan (G) test and galactomannan (GM) test were negative. A computed tomographic (CT) scan of the chest showed massive patchy, nodular, and linear high-density shadows in bilateral area, more evident on the right, with local consolidation (Figure 1(a)). The patient was administered intravenous azithromycin (0.5 g, daily), levofloxacin (0.5 g, daily), oral ethambutol (0.75 g, daily) and prednisone (10 mg, daily). After 14 days of treatment, he still complained of progressive fatigue and respiratory symptoms. Fever started to spike with the temperature rising up to 40.2°C and the level of CRP rose to 120 mg/L. Therefore, follow-up chest CT was performed to evaluate the pulmonary lesions and showed a progression of pulmonary infiltration, presenting with diffuse bilateral patchy ground-glass opacities or consolidation opacities with blurred margins (Figure 1(b)). Considering the possibility of a mixed infection, repeat diagnostic bronchoscopy was recommended to obtain BALF specimens for further mNGS detection. As indicated by the mNGS result, pathogenic species detected in this case consisted of intracellular mycobacterium (1 sequence), EB virus (13,536 sequences), and enterovirus D68 (EV-D68; 39,992 sequences). Briefly, the patient had a 4-month history of recurrent fever, chest tightness, and dry cough. NTM infection had been confirmed by BALF mNGS at an outside hospital 20 days prior to admission. After 14 days of treatment with anti-NTM therapy and low-dose corticosteroids, he acutely deteriorated, presenting with spiking fever, elevated CRP, and worsening pulmonary infiltrates. Repeat BALF mNGS revealed a predominance of EV-D68 over NTM, suggesting that viral infection coincided with the acute exacerbation, whereas NTM likely represented a pre-existing, subacute process. Given the marked predominance of viral reads, the patient’s rapid clinical deterioration, and the lack of therapeutic response to broad-spectrum antibacterial treatment, viral infection was considered more likely to account for the acute disease severity. In contrast, NTM typically cause subacute or chronic pulmonary disease, even in immunocompromised hosts, and the extremely low mycobacterial read count, together with the clinical course, made NTM a less likely primary etiologic agent in this case. A higher dosage of intravenous methylprednisolone (20 mg, twice a day) was prescribed. Symptoms of fever, dry cough, chest stuffiness and pulmonary consolidation in chest CT gradually improved within 7 days of treatment (Figure 1(c)). This patient acquired a marked clinical recovery from viral pneumonia and kept afebrile within 2-month follow-up.

Figure 1.

Changes of pulmonary CT manifestations in case no.1 during hospital stay. (a) Initial CT scan on admission revealed massive patchy, nodular, and linear high- density shadows in bilateral lungs, more evident on the right, with local consolidation. (b) Second CT on the 15th day of hospitalization showed a progression of pulmonary infiltration, presenting with diffuse bilateral patchy ground-glass opacities or consolidation opacities with blurred margins. (c) Third CT on the 24th day of hospitalization demonstrated a significant improvement in pulmonary consolidation.

Case 2

A previously healthy 66-year-old woman was referred to the emergency department (ED) on August 28, 2024, for dyspnea, low-grade fever, cough with white mucous sputum and documentation of patchy consolidation mainly in the left lower lobe of the lung in chest CT scan from another primary care clinic. Upon arrival, the physical examination revealed no significant findings except for a high respiratory rate of 29/min. Oxygen saturation was 96% under an oxygen supply of 6 L/min via mask. Laboratory findings were as follows: WBC, 5860/mm³; neutrophils, 69.3%; CRP, 13.83 mg/L; partial pressure of oxygen, 56.2 mmHg. The patient’s IgM antibody test was negative for Mycoplasma pneumoniae. Reverse transcriptase polymerase chain reaction (RT-PCR) for COVID-2019 and influenza A, B revealed negative results in nasopharyngeal specimens. An MTB-PCR test via sputum sample was performed, confirming MTB infection on hospital day 4. And chest CT revealed diffuse large-scale consolidations and tree-in-bud appearance on the left lung, with ground-glass opacities, suggesting tuberculosis activation. The conventional doses of oral isoniazid, rifapentine, ethambutol and pyrazinamide were prescribed to the patient, along with intravenous methylprednisolone (40 mg, daily), considering the severe inflammation in the lungs. Despite administration of both anti-MTB and anti-inflammation agents, pulmonary consolidation did not improve and the symptoms of dyspnea and tachypnea continued to progress. The peripheral oxygen saturation dropped to below 90% even after minor movements on the bed. To verify whether there was other coexisting pathogens-induced pneumonia, the patient underwent bronchoscopy examination with collection of BALF specimens, and these samples were sent for an NGS test on the 14th day after admission to the hospital. NGS results showed that MTB (10,975 sequences), EV-D68 (1,315 sequences) and Pneumocystis jirovecii (15 sequences) were in the BALF. Pneumocystis jirovecii was regarded as colonization and not responsible for the invasive lung infection. Several studies indicate that concurrent viral infections can exacerbate mycobacterial disease severity through modulation of host immune responses.^9,11 Given the exaggerated pneumonic inflammatory response caused by the coexistence of MTB and EV-D68, the dosage of intravenous methylprednisolone was increased to 40 mg, twice a day, to alleviate inflammation. The manifestations of respiratory failure improved significantly after adjusting the treatment plan. The third CT scan was taken on the 21st day, and the results showed that the infiltration of the lung lobes had dissipated well. The patient was discharged without significant symptoms. Overall, this patient presented with acute-onset dyspnea, low-grade fever, and productive cough, with chest CT revealing severe pulmonary involvement. MTB infection was confirmed by sputum PCR on hospital day 4. Despite standard anti-MTB therapy, her condition rapidly deteriorated. BALF collected on day 14 and analyzed by NGS revealed concurrent MTB and EV-D68. Initiation of corticosteroid therapy led to rapid improvement of her respiratory symptoms. These findings indicated that the coexistence of MTB and EV-D68 likely contributed to the severity of the pulmonary disease, with viral infection exacerbating the inflammatory response on top of underlying tuberculosis.

Case 3

A 57-year-old male presented to the infectious disease department with productive cough for 12 days on August 24, 2024. He came to the hospital because he had an intermittent productive cough with yellow, purulent sputum associated with chest heaviness at rest. This patient had been diagnosed with hypertension for 20 years, gout for 11 years and chronic kidney disease for 5 years. The laboratory results were as follows: WBC, 7.29 × 10⁹/L, with a neutrophil ratio of 78.5%, hemoglobin, 89 g/L; Inflammatory marker levels were increased significantly: CRP, 153.49 mg/L; ESR, 115 mm/h; Blood biochemical index results showed that creatine increased to 277 μmol/L, uric acid increased to 454 μmol/L and blood urea nitrogen increased to 14.55 mmol/L. The results of G test, GM test and sputum culture were negative. Subsequent chest CT revealed multiple scattered patchy opacities in both lungs. Then, bronchoscopy showed purulent sputum at the affected sites. mNGS analysis of BALF samples indicated the presence of MTB (2 sequences) and EV-D68 (66,847 sequences) in this patient. Following diagnosis, the patient received tailored anti-infection therapies including oral isoniazid, rifapentine, ethambutol and intravenous moxifloxacin, methylprednisolone (40 mg, daily). Mucolytic drugs were also employed to facilitate sputum expectoration. His cough was obviously relieved after 6 days of treatment. The latest lung CT scan was taken on the ninth month, and the results showed that the pulmonary inflammation changes had essentially resolved. Anti-MTB therapy was eventually discontinued.

Discussion

To our knowledge, based on the available literature, few case series have described EV-D68 and mycobacterial coinfections in China. Although there have been multiple outbreaks of EV-D68 in other countries, the detection rate of EV-D68 (0.18%–0.23%) has remained at low levels in China for the past decades.^12,13 Given the increased susceptibility to viral infections among patients with mycobacterial disease, vigilance for the potential spread of EV-D68 is warranted. This is particularly important in countries with a high tuberculosis burden, such as China.

EV-D68 is a single-stranded positive-sense RNA virus, which belongs to the enterovirus genus of the Picornaviridae family and mostly causes respiratory illness or neurological complications such as acute flaccid myelitis (AFM) in severe cases. EV-D68 was first isolated in 1962 from pharyngeal swabs of pediatric patients with acute respiratory illness. It was largely underestimated for decades until major outbreaks occurred in 2014 across the United States, Canada, Europe, and Asia.¹⁴ Since then, EV-D68 has resulted in intermittent widespread circulations among children worldwide every 2–4 years.¹⁵ The virus was detected at low level across the United States from September 2023. The prevalence of EV-D68 significantly increased from late spring in 2024 and reached a peak in September 2024. All three patients in our study denied any travel history to the United States during this epidemic. It should be noted that EV-D68 never led to a national outbreak in mainland China as in other countries. A retrospective study including 3997 children hospitalized with community-acquired pneumonia in Shanghai found that only nine samples were EV-D68 positive within an eight-year period (2013–2020).¹² This likely indicates a rising rate of EV-D68 infection among the general population in China, and that large outbreaks could occur following cumulative mutations due to the genetic instability.¹²

Another possible explanation for the seemingly increased detection of EV-D68 in our case series is the limited awareness and under-recognition of EV-D68 infection in adult populations. Most studies focused on the pediatric cases, while the reports related to its clinical impact on adults are extremely limited. As far as we know, the detection of EV-D68 is not included in regular surveillance when adult patients with respiratory symptoms or fever come to hospital. The identification of viruses in our patients with mycobacterial infection was facilitated with mNGS, which can simultaneously detect a broad range of bacterial, viral, fungal or parasitic DNA/RNA sequences with high accuracy. Moreover, the epidemiology of EV-D68 may not be accurately represented because the majority of the data regarding this virus were collected in hospitals and do not take into account the asymptomatic cases and the cases too mild to require hospitalization.^12,16,17

In our case series, the detection of EV-D68 was most consistent with active viral infection rather than incidental colonization. Although molecular detection alone cannot definitively distinguish colonization from infection, several lines of evidence supported a clinically significant role for EV-D68 in these patients. First, all patients presented with acute respiratory symptoms and corresponding imaging abnormalities that were not fully explained by mycobacterial infection alone. Such clinical and radiographic features, including respiratory distress, wheezing, and hypoxia, are well-recognized manifestations of EV-D68 infection.¹⁸ Asymptomatic colonization with EV-D68 appears to be uncommon. While non-polio enteroviruses are widespread and may occasionally be detected subclinically, epidemiological and serological studies suggest that EV-D68 detection typically reflects recent infection rather than long-term carriage.¹⁹ In our cases, viral detection occurred in the context of acute symptom onset and disease progression, rather than during convalescence or in asymptomatic individuals. Finally, the temporal relationship between viral detection and clinical course further supports a pathogenic role for EV-D68. Patients showed limited or no sustained response to broad-spectrum antibiotics, whereas clinical improvement followed supportive care and, when appropriate, anti-mycobacterial therapy.

Some studies suggested that EV-D68 infection was associated with more severe respiratory illness, such as pneumonia and exacerbation of small airway disease, in adults and elderly with underlying comorbidities.¹⁶ So far, the interaction between EV-D68 and PTB/NTM has not been well defined yet. There have been several reports demonstrating significant percentages of patients treated for tuberculosis are left with sequelae of the disease, which may increase the susceptibility of patients to viral infection.^20,21 However, all three patients in the present study were newly diagnosed with mycobacterial infection without distinct structural destruction of the lung shown on chest CT scans, such as bronchiectasis and cavity. Notably, except for one patient with GATA2 syndrome, the other two patients denied a history of immunosuppressive diseases or taking immunosuppressive medications. This differs from many reported adult EV-D68 cases, in which severe disease is often associated with advanced age, chronic lung disease, or overt immunocompromised status. Therefore, rather than post-tuberculosis structural damage alone, it is plausible that immune dysregulation related to active PTB/NTM infection itself may predispose these patients to EV-D68 infection or exacerbate disease severity. It is important to note that these cases described the co-occurrence of mycobacterial infection and EV-D68, and, due to the descriptive nature of the study, a causal relationship cannot be established. The observed association should not be interpreted as evidence that EV-D68 directly determines disease severity.

It was reported that most cases of EV-D68 are mild or asymptomatic and remain undiagnosed.^22,23 In adults, upper respiratory tract involvement is more commonly described, whereas severe lower respiratory tract disease is relatively less frequently reported.^13,24 In contrast, the patients in our study presented predominantly with severe lower respiratory symptoms, including wheezing, dyspnea, chest tightness, abnormal oxygen saturation, and increased respiratory rate, which appeared more pronounced than typically observed in isolated PTB/NTM infection. Similar severe respiratory manifestations have been described in a limited number of adult EV-D68 pneumonia reports.²⁵ Radiologically, patchy opacity, perihilar haziness, focal haziness, infiltrates and consolidation were predominant features, which were also observed in CT scans of our patients.¹⁶ These findings suggest that coinfection with mycobacteria and EV-D68 may lead to more severe respiratory illness in adults than infection with either pathogen alone. Additionally, the characteristic manifestations of AFM have not been observed in these severe cases in our study. However, due to the small sample size, it is difficult to make a definite conclusion regarding the incidence of AFM in adults.

As with most viruses, the medical field lacks effective antiviral treatments for EV-D68.²⁶ Presently, there are scarce studies on the therapeutic effects of glucocorticoids in infections caused by EV-D68. Recent clinical trials have shown that glucocorticoids offer advantages over conventional therapy in inhibiting excessive inflammatory response and modulating cytokine release in patients with severe community-acquired pneumonia.²⁷ All patients in this study achieved a significant relief of clinical symptoms after being treated with glucocorticoids. Short-term application of glucocorticoids may be a feasible therapeutic option to alleviate excessive inflammatory responses among these patients. However, the rationale for glucocorticoid use in the setting of suspected or concurrent mycobacterial infection requires careful consideration. Meta‑epidemiological analyses indicate that corticosteroid use is associated with an elevated risk of developing active tuberculosis, particularly at higher doses and longer durations of therapy. Corticosteroid doses equivalent to > 15 mg/day of prednisone administered for 2–4 weeks or longer have been identified as a risk factor for tuberculosis development, and risk appears to increase with higher daily doses and prolonged exposure.²⁸ Conversely, evidence specific to short-term, low-dose corticosteroid use and risk of reactivating latent tuberculosis is currently limited.²⁹ In our cases, high-dose corticosteroids were administered for a short period, and once clinical symptoms improved, the dosage was rapidly tapered until discontinuation. WHO guideline recognizes corticosteroids as adjunctive therapy in certain forms of tuberculosis (e.g., meningitis and pericarditis),³⁰ but recommends cautious use and strict patient selection, balancing anti-inflammatory benefits against the risk of immunosuppression and bacterial spread. With respect to glucocorticoid tapering in viral respiratory infections, available evidence suggests that systemic steroids should be used for the shortest effective duration and adjusted according to clinical response rather than a fixed schedule. Experience from severe viral pneumonias, such as COVID-19, indicates that systemic corticosteroids are typically administered for short courses of up to approximately 10 days and may be discontinued or rapidly tapered once respiratory status improves.³¹ As no EV-D68–specific tapering recommendations are currently available, dose reduction in our cases was guided by clinical improvement and the aim to minimize potential harms associated with prolonged immunosuppression. Therefore, glucocorticoids should be used with caution in cases with possible mycobacterial involvement, with careful monitoring and concurrent appropriate antimicrobial therapy.

Conclusion

In conclusion, the case series demonstrates the clinical characteristics of the adult patients with mycobacterium EV-D68-associated pneumonia. The patients with mycobacterial infection had a higher risk of EV-D68 infection. All patients presented with more severe illness but a relatively favorable prognosis after receiving a sufficient dosage of glucocorticoids. This study is limited by the small sample size, lack of control cases, and its descriptive design. As such, while the findings suggested a potential association between mycobacteria and EV-D68, further controlled studies are required to investigate the nature and mechanisms of their interaction. Although our findings are based on a small number of cases from a single center, they raise the possibility that EV-D68 coinfection may occur in adult patients with tuberculosis or NTM infections in other high TB burden settings. Clinicians in such regions should be aware of EV-D68 as a potential cause of acute respiratory deterioration that is disproportionate to mycobacterial disease activity or unresponsive to antibacterial therapy. Larger multicenter or prospective studies are needed to determine the true prevalence and clinical impact of EV-D68 in this population.

Supplemental Material

sj-docx-1-tai-10.1177_20499361261432918 – Supplemental material for Enterovirus D68 and mycobacterial coinfection: case report

Supplemental material, sj-docx-1-tai-10.1177_20499361261432918 for Enterovirus D68 and mycobacterial coinfection: case report by Qiongling Bao, Xiaoqian Zhang and Jing Guo in Therapeutic Advances in Infectious Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Jing Guo

Supplemental material

Supplemental material for this article is available online.

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