Interstitial Lung Disease or COVID-19? A Complex Pulmonary Differential Amid a Global Health Crisis

Reactivation of Histoplasmosis

Histoplasmosis is a prevalent endemic fungal infection in the United States caused by the pathogen Histoplasma capsulatum.⁵ Its manifestations are variable and may range from asymptomatic infection to a self-limiting illness characterized by mild flu-like symptoms — including fever, chills, headache, muscle aches, cough, and chest discomfort that appear within 3 to 14 days after fungal exposure — to life-threatening progressive disseminated disease.

Histoplasmosis clinical presentation depends on the degree of exposure, underlying immune comorbidities, and the degree of pre-existing lung dysfunction. The fungus dwells in soil and is highly prevalent in the Ohio and Mississippi River valleys.⁵ It thrives in areas contaminated with bird or bat excrement; therefore, high-risk activities include cleaning chicken coops, cleaning attics and barns, caving, construction, and other activities that churn the soil.⁶

Those most at-risk include the immunosuppressed, those with underlying lung disease, and the elderly. While the majority of patients exposed to H capsulatum remain asymptomatic or experience minimally symptomatic infection, some develop acute infection that requires antifungal therapy. On chest imaging, both acute and chronic changes may be seen, including lobar or patchy pulmonary infiltrates and mediastinal adenopathy.

Laboratory abnormalities include anemia, leukopenia, thrombocytopenia, hepatic enzyme elevation, and/or adrenal insufficiency.⁵ Bronchoalveolar lavage, culture, and serologies are often used to make the diagnosis of localized pulmonary histoplasmosis. Because it may take 4 to 6 weeks to mount an antibody response, serology is typically negative in the first month following infection. Disseminated histoplasmosis may affect multiple organ systems including joints, vasculature, the genitourinary system, and the central nervous system. Reactivation of prior infections is possible with aging and immunosuppressed states.

Risks of COVID-19 in Patients With ILD Treated With ARBs

Patients with COVID-19 pneumonia are at risk for developing lung damage manifested as ILD. Conversely, people with any chronic lung disease are at higher risk for contracting COVID-19.⁷

Mechanistically, SARS-CoV-2 gains entry into type II pneumocytes through the angiotensin-converting enzyme II receptor.⁷ This would imply a potential therapeutic benefit associated with the use of ARBs; however, upregulation of the receptor may in fact facilitate infection in these patients. Early data regarding the positive or negative risks of contracting COVID-19 in patients being treated with ARBs and angiotensin converting enzyme (ACE) inhibitors are inconclusive.⁸ Over 55 current clinical trials are planned or are active and recruiting in this space⁹ 

The renin-angiotensin system has been implicated in the pathogenesis of lung fibrosis.  Angiotensin II regulates cell growth and fibrosis. Angiotensin peptides, as well as angiotensin I and II expressions, are increased in lung tissue from patients with idiopathic pulmonary fibrosis (IPF). Both ACE inhibitors and ARBs have been found to decrease lung fibrosis in animal models,¹⁰ but paradoxically, at least 1 report has implicated their use in the development of subclinical ILD.¹⁰ ARBs and ACE inhibitors therapy is exceptionally common across a wide spectrum of cardiovascular disorders, and current guidelines recommend continuing their use until more data become available regarding the risks in patients with COVID-19. 

Comparing Interstitial Lung Disease and COVID-19

Mrs B’s case highlights the complexity of differential diagnosis in the acute evaluation of patients presenting with respiratory symptoms during the COVID-19 pandemic. Clinical clues include travel history, the timing and location of recent hospitalizations (eg, during the beginning of the pandemic), and more distinctive symptoms that may occur as the disease progresses. For example, fever is a more prominent symptom in COVID-19, whereas ILD is less likely to present with a marked increase in temperature. Both conditions are characterized by malaise and dry cough, but COVID-19 more typically has associated anosmia (loss of smell) and ageusia (loss of taste) and may have associated GI symptoms as well.

From a laboratory perspective, lymphopenia is more common in COVID-19; as the disease progresses, abnormalities may occur in coagulation factors. Imaging is perhaps the most distinguishing feature, although early in the progress of COVID-19 these findings may be similar. While both may have an appearance of ground glass on a chest X-ray, consolidation is more typical of COVID-19, particularly in the peripheral lower lobes. Ultimately, the diagnosis is secured with a positive RT-PCR assay for the presence of the SARS-CoV-2 virus.

Conclusion

There are many ways that the COVID-19 pandemic affects patients with ILD, given their common presenting symptoms and risk factors for poor outcomes.¹¹ Mrs B’s diagnosis and treatment plan was accurate due to astute clinical care and a broad differential diagnosis. Unfortunately, she remains at high risk for contracting COVID-19 in the future given her many multiple risk factors. It was recommended that the patient stay off hydroxychloroquine after completion of steroids, given her drug-related retinopathy. 

Multiple strategies have been employed to reduce potential exposure to COVID-19 for patients with ILD. These include physical distancing (eg, following local health recommendations, limiting in-person visits, and using phone and video conferencing when feasible); emphasizing vigilant hygiene practices (eg, hand washing, not touching the face, disinfecting surfaces, using a face mask, deferring nonessential medical care like blood work, pulmonary function tests, imaging, and procedures); and rethinking treatments for ILD including supportive care (eg, virtual education and pulmonary rehabilitation, early discussion of advance directives), and active treatment (eg, consider how COVID-19 affects risks and benefits of initiating or continuing ILD therapies).¹¹

Vaccine development may diminish the risks of COVID-19 contagion. However, given the speed with which current vaccine development is occurring, it is unclear that there will be sufficient data regarding the safety and efficacy of a COVID-19 vaccine in patients with ILD. Ultimately, an informed discussion of the potential risks and benefits and shared decision-making will be required once a vaccine is available. 

Nicole Uzzo is a student and research volunteer in molecular biology at Temple University – Fox Chase Cancer Center in Philadelphia, Pennsylvania. Cheryl James, PA, is a physician assistant currently working as a healthcare consultant, Philadelphia, Pennsylvania. Rohit Kumar, MD, is an associate professor in the Department of Medicine and Director, Respiratory and Pulmonary Function Service at Temple University – Fox Chase Cancer Center, Philadelphia, Pennsylvania.

References

1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
2. Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:4.
3. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult lung and heart-lung transplant report—2011. J Heart Lung Transplant. 2011;30(10):1104-1122.
4. Gupta S, Ferrada MA, Hasni SA. Pulmonary manifestations of primary Sjögren’s syndrome: underlying immunological mechanisms, clinical presentation, and management. Front Immunol. 2019;10:1327.
5. Knox KS, Hage CA. Histoplasmosis. Proc Am Thorac Soc. 2010;7(3):169-172.
6. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French M, Biesecker JL. A large urban outbreak of histoplasmosis: clinical features. Ann Intern Med. 1981;94(3):331-337.
7. Southern BD. Patients with interstitial lung disease and pulmonary sarcoidosis are at high risk for severe illness related to COVID-19. Cleve Clin J Med. Published online May 14, 2020. doi: 10.3949/ccjm.87a.ccc026
8. Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol. 2020;5(7):825-830.
9. ClinicalTrials.gov. ARB | COVID-19. Accessed November 20, 2020. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=ARB&cntry=&state=&city=&dist=..
10. Gannon WD, Anderson MR, Podolanczuk AJ, et al. Angiotensin receptor blockers and subclinical interstitial lung disease: the MESA study. Ann Am Thorac Soc. 2019;16(11):1451-1453.
11. Wong AW, Fidler L, Marcoux V, et al. Practical considerations for the diagnosis and treatment of fibrotic interstitial lung disease during the COVID-19 pandemic. Chest. 2020;158(3):1069-1078.

This article originally appeared on Clinical Advisor