Cytomegalovirus pneumonia in an ‘apparently immunocompetent’ young male

INTRODUCTION

Cytomegalovirus (CMV) is a ubiquitous virus of the Herpesviridae family, frequently acquired early in life. It is usually transmitted by infectious body fluids such as saliva, urine, and genital fluids or by the transplacental route.¹ The clinical picture ranges from asymptomatic disease to mononucleosis-like syndrome (primary CMV). While severe life-threatening CMV disease is well documented in certain immunocompromised risk groups, severe infection with symptomatic pneumonia in immunocompetent hosts has been rarely seen.² We present a CMV pneumonia diagnosed in an apparently healthy individual whose serology for HIV was negative.

THE CASE

A 35-year-old gentleman presented to us with a dry cough, fever, malaise and shortness of breath for 3 weeks. There was no loss of appetite or weight loss, nor past history of tuberculosis or tuberculosis contact. There was no history of previous hospitalization or medical care visits. He was febrile with a temperature of 104 °F, heart rate of 130/minute, blood pressure 138/80 mmHg, respiratory rate 30/minute, oxygen saturation 94% on high-flow nasal cannula at 40% oxygen and 40 L/minute flow. Bilateral crepitations were heard on auscultation.

Routine laboratory investigations, including a complete hemogram, liver and kidney function tests, and blood glucose values, were normal. Chest X-ray showed bilateral reticulations. Contrast-enhanced computed tomography thorax showed bilateral random nodules with areas of consolidation in left upper lobe with no obvious mediastinal lymphadenopathy (Fig. 1a and b). Differential diagnoses included miliary tuberculosis, non-tuberculous mycobacteria, fungal infections such as histoplasmosis and cryptococcosis, metastatic lung malignancy, and sarcoidosis. Bacterial and fungal infections were ruled out by normal serum procalcitonin and negative bacterial and fungal culture and GeneXpert from bronchoalveolar lavage (BAL). BAL Grocott’s methenamine silver stain (GMS) was negative. Serum angiotensin-converting enzyme was within normal limits. The patient was empirically started on antitubercular treatment (ATT) in view of miliary nodules, despite which the fever persisted. As there was no response, transbronchial lung biopsy was done, which showed histiocytes with moderate inflammatory infiltrate rich in lymphocytes, accompanied by occasional large cells with large nuclei inclusion bodies (in airway epithelial cells) (Fig. 1c) GMS stain was negative on histopathology and there was no evidence of granuloma. CMV deoxyribonucleic acid (DNA) level in serum was 1890 copies/ml. Immunoglobulin (Ig)M for CMV was positive and the diagnosis of CMV pneumonia was made. There was no evidence of cytopenia to suspect bone marrow involvement of CMV, fundus and neurological examination was unremarkable, liver enzymes were in normal range and ultrasonography of abdomen showed no significant abnormality.

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FIG 1.

(a and b) CT chest showing random nodules forming consolidation, (c) histopathology of lung biopsy showing large cells with large nucleus inclusion bodies (in airway epithelial cells) (Black arrow), (d) CT chest showing resolution of lung nodules.

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Antibiotics were stopped and he was started on injection ganciclovir 5 mg/kg 12 hourly. The fever responded, oxygenation improved (SpO₂ 94% on ambient air) and the patient was discharged on oral valganciclovir 900 mg twice daily for 4 weeks. ATT was stopped after the mycobacterial culture showed no growth of mycobacteria after 6 weeks. Extensive immunological work-up was done. Serum immunoglobulins (IgA, IgM, IgG and IgE) were normal. The HIV enzyme-linked immunosorbent assay, checked twice, was non-reactive, and the anti-nuclear antibody test was negative. CD4 count was 167/cmm. The patient was started on co-trimoxazole prophylaxis due to low CD4 counts. After 4 weeks of valganciclovir, a repeat CT thorax showed complete resolution (Fig. 1d). CD4 counts were repeated after 8 weeks when he was disease-free, which was again found to be low (170/cmm). The patient was not on any therapy which could explain low CD4 count. Hence, a diagnosis of idiopathic CD4 lymphocytopenia was made and the patient was started on co-trimoxazole prophylaxis.

DISCUSSION

Idiopathic CD4 lymphocytopenia (ICL) is defined as CD4⁺ T cell counts below 300 cells/µl or <20% of total lymphocytes measured at least twice 6 weeks apart in the absence of any disease or therapy that could be associated with lymphopenia.³ There is no clear sex predilection. Patients usually present in the 3rd or 4th decade of life.⁴

Patients with ICL may present with opportunistic infections, malignancies or autoimmunity. In a study by Yarmohammadi and Cunningham-Rundles, 18 patients (75%) had opportunistic infections, 10 (41%) had malignancies, 5 (20%) had autoimmunity and 3 (13%) had unexplained demyelinating or other neurological diseases. Amongst infections, papilloma infections causing skin or mucosal warts were most common, followed by invasive herpes, tuberculosis and other mycobacterial infections. Five patients (21%) had lymphoma (2 with non-Hodgkin lymphoma, 1 with Hodgkin lymphoma and 1 with primary leptomeningeal lymphoma). 5 patients had solid tumours including prostate, papillary thyroid, colon, skin squamous cell carcinoma and pituitary adenoma. Another 5 cases had autoimmunity, including immune thrombocytopenia, haemolytic anaemia, Sjogren syndrome, systemic lupus and lichen planus.⁵ ICL can be sub-classified into two types in terms of the presence or absence of CD8 T lymphocytopenia. It is a heterogeneous syndrome that can be accompanied by B cell and/or NK cell lymphocytopenia.⁶

Primary CMV infection is usually asymptomatic or presents with fever which is self-limited or sometimes prolonged for 2–3 weeks. Pulmonary manifestations of CMV are rare and vary from dry cough to interstitial pneumonia.⁷ Hypoxaemia is frequently present in patients with CMV pneumonia. Radiologically, pulmonary infiltrates may be limited to one lobe or diffuse interstitial infiltrates,⁸ as seen in our patient; the patient had miliary nodules and areas of consolidation in the bilateral upper lobes. The laboratory diagnosis is based on serological tests (CMV IgM antibody, CMV DNA) or histopathological features (intranuclear inclusions surrounded by clear halo).⁹

In a literature review, Grilli et al.⁷ found 13 cases of CMV pneumonia in immunocompetent hosts, 12 of them were adults (21–73 years old). Histological diagnosis was achieved in 6 patients and rest were diagnosed serologically.

Treatment for ICL involves treating and preventing opportunistic infections;¹⁰ however, there is no evidence supporting preventive therapy for CMV pneumonia. Cytokine therapies with interleukin (IL)-2 and IL-17, which could improve survival and help in CD4 and CD8 cells, are still under trial.^11,12

In our patient, the diagnosis of CMV pneumonia was suspected when the patient was not responding to any treatment. Positive histopathology and serology for CMV pneumonia inspired the search for immunodeficiency disorders. A detailed literature review was done on PubMed using Mesh terms including ([{cmv pneumonia} OR {cytomegalovirus pneumonia}] AND [{lymphopenia} OR {idiopathic CD4 lymphocytopenia} OR {CD4 lymphocytopenia}]). Six articles were found after excluding HIV-positive case reports (Table 1).^8,13–17

This patient highlights the importance of an extensive evaluation of immunocompromised status in patients presenting with opportunistic infections, so that uncommon aetiologies, such as CMV pneumonitis, can be diagnosed and treated in a timely manner. ICL is rare condition which should be sought for in patients presenting with opportunistic infection (OI), if HIV serology is negative.