Pneumocystis pneumonia causing cavitating lung nodules in an immunocompetent individual

Abstract

Pneumocystis jirovecii pneumonia (PCP) is a potential life-threatening pulmonary infection which commonly manifests in immunosuppressed patients especially with HIV, with underlying malignancies, severe malnutrition as well as those on immunosuppressive treatments. There have been case reports of symptomatic PCP in individuals with a normally functioning immune system with typical clinical features and radiologic findings of bilateral and diffuse interstitial opacities. However, PCP in immunocompetent individuals presenting with lung nodules had been rarely reported. We report a 53-year-old immunocompetent gentleman who presented with subacute cough, progressive shortness of breath and radiographic findings of multiple lung nodules with central cavitation. The diagnosis of PCP was made by detection of PCP DNA PCR in bronchoalveolar lavage sample following fibreoptic bronchoscopy. This case also highlights the atypical radiographic findings of multiple cavitating lung nodules as a presentation of PCP in an immunocompetent patient.

Background

Pneumocystis jirovecii pneumonia (PCP) remains a potential life-threatening pulmonary infection in immunocompromised individuals.¹ This opportunistic infection is caused by the unicellular yeast such as fungus, Pneumocystis jirovecii.^{2 3} Once inhaled, the trophic form of the pathogen replicates in the alveoli with increased alveolar capillary permeability. This culminates in hypoxaemia with increased alveolar–arterial gradient, respiratory alkalosis and reduced vital capacity.^{2 3} The typical symptoms manifest over days to weeks and include dry cough, exertional breathlessness, fever, malaise, night sweats and sometimes weight loss. Uncommonly, extrapulmonary sites such as the liver, kidneys and the eyes may be affected in immunocompromised patients.^{3 4} The diagnosis of the disease commonly involves detection of Pneumocystis jirovecii trophozoites and or cysts by appropriate histopathological staining on respiratory samples such as induced sputum, bronchoalveolar lavage (BAL) and lung biopsy samples. The cysts usually give the appearance of crushed ping-pong balls and are present in aggregates of 2–8.^{3 4} Molecular diagnosis by PCP DNA PCR is another sensitive diagnostic modality.⁴

Cases are commonly known to cause significant burden of disease in patients with HIV; especially in those with a CD4 count less than 200 cells/µL.² In addition, infections are also established in individuals with underlying malignancies, those with severe malnutrition as well as those on immunosuppressive treatment for autoimmune disease and solid organ transplantation.^{3 5} However, reports of symptomatic PCP in individuals with a normally functioning immune system remain rare.^{2 6 7}

In stereotypical PCP, radiological findings are similar in HIV-positive and HIV-negative patients with typical bilateral and diffuse interstitial opacities extending from the perihilar region. Pneumothoraxes and pneumatoceles may also be present. However, cystic changes are not commonly described in HIV-negative patients.⁸ There is no current literature documenting multiple lung nodules with evidence of central necrosis.

Here, we report a case of a middle-aged immunocompetent gentleman managed for cavitating lung nodules caused by PCP.

Case presentation

A 53-year-old gentleman presented to respiratory outpatients with a 2-month history of dry cough and mild exertional shortness of breath. He reported no fever, chest pain, haemoptysis or weight loss. Medical history included controlled systemic hypertension, depression, gastro-oesophageal reflux disease and dyslipidaemia but he was otherwise fit and well. His medication history included lisinopril, atorvastatin, citalopram and lansoprazole. He was a never smoker and only took alcoholic beverages on very rare occasions. There was no occupational exposure to organic or inorganic dust.

On examination, his observations were: respiratory rate 18 breaths/minute, heart rate 76 beats/minute, blood pressure 124/64 mm Hg, oxygen saturations 94% (room air) and oral temperature of 36.9°C. He had no peripheral lymphadenopathy or oedema. Chest examination revealed crackles in the middle and lower lung zones bilaterally. His cardiovascular, neurological and abdominal examinations were otherwise largely unremarkable.

Investigations

His full blood count showed a haemoglobin count of 160 g/L (130–180 g/L); white cell count 10×10⁹/L (4–11); neutrophils 5.74×10⁹/L (2.0–7.5), lymphocytes 3.2×10⁹/L (1.5–4.5), platelets 229×10⁹/L (15—400). His liver function tests, blood chemistries and renal function were normal.

Autoimmune screens (antinuclear antibodies, antineutrophilic cytoplasmic antibodies, antiglomerular basement membrane antibodies and rheumatoid factor levels) were all within normal titers. Screening tests for allergic bronchopulmonary aspergillosis were also normal with total serum IgE levels of 22.5 kU/L (reference range <114 kU/L), aspergillus IgG levels of 16.4 mgA/L (reference range <40 mgA/L). Tuberculous QuantiFERON Assay was also negative. Blood borne virus screen including hepatitis B, hepatitis C and HIV antigen and antibody were negative.

Initial chest radiograph (figure 1): nodular infiltrates in both lung bases, worse on the left hemithorax.

Figure 1.

AP (anterior-posterior projection) chest radiograph taken on first presentation. Demonstrates bilateral nodular infiltrates, worse on the left hemithorax.

CT of the thorax, abdomen and pelvis (figure 2): multiple lung nodules of varying sizes, some exhibiting central cavitation. No metastatic malignancy identified.

Figure 2.

Axial slice of CT of the thorax, abdomen and pelvis taken during investigations. CT demonstrated multiple lung nodules, some of which demonstrated cavitation (highlighted with arrows in blue).

Pulmonary function tests: showed restrictive pattern with normal gas transfer; forced expiratory volume in 1 second 2.79 L (75% predicted), forced vital capacity 3.33 L (71% predicted); diffusion capacity of 8.31 mM/min/kPa (79% predicted).

Initial fibreoptic bronchoscopy: no gross abnormalities. BAL samples obtained were negative for bacterial culture, acid-fast bacilli and culture for Mycobacterium tuberculosis complex.

Transthoracic echocardiogram was largely unremarkable.

Differential diagnosis

As part of further investigations to unravel the cause of his cavitating lung lesions, he underwent video assisted thoracoscopic surgery. Histology results from this procedure demonstrated granulomatous lesions with yeast such as organisms. This created a suspicion of a fungal disease, specifically Cryptococcus and Pneumocystis disease. Subsequently, serology for cryptococcal antigen was sent, but was returned negative. This prompted a repeat flexible bronchoscopy, and repeated BAL samples were sent for Pneumocystis jirovecii PCR molecular analysis. These returned positive.

As PCP is uncommon in immunocompetent individuals, further immunological assessment was carried out. Immunoglobulin profile showed absolute reduction in IgM levels 0.05 g/L (0.5–2 g/L); immunoglobulin A levels of 2.58 g/L (0.8–4 g/L) and IgG levels of 9.3 g/L (5.3–16.5 g/L). He was then referred for further evaluation with the immunologist. A peripheral blood lymphoproliferative panel raised the possibility of a small B cell clone (CD19 positive, CD5 positive) which prompted further assessment by the haematologist. Bone marrow examination done was normal ruling out any cytological abnormalities. The CD3, CD4 and CD8 counts were normal being 1681 cells/µL (700–1200), 759 cells/µL (300–1400) and 841 cells/µL (200–900), respectively. Following specialist advice, his isolated IgM deficiency this was not deemed to have a significant clinical impact.

Treatment

He was started taking oral co-trimoxazole 120 mg/kg in four divided doses for 21 days as outpatient with significant improvement in symptoms within 5–7 days of commencement of chemotherapy.

Outcome and follow-up

Following antimicrobial treatment, he had two, six monthly out-patient follow-up visits with a repeat chest radiograph (figure 3) showing significant resolution of pulmonary lesions.

Figure 3.

AP (anterior-posterior projection) repeat chest radiograph taken showing gross resolution of bilateral nodular infiltrates.

Discussion

Pneumocystis pneumonia is a recognised pulmonary condition in immunocompromised individuals, but our case report highlights an uncommon presentation of PCP in an immunocompetent individual as well as atypical radiographic findings of cavitating lung nodules. The disease was presumed to occur as a result of reactivation of latent infection, but the literature suggests that environmental exposure via airborne transmission or interpersonal contamination may contribute significantly.^{8 9} It is also postulated that immunocompetent individuals may serve as non-symptomatic carriers of the disease.^{1 4} Though our patient had an incidental finding of an isolated IgM deficiency, the condition can be largely asymptomatic and is not associated with defects in innate immunity, T cells subsets and T cell function which are fundamental in the pathogenesis of PCP.^{10 11} His CD3, CD4 and CD8 levels were also within normal range.

Typical presentation of the disease is characterised by rapidly progressing symptoms in immunocompetent individuals; interestingly our patient had a relatively indolent course which is usually reported in HIV-related immunocompromised patients.³

Regarding radiologic findings of PCP in immunocompetent individuals, a review of the literature by Ide et al reported predominant findings of bilateral alveolo-interstitial infiltrates.² In addition, a single lung nodule was reported by Harris et al while Nejmi et al described radiologic results of reticulonodular opacities in the right lung.^{6 12} The discovery of bilateral lung nodules in our patient with some of them demonstrating areas of central necrosis is novel and adds to the wide spectrum of radiologic findings in immunocompetent individuals.

Generally, diagnosis is potentially challenging as the organism is not grown by conventional culture techniques and there is no clear-cut gold standard. Thus, confirmation of the disease is commonly achieved by laboratory based histopathologic staining of respiratory specimens such as expectorated or induced sputum, tracheal secretions, BAL or lung biopsies.⁴ The identification of Pneumocystis jirovecii DNA by molecular analysis using PCR technique on BAL as in our case is relatively modern and is deemed the most sensitive modality (98%) for PCP diagnosis.^{4 12} The PCR technique also has about 91% ability in correctly identifying individuals without PCP which further strengthened our diagnosis.¹³It is also important to emphasise that sputum induction may be less sensitive in patients without HIV infection because the associated immunodeficiency typically leads to a greater alveolar load of Pneumocystis organisms.² In general, the diagnostic yield of BAL is 90%, and this may be increased if multiple lobes are sampled.^{14 15} Open lung biopsy provides the greatest amount of tissue for the diagnosis and shows nearly 100% sensitivity and specificity. However, the invasive nature of the sampling means it is reserved for cases where bronchoscopy findings are non-diagnostic.¹⁵

Serological assessment of beta D-glucan (BDG) and lactate dehydrogenase levels may also assist with diagnosis but are not confirmatory. In patients without HIV infection, BDG levels should be interpreted in the context of the clinical and radiologic findings with its specificity significantly improved in people living with HIV.¹⁶

The first-line treatment of PCP is co-trimoxazole (trimethoprim–sulfamethoxazole) administered orally or intravenously at 120 mg/kg in divided doses for a total of 14–21 days.⁴ Alternative second-line agents include pentamidine, dapsone and atovaquone. A case report has also suggested the potential use of caspofungin in HIV-positive individuals who are unresponsive to conventional agents, but its usefulness remains unknown in patients without HIV.¹⁷ Corticosteroids are indicated in patients with moderate-to-severe hypoxia (PaO₂ less than 70 mm Hg or an arterial–alveolar O₂ gradient more than 35 mm Hg).⁴ Supplemental oxygen is also of significant therapeutic effect in hypoxic patients. The response to therapy is usually observed in 4–5 days in patients without HIV as exhibited by our patient.

Primary or secondary prophylaxis with co-trimoxazole, dapsone or nebulised pentamidine may be indicated in immunosuppressed individuals but the evidence for secondary prophylaxis in immunocompetent individuals is yet to be established.⁴

We have highlighted the case of PCP in an immunocompetent individual with atypical radiologic evidence of lung nodules some of which were necrotic. This emphasises the need to consider fungal disease especially PCP in the evaluation of patients with subacute to chronic respiratory symptoms regardless of their immune status.

Learning points.

• This case highlights the importance of considering atypical infections as differential diagnosis in patients presenting with bilateral cavitating nodules.

• It is also pertinent to consider full screen for atypical infections from bronchoalveolar lavage sample if the patients are unwell.

• Immunocompetent individuals may also have a relatively indolent course of Pneumocystis pneumonia (PCP) in terms of presenting symptoms.

• PCP treatment in immunocompetent patients does not require modification as they respond well to standard treatment therapy.

• Isolated IgM deficiency does not count towards to immunodeficiency, and should be taken in clinical context.