Pneumocystis jirovecii pneumonia in newly diagnosed treatment-naïve chronic lymphocytic leukaemia

Abstract

A 78-year-old man with newly diagnosed treatment-naïve chronic lymphocytic leukaemia (CLL) was referred to a pulmonary clinic for 1 month of dry cough and dyspnoea on exertion. Further workup with CT of the chest showed patchy ground-glass opacities predominantly on the right side. The patient was started on empiric antibiotic for presumed community-acquired pneumonia but did not have any improvement in his symptoms and eventually required supplemental oxygen. Bronchoscopy with bronchoalveolar lavage from the right middle lobe showed Pneumocystis jirovecii cysts on Grocott methenamine silver stains. The patient was HIV negative. He was placed on P. jirovecii pneumonia (PJP) treatment with clindamycin and primaquine due to history of significant allergy to sulfa drugs. The patient’s symptoms completely resolved after a 21-day course of treatment and no longer needed supplemental oxygen. This case highlights the importance of keeping PJP infection in differential diagnosis in both treated and untreated patients with CLL with dyspnoea and pulmonary infiltrates.

Background

Pneumocystis jirovecii pneumonia (PJP) is a common opportunistic infection in immunocompromised hosts with HIV or those receiving immunosuppressive therapy for treatment of malignancies, autoimmune conditions or transplantation.¹ Chronic lymphocytic leukaemia (CLL) is a clonal malignancy of B lymphocytes that often occurs with older age. Patients with CLL have inherent immune defects in humoral and cell-mediated immunity.² Despite the characteristic immune incompetent lymphocytes, CLL is not often considered a risk factor for developing PJP. Treatment for CLL with fludarabine, cyclophosphamide and rituximab (FCR) or Bruton kinase inhibitor, ibrutinib, is associated with increased risk of development of PJP.³ Here, we report a case of PJP infection in treatment-naïve patients with CLL with dyspnoea and pulmonary infiltrates.

Case presentation

A 78-year-old man with a history of hypothyroidism and newly diagnosed treatment-naïve CLL [t (14;18) (q32; q21) diagnosed using conventional cytogenetic analysis and fluorescence in situ hybridization] presented to the pulmonary clinic for 1 month with dry cough and dyspnoea on exertion. The patient was diagnosed 1 month earlier with CLL Rai Stage II. The patient is a farmer and no longer could perform his work due to generalised weakness and dyspnoea. He denied fever, chills, night sweats, hemoptysis, mucous production and weight loss. He was a never smoker and had no history of lung disease. He was afebrile, blood pressure 109/69 mm Hg, heart rate 77 beats per min and saturation 91% on room air. His physical examination was notable for bibasilar crackles. The patient desaturated to 82% during 6-minute walk test and required three litres per minute supplemental oxygen with exertion. As the patient desaturated with minimal exertion and required oxygen, we determined not to get an arterial blood gas (ABG).

Investigations

A CT of the chest with contrast showed patchy ground-glass opacities predominantly on the right side (figure 1). Pulmonary function tests showed normal spirometry and lung volumes but with decreased diffusing capacity of carbon monoxide at 54% predicted. At the time of his pulmonary clinic appointment, his leucocyte count had increased from 54 to 72 x 10⁹/L in a span of 1 month and white blood cell count showed no peripheral eosinophilia. The patient was negative for COVID-19 and other common respiratory virus infections. He was empirically treated for community-acquired pneumonia (CAP) with amoxicillin–clavulanate for 7 days. The patient underwent bronchoscopy with bronchoalveolar lavage (BAL) after no improvement in symptoms with antibiotics. Grocott methenamine silver stain from the right middle lobe BAL sample showed P. jirovecii cysts (figure 2). Rest of the infectious workup was negative, including for HIV infection and negative BAL cytology.

Figure 1.

CT of the chest (axial and coronal views): blue arrow showing patchy ground glass changes in right upper and lower lobes.

Figure 2.

Grocott Methenamine Silver stain from bronchoalveolar lavage sample: blue arrow highlighting few Pneumocystis jirovecii cysts.

Differential diagnosis

The differential diagnosis for a patient with CLL with dyspnoea, cough and pulmonary infiltrates includes CAP, atypical pneumonia in immunocompromised host, drug-induced pneumonitis, leukaemic infiltration of lung parenchyma and pulmonary leukostasis. CLL is not considered as immunocompromised state and around half of these patients will have indolent chronic course even without treatment.⁴ Community-acquired pathogens are the most common cause of pneumonia with atypical infection seen in neutropenic and immunocompromised patients. Our patient did not respond to empiric treatment of CAP with amoxicillin–clavulanic acid. He was not on any immunosuppression medications including glucocorticoids and was not on any medications that can cause pneumonitis. Leukaemic pulmonary infiltration and pulmonary leukostasis is usually seen in patients with hyperleucocytosis and blast crisis, which our patient did not have. Patients with hyperleucocytosis can have pseudohypoxaemia or leucocyte larceny which is caused by high number of metabolically active leucocytes that consume oxygen in ABG sample and cause hypoxaemia but have normal pulse oxygen saturation. Even though our patient did not have ABG, pseudohypoxaemia is unlikely as his pulse oximetry showed desaturation with exertion.

Treatment

The patient had a history of a significant allergic reaction to sulfa drugs. Due to his new oxygen requirements and worsening of symptoms, he was started on atovaquone 750 mg two times per day and prednisone taper pending glucose-6-phosphate-dehydrogenase deficiency (G6PD) test. Atovaquone was changed to a clindamycin and primaquine combination after a few days when the patient was confirmed not having G6PD deficiency.

Outcome and follow-up

The patient was treated with clindamycin and primaquine in combination with prednisone taper for total 21 days with complete resolution of symptoms. He no longer needed supplemental oxygen on follow-up clinic visit. He is closely following with the oncology team and the plan is to start PJP prophylaxis before treatment of his CLL.

Discussion

P. jirovecii is a known opportunistic pathogen in immunocompromised patients. P. jirovecii pneumonia (.PJP in a treatment-naïve patients with CLL is rare but has been previously reported.^4–6 In 1980s, with the rise of HIV infection, PJP became quite common in these patients with low CD4+ count. With the development and advancement of antiretroviral therapy (ART), PJP is much less common in those infected with HIV. Patients with HIV negative in immunocompromised states due to malignancy, chemotherapy, autoimmune conditions on immunosuppressive therapy and organ transplant recipients on immunosuppressive therapy are also susceptible to PJP.

Patients with HIV positive and HIV negative with PJP present with different clinical courses. The mortality rate in HIV-associated PJP is currently 10%–15%; whereas in non-HIV-infected populations, the mortality rate related to PJP ranges between 30% and 50%.⁷ The higher mortality in non-HIV-related PJP is likely due to acute presentation, lack of standardised risk factors, late diagnosis and lack of PJP prophylaxis when compared with known established risk factors (CD4 count <200/μL), use of standard PJP prophylaxis and advancement in ART therapy in patients with HIV. Patients with HIV positive tend to have a more indolent course with higher organism burden, whereas patients with HIV negative tend to have a more acute presentation with lower organism burden and sudden hypoxaemia.^{2 3} Our patient does not fit the typical presentation of non-HIV with PJP due to his subacute presentation.

This case presentation is unique in comparison to the prior reported cases as our patient had never been on any immunosuppressive therapy as noted in one case report with a patient with a history of myasthenia gravis, papillary thyroid carcinoma and spontaneous splenic rupture who was treated with chronic low dose prednisone and mycophenolate mofetil until he developed a lymphocytosis that led to his diagnosis of CLL: likely predisposing the patient to PJP.⁴ Additionally, this case was unique in the timeframe from presentation to diagnosis of both CLL and PJP. The prior case noted the patient had been diagnosed with CLL for 4 years prior to developing PJP,⁵ whereas our case showed the diagnosis with CLL was almost simultaneous with the diagnosis of PJP.

Patients with CLL who undergo chemotherapy with the standard treatment of FCR therapy or Bruton kinase inhibitor, ibrutinib, have increased risk for developing PJP.³ Treatment with these medications causes impaired T-cell function and possibly B-cell and NK cell abnormalities.⁴ When using these treatments, patients are initiated on PJP prophylaxis.⁴ Untreated patients with CLL despite having a dysfunctional immune system are not as susceptible to PJP, but this case in particular warrants a more thoughtful approach to patients with CLL dyspnoea and pulmonary infiltrates. The use of steroids in non-HIV-related PJP was extrapolated from HIV-related PJP infections. A recent meta-analysis in non-HIV-related PJP showed a probable benefit of decreasing mortality in hypoxemic non-HIV PJP patients (OR, 0.69; 95% CI, 0.47 to 1.01; p=0.05). Furthermore, in a subgroup analysis, adjunctive steroids showed a significantly lower mortality in non-HIV PJP patients with respiratory failure compared with no steroids (OR, 0.63; 95% CI, 0.41 to 0.95; p=0.03).⁸ We treated our patient with prednisone taper for 21 days due to new oxygen desaturation at rest and need for supplemental oxygen.

Patient’s perspective.

During his clinic visit, the patient stated, ‘I felt better in three to 3–4 days after starting treatment and feels like I can do regular activities without any discomfort now’.

Learning points.

• Previously reported cases suggest Pneumocystis jirovecii pneumonia (PJP) infection in treatment-naïve patients with chronic lymphocytic leukaemia (CLL) may have more subacute presentation similar to patients with HIV when compared with acute presentation seen in immunocompromised patients with non-HIV

• Early diagnosis and use of adjunctive steroids in patients with acute hypoxic respiratory failure may help in decreasing morbidity and mortality in non-HIV-related PJP infections.

• This case highlights the importance of keeping PJP infection in differential diagnosis in both treatment and treatment-naïve patients with CLL with dyspnoea and pulmonary infiltrates.

Ethics statements

Patient consent for publication

Obtained.