Introduction
Pneumocystis pneumonia (PCP) is an opportunistic fungal infection. Infection can occur in HIV-positive and HIV-negative individuals with risk factors including but not limited to hematologic malignancy, connective tissue disorders, and exposure to immunosuppressive agents [ 10 ]. Patients without a history of HIV immunosuppression often have rapid onset and progression of symptoms with more severe lung injury leading to a higher risk of respiratory failure and mortality [ 7 , 10 ]. Critical in the host defense against P. jirovecii is an adequate CD4 T lymphocyte response with depletion inhibiting proper immune system reaction [ 7 ].
Idiopathic CD4 lymphocytopenia (ICL) was first described in literature in 1992 with recent conclusions attributing the disorder to various clinical and immunological states [ 5 ]. ICL is a syndrome defined by the Centers for Disease Control and Prevention (CDC) as an absolute CD4 cell count less than 300 cells/mm 3 or less than 20 % of total T lymphocytes on more than 1 occasion, without evidence of HIV infection, and absence of any other immunodeficiency or immunosuppressive therapy [ 12 ]. Here, we report a patient with no history of underlying immunosuppression who sought care for persistent singultus and was subsequently diagnosed with PCP likely due to underlying idiopathic CD4 lymphocytopenia (ICL).
Case report
A 71-year-old male presented with a productive cough with yellow-colored sputum, shortness of breath, self-reported maximum fever of 102 °F, hemoptysis, and nausea and vomiting. His chief complaint was persistent hiccups lasting for three weeks. Past medical history is pertinent for second degree Mobitz type II with left bundle branch block and permanent pacemaker placement, remote colon cancer without recurrence, hypertension, and hyperlipidemia. He had been seen six months prior for similar symptoms and diagnosed with pneumonia with a computed tomography (CT) scan showing diffuse opacities throughout both lungs with evidence of early cavitation ( Fig. 1 ). He had no history of tuberculosis or travel to endemic regions. His vital signs upon presentation were: blood pressure 106/71, heart rate 85 beats/minute, temperature 37.2 C, respiratory rate 14 breaths/minute, SpO2 92 % on room air. Physical exam was pertinent only for diffuse rhonchi on lung auscultation. The patient was not noted to be in respiratory distress.
Initial laboratory tests were: hemoglobin 15.7 g/dL, total white blood cell count 17.0 (x 10 9 cells/L), neutrophils 14.8 (x 10 9 cells/L), lymphocytes 0.3 (x 10 9 cells/L), monocytes 1.7 (x 10 9 cells/L), platelets 540 (x 10 9 cells/L), and procalcitonin 0.132 ng/mL. HIV-1 antigen and HIV-1/HIV-2 antibodies were not detected. The respiratory viral pathogen panel by PCR was negative. Legionella and pneumococcal urine antigens were negative. Blood cultures later returned negative. Chest x-ray (CXR) revealed worsening diffuse pulmonary consolidations compared to prior imaging months before. CT scan showed diffuse opacities throughout both lungs which were coalescent with numerous cavitations and extensive mediastinal and hilar adenopathy ( Fig. 2 ). He was admitted on 3 L nasal cannula. He was initially treated for presumed multifocal pneumonia and started on doxycycline and ceftriaxone in the setting of an elevated QTc. Pulmonary service was consulted, and noninfectious etiologies were heavily considered due to the chronic nature and lack of significant systemic symptoms. Immunoglobulin levels, serum and urine electrophoresis, and markers of connective tissue disorders were ordered. Bronchoscopy with bronchoalveolar lavage (BAL) showed mild airway inflammation with mild thick clear mucus without gross hemorrhage. Fluid was sent for fungal culture, acid-fast bacillus (AFB), bacterial culture, cell count differential, and cytology.
Immunoglobulin results revealed an IgG level of 632 mg/dL and undetectably low IgM and IgA. The kappa and lambda light chain ratio was normal, and urine immunofixation revealed lambda light chain. Serum immunofixation revealed multiple bands in IgG kappa and IgG lambda which led to consideration of a polyclonal process. In this setting of hypogammaglobulinemia, light chain multiple myeloma could not be excluded. This necessitated the need for a bone marrow biopsy which was not performed due to patient's worsening clinical condition. A myeloma bone survey was ordered and initiated but patient was unable to complete due to worsening hypoxemia. Markers of connective tissue disorders were all negative. BAL Aspergillus galactomannan was negative. Cytology microscopic exam was pertinent for P. jirovecii .
With return of these results, patient was started on Bactrim. Steroids were held out of concern for additional underlying fungal infection. A few weeks into his hospitalization he developed chest pain and imaging revealed a small, apical spontaneous L sided pneumothorax likely due to the underlying cystic disease. This was treated supportively without chest tube placement. He then developed an increased dense consolidation in right lung suspicious for superimposed bacterial pneumonia, however, he was not a candidate for bronchoscopy due to his elevated oxygen needs. He was subsequently transferred to the intensive care unit and placed on vancomycin and cefepime. Patient's oxygen requirement escalated to high-flow nasal cannula. He was known to be DNR/DNI. One colony of penicillium species on one plate from sputum culture was isolated. This was felt to be of uncertain significance. Out of an abundance of caution, itraconazole was administered. Fungitell, QuantiFERON, Coccidioides, Histoplasma, and Blastomycosis were ordered and negative. An absolute CD4 + T-cell count was 7 cells/uL. Given his hypogammaglobulinemia and extremely low CD4 + T-cell count, one dose of intravenous immunoglobulin (IVIG) was administered. Unfortunately, his respiratory failure continued to significantly worsen. Repeat imaging revealed extensive, worsening consolidations bilaterally with diffuse underlying interstitial processes ( Fig. 3 , Fig. 4 ). Palliative care was engaged, and the patient and family ultimately decided to pursue comfort-based care given the grim prognosis. The patient succumbed to his illness 24 days after admission.
Discussion
Pneumocystis jirovecii is the etiologic agent of Pneumocystis pneumonia (PCP) which develops in hosts with impaired immunity due to HIV or other causes of immunosuppression. Symptoms are nonspecific and include progressive dyspnea, non-productive cough, low-grade fever, and often an initial CT appearance of ground glass opacities [ 7 ]. PCP has been historically associated with HIV + individuals, however, recent attention has been directed towards patients who are non-HIV immunosuppressed. There has been a documented decrease in deaths attributed to PCP in the setting of HIV infection with the development of antiretroviral therapy and PCP prophylaxis [ 9 ]. However, new epidemiologic patterns have emerged with incidence and mortality rates of PCP increasing in non-HIV immunosuppressed patients. This suggests the need for re-evaluation of prophylaxis protocols in patients with underlying diagnoses including but not limited to systemic inflammatory disease, hematologic malignancies and in those that require immunosuppressive therapies [ 6 ].
Many patients without known underlying immunosuppression follow a clinical course similar to that presented above where the diagnosis of PCP leads to further workup and discovery of an underlying immunologic or hematologic disorder. The combination of T-cell depletion and hypogammaglobulinemia ultimately led to a defective adaptive immune response for the patient above with lethal progression of the disease course. As evidenced by the electrophoresis findings for the patient, it was hypothesized that he may have had an underlying plasma cell dyscrasia thus leading to immunologic deficiencies. Planned oncologic evaluation included bone marrow biopsy pending improvement of clinical condition which was unfortunately unable to be completed.
As ICL presents similarly to HIV/AIDS with opportunistic infections and low CD4 count, it has previously been described as AIDS without HIV [ 5 ]. However, as described above, it is important to distinguish that morbidity and mortality of HIV has significantly decreased with the development of antiretroviral therapy and antibiotic prophylaxis whereas ICL remains a largely perplexing disease with uncertainty surrounding pathophysiology, prognosis, and therapeutic strategies leading to poor outcomes [ 5 , 9 ]. Existing literature on ICL is limited to case reports and small retrospective cohort studies, however, suspicion for this diagnosis must be of a low threshold in a patient presenting with an opportunistic infection without a previously identified underlying explanation for cause [ 5 ]. Early aggressive intervention is critical for survivability in patients with a critically low CD4 cell count [ 5 ].
Finally, of note, persistent singultus has been previously documented in few case reports as a symptom of pneumonia with theories suggesting diseased lower lung lobes causing direct irritation of the diaphragm. This was felt to be likely present in this patient's case [ [1] , [2] , [3] , [4] , 8 , 11 ].
Conclusion
PCP, caused by P. jirovecii, is an opportunistic infection with a high mortality rate. It is essential to maintain a broad differential diagnosis as evidenced by the case above of an individual diagnosed with PCP after presenting with a presumed multifocal bacterial pneumonia. Although most commonly associated with HIV, PCP can affect individuals with any causes of immunosuppression such as immunosuppressive therapy, underlying immunologic disorders, hematologic malignancies, or inflammatory disorders [ 10 ]. Of these immunologic abnormalities, ICL must be considered in patients diagnosed with opportunistic infections without explanation of underlying immunosuppressive etiology as to prevent progression of disease and mortality such as that of the case above.
CRediT authorship contribution statement
Julia Schearer: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Christopher Merrick: Conceptualization, Formal analysis, Investigation, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.
Prior abstract publication/presentation
Not applicable.
Funding information
Not applicable.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Handling Editor: DR AC Amit Chopra
Contributor Information
Julia Schearer, Email: julia.schearer@co.rvu.edu.
Christopher Merrick, Email: christopher.merrick@uchealth.org.
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