To the Editor:
Lymphocytopenia has been identified as a common laboratory finding in patients with
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, particularly
among those with more severe presentations (1); however, there are limited data on
which specific lymphocyte populations may be affected or the clinical sequelae. In
this report, we describe the case of a woman with hypoxemic respiratory failure found
to have coinfection with SARS-CoV-2 and Pneumocystis jirovecii, a pathogen commonly
seen in patients with defects in T-cell immunity.
An 83-year-old female nonsmoker presented to our hospital on March 12, 2020, with
fevers, malaise, headache, dry cough, and dyspnea. She had a history of mild intermittent
asthma, managed with an albuterol inhaler as needed, mitral valve prolapse with moderate
to severe mitral regurgitation, and mild to moderate ulcerative colitis, which was
well controlled on oral budesonide (3 mg daily and being tapered) as well as maintenance-dose
sulfasalazine (1,500 mg twice daily). Her symptoms had started approximately 2 weeks
prior to presentation, shortly after travel from Florida to Massachusetts, and had
failed to improve with courses of azithromycin and amoxicillin-clavulanate. In the
emergency department, she had a fever of 39.3°C and oxygen saturation of 86% on room
air, which improved to 95% on 5 L/min of supplemental oxygen by nasal cannula. Initial
laboratory evaluation revealed leukocytosis and relative lymphocytopenia (absolute
lymphocyte count, 1,090 cells/μl) (Table 1). Chest computed tomography was notable
for diffuse bilateral ground-glass opacities with patchy bands of atelectasis and
small nodular foci of consolidation with a distribution suggestive of a viral pneumonia.
Subtle cystic changes were also seen in the affected regions (Figure 1). She was admitted
to the medical intensive care unit and placed on strict isolation precautions given
concern for community-acquired SARS-CoV-2. She developed worsening tachypnea with
a respiratory rate of 40 breaths/min and hypoxia with an oxygen saturation of 80%
requiring supplemental oxygen through a nonrebreather mask at a rate of 15 L/min.
An arterial blood gas measurement showed a PaO2
of 63 mm Hg on 15 L/min of supplemental oxygen. She was intubated for hypoxemic respiratory
failure and supported on low Vt ventilation according to the Acute Respiratory Distress
Syndrome Network lower Vt protocol. Her PaO2
/Fi
O2
was consistent with moderate acute respiratory distress syndrome.
Table 1.
Clinical Laboratory Results
Measure
Result
Reference
Hematology and chemistry
Hb, g/dl
8.9
11.5–16.4
Hematocrit, %
27.3
36–48
Leukocytes, ×103/μl
15.2
4–10
Differential, %
Neutrophils
89.5
40–70
Lymphocytes
7.2
22–44
Monocytes
2.4
4–11
Eosinophils
0.0
0–8
Basophils
0.2
0–3
Platelets, ×103/μl
562
150–450
Ferritin, μg/L
54
13–150
Procalcitonin, ng/ml
0.1
0.00–0.08
Lactate dehydrogenase, U/L
348
135–225
Microbiology
Respiratory culture (tracheal aspirate)
3+ neutrophils, negative Gram stain, and no growth on culture
No growth
Blood culture
No growth
No growth
SARS-CoV-2 (COVID-19 PCR)
Positive
Negative
Influenza A and B PCR
Negative
Negative
Parainfluenza PCR
Negative
Negative
Adenovirus PCR
Negative
Negative
Respiratory syncytial virus PCR
Negative
Negative
Human metapneumovirus PCR
Negative
Negative
Rhinovirus PCR
Negative
Negative
S. pneumoniae urine antigen
Negative
Negative
Legionella urine antigen
Negative
Negative
Histoplasma urine antigen
Negative
Negative
Coccidioides urine antigen
Negative
Negative
Blastomyces urine antigen
Negative
Negative
Cryptococcal antigen
Negative
Negative
Galactomannan antigen
0.08
0–0.49
(1,3)-β-d-glucan, pg/ml
305
<80
Pneumocystis jirovecii PCR
Positive
Negative
Immunology
CD4+ T lymphocytes (absolute)
291
441–2,156
Definition of abbreviations: COVID-19 = coronavirus disease; SARS-CoV-2 = severe acute
respiratory syndrome coronavirus 2; S. pneumoniae = Streptococcus pneumoniae.
Figure 1.
Chest computed tomographic image. Shown is a representative axial image from the patient’s
chest computed tomography scan. Red arrows indicate cystic changes.
A broad infectious workup for viral, bacterial, and fungal organisms (Table 1) confirmed
the diagnosis of SARS-CoV-2 infection based on positive detection for the presence
of SARS-CoV-2 RNA from a nasopharyngeal swab (Nucleocapsid [N]1 target [Cycle threshold
(Ct) 31.33]; N2 target [Ct 33.38]; RNase P control [Ct 25.66]), a qualitative test
result (positive when Ct <40.00 for N1 and N2 targets) reported by the Massachusetts
State Public Health Laboratory, using its Food and Drug Administration Emergency Use
Authorization–approved CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel. In addition,
a serum (1,3)-β-d-glucan level was markedly elevated at 305 pg/ml (reference value
<80 pg/ml), prompting additional testing for P. jirovecii with a qualitative real-time
PCR assay from a tracheal aspirate, which was positive (fluorescent value 0.160 at
melting temperature of 62.4°C; minimum fluorescent signal intensity for positive test
≥0.020). Notably, she had no apparent clinical characteristics associated with false-positive
(1,3)-β-d-glucan measurements, such as exposure to hemodialysis membranes, intravenous
immunoglobulin, albumin, gauze packing, or intravenous β-lactam antibiotics. HIV-1/2
antibody/antigen testing was nonreactive. However, a CD4+ T lymphocyte count was low
at 291 cells/μl (reference value, 441–2,156 cells/μl), as was the CD4+/CD8+ ratio
(1.18; reference value, 1.20–5.30). She was treated with trimethoprim-sulfamethoxazole
and successfully extubated on hospital day 7. A follow-up serum (1,3)-β-d-glucan level
obtained 1 week after initiating treatment was significantly reduced (90 pg/ml). Moreover,
a follow-up CD4+ T lymphocyte count obtained 10 days after initial presentation demonstrated
improvement (730 cells/μl).
CD4+ T lymphocytes play a critical role in the immune response against P. jirovecii.
Classically, when patients with untreated HIV develop severe CD4+ lymphocytopenia
(<200 cells/μl), the risk of Pneumocystis pneumonia increases significantly (2). In
the present case, we hypothesize that SARS-CoV-2 infection led to a state of functional
immune suppression related to CD4+ lymphocytopenia, which then predisposed the patient
to P. jirovecii infection. Although the patient’s CD4+ T-cell count was >200 cells/μl,
the sample was collected nearly a week into her course after her total lymphocyte
count had started to recover. It is also possible that an underlying immune defect
predisposed the patient independently to SARS-CoV-2 and P. jirovecii infection; however,
the patient did not have a known underlying immunodeficiency, nor did she have any
classical risk factors for Pneumocystis pneumonia, such as malignancy, organ transplantation,
or prolonged exposure to systemic corticosteroids. Although patients with inflammatory
bowel disease on systemic corticosteroids, biologics, and other immunosuppressants
may be at increased risk of Pneumocystis pneumonia (3), the overall incidence in ulcerative
colitis is low (approximately 8/100,000 person-years) (4) and has not been associated
with oral budesonide use (5). Given the high sensitivity of P. jirovecii PCR (6),
Pneumocystis colonization cannot be completely excluded. However, taken together,
the highly positive PCR test, significant elevation in (1,3)-β-d-glucan, cystic lesions
on chest imaging, progressive hypoxemia in the setting of CD4+ lymphocytopenia, and
response to trimethoprim-sulfamethoxazole therapy are highly supportive of a diagnosis
of Pneumocystis pneumonia.
Respiratory viral infections, particularly influenza, predispose patients to the development
of secondary bacterial infections (7) and invasive fungal infections, including aspergillosis,
most notably in immunocompromised patients (8). Although no cases of Pneumocystis
pneumonia have been reported in patients infected with SARS-CoV-1 or Middle East respiratory
syndrome coronavirus, coinfection with P. jirovecii has been reported in HIV and hematopoietic
stem cell transplant patients with influenza A infection (9, 10). Furthermore, two
cases of Pneumocystis pneumonia and H1N1 influenza A coinfection have been reported
in immunocompetent patients, possibly secondary to influenza-induced CD4+ lymphocytopenia
(11).
There is emerging evidence that patients with SARS-CoV-2 are at high risk for coinfection
(12), and this case highlights the importance of being vigilant about excluding treatable
respiratory pathogens, including P. jirovecii. Because COVID-19 and Pneumocystis pneumonia
may share common clinical features (e.g., bilateral multifocal infiltrates and profound
hypoxemia), coinfection with P. jirovecii may not be appreciated in patients with
severe SARS-CoV-2 infection. It may therefore be reasonable to consider additional
diagnostic testing for P. jirovecii in patients with SARS-CoV-2 infection, particularly
when there are other clinical characteristics that may support coinfection (e.g.,
elevated lactate dehydrogenase, cystic findings on chest computed tomography), even
in the absence of classical P. jirovecii risk factors. Finally, this case extends
the potential utility of (1,3)-β-d-glucan testing for diagnosing Pneumocystis pneumonia
(13) in patients with suspected SARS-CoV-2 infection, which is particularly relevant
given concerns about healthcare transmission associated with performing bronchoscopy
in these patients.