Disseminated Nocardiosis in Idiopathic CD4 Lymphocytopenia: A Rare Case and Literature Review

Abstract

Nocardiosis typically affects immunocompromised patients; however, the clinical characteristics of idiopathic CD4 lymphocytopenia (ICL) remain poorly understood. A 64-year-old patient was diagnosed with ICL following disseminated nocardiosis, including bacteremia, pneumonia, knee arthritis, and brain abscess. The patient underwent trimethoprim-sulfamethoxazole therapy with frequent dose adjustments based on the renal function, ranging from 2 to 12 single-strength tablets daily over 5 months of hospitalization. While he had a 1-year uneventful course of lifelong prophylaxis, he experienced prolonged recovery in physical activity. A literature review highlighted the life-threatening nature of nocardiosis in ICL, underscoring the importance of a timely diagnosis and tailored management strategies.

Introduction

Nocardia are aerobic, Gram-positive bacteria of the order Mycobacteriales, commonly found in soil, water, and decaying organic matter. Nocardiosis is generally considered an opportunistic infection that primarily affects patients with impaired cell-mediated immunity, particularly those receiving immunosuppressive therapy or those with acquired immunodeficiency syndrome (AIDS). Because antimicrobial susceptibility patterns vary depending on the species, identifying the Nocardia genus is essential for selecting appropriate antibiotics. The detection of Nocardia is challenging, largely because of the difficulty in isolating and culturing the organism, especially when relying solely on conventional microbiological methods. Consequently, contemporary techniques such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 16S ribosomal RNA gene sequencing have been used to accurately identify the Nocardia genus (1).

Idiopathic CD4 lymphocytopenia (ICL), a rare cause of cell-mediated immunodeficiency, was first defined by the Centers for Disease Control and Prevention (CDC) in 1992 (2). It is characterized by persistent CD4-positive lymphocyte counts of ≤300 cells/μL without identifiable causes such as human immunodeficiency virus (HIV) infection (3). Owing to its rarity, systematic clinical studies on ICL are limited, leaving many aspects of its epidemiology, including its prevalence, unclear.

Opportunistic infections, such as cryptococcal and mycobacterial infections, are more common in ICL, whereas nocardiosis is extremely rare (4). Although a few reports have shown that nocardiosis occurs in patients with ICL (5-12), it remains unclear whether the clinical course of nocardiosis in ICL differs from that in other immunocompromised patients.

We herein report a Japanese patient with disseminated nocardiosis who had newly diagnosed ICL with bacteremia, pneumonia, septic knee arthritis, and brain abscess.

Case Report

A 64-year-old Japanese man with no medical history of diabetes mellitus (DM), corticosteroid use, or autoimmune disease was referred to our hospital for disseminated nocardiosis. Five months earlier, he had developed generalized fatigue and a persistent cough. These symptoms did not resolve after one month, prompting a visit to another hospital. Chest computed tomography (CT) revealed multiple bilateral cavitary lung nodules, although bronchoscopy revealed no evidence of malignancy or mycobacterial infection. The patient experienced a prolonged fever of unknown origin. Three months before admission, he was brought to the emergency department of a second hospital with a persistent fever, cough, and loss of consciousness. He was then diagnosed with septic shock and admitted to the intensive-care unit.

Nocardia sp. were isolated from multiple specimens, including blood, sputum, urine, and bilateral knee joint fluids. A cerebrospinal fluid (CSF) analysis showed elevated white blood cell counts (2,782 /μL, 97% neutrophils, 3% lymphocytes), high protein levels (137 mg/dL), and low glucose concentration (16 mg/dL, blood glucose 141 mg/dL), with an opening pressure of 130 mmHg, suggesting meningitis, although the CSF culture did not yield any organisms. The patient was diagnosed with disseminated nocardiosis with bacteremia, pneumonia, septic knee arthritis, and meningitis.

Initial antimicrobial therapy with trimethoprim-sulfamethoxazole, amikacin, and meropenem improved the patient's condition. A switch to monotherapy with trimethoprim-sulfamethoxazole was made based on antimicrobial susceptibility testing (Table 1); however, this had to be discontinued after a total treatment period of 8 weeks because of progressive renal impairment to an estimated glomerular filtration rate (eGFR) of 24.6 mL/min/1.73 m². Two weeks later, the fever and altered consciousness returned, and a brain abscess was identified on magnetic resonance imaging (MRI). Trimethoprim-sulfamethoxazole and amikacin were resumed, which led to clinical improvement. The patient was transferred to our hospital three months after the initial admission for a further evaluation and treatment.

Table 1.

Minimum Inhibitory Concentrations of Nocardia Species in the Current Case.

Antimicrobial agents	MIC (μg/mL)a	Interpretationb
Amoxicillin-clavulanate	>16	R
Ceftriaxone	>32	R
Imipenem	>8	R
Amikacin	≤8	S
Levofloxacin	2	I
Trimethoprim-sulfamethoxazole	≤2/38	S
Linezolid	≤8	S
Minocycline	8	R

I: intermediate, MIC: minimum inhibitory concentrations, R: resistant, S: susceptible

^aMICs were determined using the broth microdilution method according to CLSI document M24-A2.

^bInterpretative criteria were based on CLSI document M24S 2nd Edition.

On admission, the patient was lethargic and disoriented, with a Glasgow Coma Scale score of 14 (E4V4M6). A physical examination revealed no remarkable findings, except for a crusted herpes zoster rash on the left buttock. He was afebrile, and his vital signs were normal. Lung, cardiovascular, and abdominal examinations yielded no remarkable findings. A neurological examination revealed no cranial nerve dysfunction or motor paralysis of the extremities. A crusted herpes zoster rash of unknown onset was observed on the left buttock. His white blood cell count was 4,130 /μL, absolute lymphocyte count was 124 /μL, and creatinine was 2.22 mg/dL (reference range: 0.65-1.07) with an eGFR of 24.6 mL/min/1.73 m². His fasting plasma glucose and hemoglobin A1c levels were 89 mg/dL (reference range: 70-120 mg/dL) and 4.6% (reference range: 4.6-6.2%), respectively.

The patient had no family history of an immunodeficiency syndrome. He had worked as a foundry worker until three years prior, after which he took a job in a nursing home. He denied any exposure to the soil or dirty water. Although the patient did not have a history of opportunistic infections, we scrutinized his immunological background because disseminated nocardiosis is atypical for immunocompetent adults. Tests for HIV and human T-cell leukemia virus type 1 (HTLV-1) antibodies were negative, and serum levels of immunoglobulins (Igs), including IgG, IgM, and IgA, were within normal limits. The results of whole-body CT, brain MRI (without contrast agent owing to renal dysfunction), and esophagogastroduodenoscopy did not reveal any signs of malignancy. However, they identified a pre-existing brain abscess (Fig. 1A) and shrunken lung nodules (Fig. 1B). No evidence of autoimmune diseases was reported. His CD4 lymphocyte count was initially 79 cells/μL (reference range: 700-1,300 cells/μL), which later increased to 119 cells/μL after 6 weeks. The diagnosis of ICL was made in accordance with the CDC's definition of “an absolute CD4 lymphocyte count of ≤300 cells/μL on more than 1 cell count at least 6 weeks apart; no evidence of infection with HIV or HTLV; and a lack of a defined immunodeficiency disease or therapy that are associated with depressed levels of CD4 lymphocyte” (3). After the diagnosis, a re-examination was conducted for the presence of other opportunistic infections, particularly those associated with cell-mediated immunodeficiency, including progressive multifocal leukoencephalopathy, Kaposi's sarcoma, and mycosis; however, these were not identified.

Figure 1.

A: Brain magnetic resonance imaging at the time of referral. Diffusion-weighted imaging revealing a hyperintense mass in the left temporal lobe (arrow), indicative of an abscess. The lesion was solitary and exhibited no changes in size compared with the previous hospital examination. B: Plain chest computed tomography image. Multiple shrunken nodules are visible in both lungs (arrows), suggesting resolution of Nocardia pulmonary involvement with antimicrobial therapy. No other abnormal findings such as lung lesions or lymphadenopathy were identified.

Molecular species identification of Nocardia sp. isolated from this patient was performed using 16S ribosomal RNA sequencing and whole-genome sequencing, which suggested that this isolate was a potentially novel species closely related to Nocardia concava (13).

Antimicrobial therapy with amikacin was discontinued after the patient was transferred to our hospital for renal dysfunction. The administration of trimethoprim-sulfamethoxazole was continued at a dose of two to six single-strength tablets per day with periodic adjustments based on renal function, as shown in Fig. 2. As the patient had ICL, lifelong administration of trimethoprim-sulfamethoxazole was planned. Although his condition gradually improved, he was unable to navigate stairs. On hospital day 80, the patient was transferred to a rehabilitation facility because of a decline in his activities of daily living. He spent four months there and an additional six months in a nursing home for further rehabilitation before eventually returning home with no signs of recurrence.

Figure 2.

Clinical course of the patient. On admission to the previous hospital, meropenem and vancomycin were initiated based on the suspicion of bacterial meningitis. However, blood culture revealed Nocardia species, and the antibacterial agents were subsequently switched to trimethoprim-sulfamethoxazole, amikacin, and meropenem. Thereafter, the patient’s renal function progressively declined, necessitating the discontinuation of trimethoprim-sulfamethoxazole. The patient was subsequently readmitted to the same hospital due to loss of consciousness, and antimicrobial therapy was resumed following the diagnosis of a brain abscess. Following transfer to our hospital, the patient was treated with trimethoprim-sulfamethoxazole and dose adjustments were performed based on the renal function. CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, ICU: intensive-care unit, MRI: magnetic resonance imaging, TMP-SMX: trimethoprim-sulfamethoxazole, #1: 300 mg q24h, #2: 400 mg q24h, #3: 200 mg q24h, #4: 200 mg q48h

Discussion

This study highlighted the importance of evaluating the immunological status of patients with disseminated nocardiosis. We herein report a Japanese patient with ICL who developed disseminated nocardiosis caused by a new Nocardia species closely related to Nocardia concava.

This report underscores the importance of confirming the immunological background when managing patients with disseminated nocardiosis. Nocardiosis is an opportunistic infection that occurs mainly in individuals with cell-mediated immune deficiency and is unusual for immunocompetent individuals to develop disseminated infections. A comprehensive analysis of the clinical manifestations of nocardiosis in patients with varied immunological profiles revealed that disseminated infection and septic shock are notably more prevalent in immunocompromised individuals than nonimmunocompromised individuals (14). Furthermore, a systematic review of 138 patients with Nocardia bacteremia showed that 81% were immunocompromised, especially those with corticosteroid use and hematological malignancy, and 29% had endovascular devices (15). According to another study, DM, corticosteroid therapy, chronic granulomatous disease, and collagen vascular diseases were reported as underlying causes of nocardiosis (16). Therefore, confirming the patient's immunological background is crucial for the diagnosis of disseminated nocardiosis. In most reports, the importance of identifying the background conditions in patients with disseminated nocardiosis is evident. However, our report highlights that adults without a history of immunodeficiency in childhood may remain immunodeficient following the diagnosis of disseminated nocardiosis. In this situation, ICL should be considered after appropriate exclusion of immunocompromised conditions, such as HIV and HTLV-1 infection. Patients with ICL are at high risk of opportunistic infections and malignancies, and an early diagnosis of ICL can aid in the early detection of other opportunistic infections and malignancies in the future (17).

Nocardiosis in patients with ICL is generally diagnosed based on the identification of the organism in samples obtained from the infected organs. However, Nocardia detection is hindered by technical challenges, including prolonged incubation periods and adjustments in culture media due to its slow growth (18). Consequently, the diagnosis commonly depends on advanced techniques, such as MALDI-TOF MS and 16S ribosomal RNA gene sequencing. These methods facilitate differentiation from other opportunistic infections, such as cryptococcosis and mycobacterial diseases.

In the present study, we conducted a literature search for cases of Nocardia infection with ICL in the PubMed database using “(Nocardia) OR (nocardiosis) AND (idiopathic CD4 lymphocytopenia)” as keywords in October 2024. We observed only 8 patients (5-12), making our patient the ninth report worldwide (Table 2). Most (87.5%) were men, and their CD4-positive lymphocyte counts ranged from 4 to 234 cells/μL. Of the total, six had pneumonia, and five had central nervous system (CNS) infections. Nocardia frequently infects the lungs and CNS, and all patients in our review were infected with either pathogen. Furthermore, although Nocardia bacteremia is extremely rare (19), our literature review revealed that bacteremia was present in two of the eight patients, including our patient. This review exclusively reviewed documented arthritis in this patient. Notably, this patient is the second reported case in which disseminated infection was identified in more than three organs. The patient's initial symptoms included respiratory symptoms and pulmonary nodule shadows, indicating potential pulmonary Nocardia infection. The subsequent delay in nocardiosis diagnosis may have facilitated the development of disseminated hematogenous CNS and joint lesions. Regarding the identification of Nocardia species, molecular biological techniques such as a 16S ribosomal RNA analysis were applied in four of the reported cases, including our patient. Owing to the recent proliferation of advanced technologies, timely and accurate identification has become increasingly feasible.

Table 2.

Literature and Characteristics of Nocardiosis in Patients with Idiopathic CD4 Lymphocytopenia.

No.	Ref.	Year	Country	Age/ Sex	Initial CD4 cells (/μL)	Nocardia species	Identification methods	Sites of infection	OIs or comorbidities	PMH	Antibiotics	Treatment duration/Outcome
1	(5)	1997	USA	54/M	208	Nocardia asteroides	NA	Left mastoiditis, meningitis, pansinusitis, pneumonia	CMV esophagitis, esophageal and pulmonary candidiasis, herpes esophagitis, PCP	Behçet’s-like syndrome	NA	NA/Death
2	(6)	2011	Turkey	19/M	230	Nocardia farcinica	NA	Brain abscess	EV-like skin eruption (HPV-16+), pulmonary TB	Purulent meningitis	Amoxicillin-clavulanic acid and ciprofloxacin	20 months/Death
3	(7)	2014	France	49/M	4	Nocardia brasiliensis	NA	Pneumopathy	Cryptococcal meningitis, M. avium lymph node infection, PML, relapsing cutaneous alternariosis	AIHA, cirrhosis, ITP, MDS	NA	NA/Improved
4	(8)	2017	USA	46/M	87	Nocardia abscessus	NA	Pneumonia	-	-	Imipenem and TMP/SMX	6 months/Improved
5	(9)	2018	Japan	66/M	129	Nocardia otitidiscaviarum	MALDI-TOF MS, 16S rRNA sequencing,	Bacteremia, meningitis	DLBCL, pneumococcal pneumonia	-	Linezolid and TMP/SMX	NA/Improved
6	(10)	2020	France	3/M	NA	Nocardia farcinica	16S rRNA and/or hsp65 sequencing	Brain abscess	-	-	NA	384 days/Improved
7	(11)	2021	India	NA/NA	212	NA	Phenotypic, metabolic, biochemical, and growth tests conducted at different temperatures	Pneumonia	NA	NA	NA	NA/Improved
8	(12)	2024	India	46/F	164	Nocardia otitidiscaviarum	Metagenomic next-generation sequencing	Pneumonia	Invasive pulmonary aspergillosis	-	Initial: TMP/SMX Recurrence: amikacin and TMP/SMX	Initial: 6 months Recurrence: NA/Improved (life-long secondary prophylaxis)
9	Present patient	2024	Japan	50/M	31	Potential new Nocardia species	16S rRNA and whole-genome sequencing	Bacteremia, bilateral knee arthritis, brain abscess, meningitis, pneumonia	Zoster	-	Initial: amikacin, meropenem and TMP/SMX Maintenance: TMP/SMX	17 months (ongoing)/Improved

16S rRNA: 16S ribosomal RNA, AIHA: autoimmune hemolytic anemia, CMV: cytomegalovirus, DLBCL: diffuse large B cell lymphoma, EV: epidermodysplasia verruciformis, HPV: human papillomavirus, ITP: immune thrombocytopenia, MALDI-TOF MS: matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, M. avium: Mycobacterium avium, MDS: myelodysplastic syndromes, NA: not available, OI: opportunistic infection, PCP: pneumocystis pneumonia, PMH: past medical history, PML: progressive multifocal leukoencephalopathy, TB: tuberculosis, TMP/SMX: trimethoprim-sulfamethoxazole, USA: United States of America

Trimethoprim-sulfamethoxazole was selected as the therapeutic agent in all patients in whom antimicrobials were mentioned, except for patient no. 2, who was characterized by resistance to trimethoprim-sulfamethoxazole. All patients underwent long-term treatment for six months or longer. Furthermore, the management of our patient involved aggressive antimicrobial therapy and careful monitoring of the renal function. In our review, no other cases involved the adjustment of antimicrobial doses according to individual conditions, such as the renal function. However, our patient's renal function exhibited significant variability throughout the acute and chronic disease phases, necessitating frequent adjustments in the dose of trimethoprim-sulfamethoxazole. The adoption of therapeutic strategies tailored to patient-specific factors is crucial for improving outcomes in complex cases.

Although the risk of death in patients with ICL was similar to that in age- and sex-adjusted general populations (17), two of the nine patients who developed Nocardia infection from the review of patients with ICL died. Patients with ICL complicated by nocardiosis are at risk of mortality, and even if they survive, they may require long-term care. Therefore, nocardiosis is a rare but significant opportunistic infection associated with morbidity and mortality in ICL patients. In addition, it is interesting to note that in at least five of seven patients, including our patient, the diagnosis of ICL was made following Nocardia infection (5,6,8,12). This result revealed that nocardiosis can lead to the diagnosis of ICL. This fact may support the suggestion that patients who develop nocardiosis with undiagnosed immunodeficiency should be suspected of having an ICL.

The long-term quality of life of ICL patients is an important consideration in their management. Several factors can significantly affect it, including lifelong prophylactic treatments, recurrent infections, and the frequency of clinical follow-up appointments. Social and emotional challenges such as feelings of isolation and anxiety are addressed through multidisciplinary care.

The decision to administer secondary prevention of nocardiosis in patients with ICL poses a significant challenge. Our literature review included a patient with pulmonary nocardiosis that recurred four years later in a patient with ICL who had not received secondary prophylaxis (12). This finding indicates that long-term secondary prevention of nocardiosis is particularly significant in the management of patients with ICL, in contrast to diseases such as AIDS, for which treatment is expected to restore the immune function. Although there is little established evidence, in a cohort of 91 patients with ICL, 55% received prophylaxis for opportunistic infection (17). Given that nocardiosis has been associated with mortality and morbidity and no effective treatment to restore immunity has been established in patients with ICL, it seems reasonable to provide trimethoprim-sulfamethoxazole for secondary prevention. However, the potential risks of lifelong prophylaxis must be considered. The long-term administration of antimicrobial agents necessitates regular monitoring to identify and address potential adverse events, including renal toxicity and allergic reactions. Few reports exist on alternative agents for secondary prophylaxis in patients for whom trimethoprim-sulfamethoxazole is contraindicated, and further research is warranted.

In addition, herpes zoster was observed in the present patient, which is consistent with findings that varicella-zoster virus is the most common viral infection among patients with ICL (4). The occurrence of herpes zoster indicates immune dysfunction, as reactivation of the virus is common in individuals with impaired cell-mediated immunity, such as those with ICL. Prevention strategies and vaccination recommendations based on CD4 counts, as outlined in HIV/AIDS guidelines, are also relevant for patients with ICL (20). Furthermore, the recombinant zoster vaccine has recently become available and is expected to demonstrate a high level of preventive potential in patients with ICL. Given the risk of herpes zoster, secondary prevention should be discussed in this patient in the future.

In conclusion, this report underscores the importance of an accurate and timely diagnosis in the management of rare opportunistic infections, particularly in patients with ICL. Advanced diagnostic techniques, including the identification of molecular species through 16S ribosomal RNA and whole-genome sequencing, play a pivotal role in identifying novel or rare pathogens and thus in guiding appropriate treatment strategies. Tailored therapeutic approaches, such as individualized dose adjustments based on patient-specific factors, are also essential for improving the outcomes in such complex cases. Further research is required to elucidate the pathophysiology of ICL, optimize diagnostic methodologies, and establish evidence-based management protocols for associated opportunistic infections.

The authors state that they have no Conflict of Interest (COI).