Haemophilus Influenzae Lymphadenopathy in a Patient With Agammaglobulinemia: Clinical-Histologic-Microbiologic Correlation and Review of the Literature

Agammaglobulinemia is the most common primary immunodeficiency, with an incidence of approximately 1 in 250000 males in the United States. These patients are at risk for frequent recurrent infections, which may become fatal if untreated. Patients have increased susceptibility to encapsulated pyogenic bacteria. Haemophilus influenzae is second only to Streptococcus pneumoniae as the bacteria most frequently implicated in infections in these patients. We present a case involving an adolescent boy with X- linked agammaglobulinemia and H influenzae cervical adenopathy, confirmed twice by culture. We correlate the clinical, microbiologic, and histologic findings. Owing to the severity of infections in this population, surgical intervention is more common than in the immunocompetent population. This description may help the pathologist in considering a differential diagnosis when examining a diagnostic lymph node biopsy in these patients.

(Arch Pathol Lab Med. 2005;129:100-103)

Haemophilus influenzae is a common pathogen that rarely warrants surgical biopsy. Within the population of patients with X-linked agammaglobulinemia (XLA), however, lymphadenopathy frequently warrants more aggressive diagnosis and management, owing to the potential severity of even common pathogens. X-Linked agammaglobulinemia, the most common agammaglobulinemia, is a disorder of B-cell maturation caused by a defect in a cytoplasmic tyrosine kinase on the X chromosome (known as Bruton tyrosine kinase, in honor of Bruton, who described the clinical presentation in 1952). Patients with XLA exhibit panhypogammaglobulinemia as a direct result of the lack of B-cell maturation. Evidence shows that although some mature B cells penetrate into the periphery, immune function remains inadequate.12 Patients present with recurrent respiratory tract infections, central nervous system infections, and septic arthritis due to encapsulated organisms and certain viruses that require circulating antibodies to generate an immune response. Common pathogens include H influenzas. Streptococcus pncumoniae, Staphylococcus aureus, Pseudomonas species, and enteroviruses. If left untreated, these infections can be fatal for patients with XLA.3 Clinically, the important relationship of XLA and H influenzae infection is well documented; however, to our knowledge no morphologic description of the affected lymph nodes exists. We present what we believe to be the first morphologic, microbiologic, and clinical correlation of XLA and H influenzae cervical lymphadenitis in an adolescent boy.

REPORT OF CASE

A 17-year-old boy with a history of XLA was seen at an outside hospital for evaluation of a progressively enlarging left neck mass. The patient’s medical history was notable for multiple unusual infections, including balanitis, chlamydial conjunctivitis, multiple episodes of pneumonia, and upper respiratory tract infections. A painless superficial pustule was present on the overlying skin in continuity with the underlying mass. The pustule was lanced and cultured and subsequently grew Haemophihis species. The patient was placed on clarithromycin, but his neck wound continued to enlarge and drain. He was then seen in consult by a general surgeon, who placed him on amoxicillin/clavulanate.

The mass remained unresponsive to antibiotic therapy, and the patient presented to otolaryngology at our institution. On physical examination, a 2-cm, nontender, exophytic, granular-appearing mass was seen in the left submandibular triangle. No purulent matter could be expressed. The patient’s mass was not associated with trauma, fever, chills, sweats, insect bite, or foreign body insertion. A computed tomographic scan confirmed a 3-cm soft tissue mass in level 2 of the left neck extending to the skin, accompanied by regional lymphadenopathy.

The patient was continued on amoxicillin/clavulanate. He subsequently underwent an uncomplicated excision of the left submandibular gland along with the adjacent soft tissue mass, regional lymph nodes, and overlying skin. A small amount of residual lymphadenopathy into level 3 of the neck was apparent at the time of surgery. At his 5-day postoperative visit, he was reexamined and found to have a well-healing left neck incision. The plan was made to continue routine local care, and he was referred to the infectious disease service for immunoglobulin transfusion therapy. The patient unfortunately did not attend his scheduled postoperative consultations.

Ten weeks later, the patient presented again with a new mass in the left upper neck. On examination, the surgical site was well healed; however, a new mass in the same area was apparent. The new mass was located just posterior to his left submandibular triangle in level 2b of the neck. He has again been referred to the infectious disease service, where a discussion about immunotherapy will be held with his parents.

Figure 1. The lymph nodes are embedded in sclerotic stroma. The peripheries of the nodes are obliterated by the sclerotic stroma (hematoxylin-eosin, original magnification 200).

Figure 2. The lymphoid-rich inflammatory infiltrate extends to the overlying epidermis (hematoxylin-eosin, original magnification 100

Figure 3. The dermal infiltrate consists of lymphocytes, histiocytes, and occasional neutrophils (hematoxylin-eosin, original magnification 400).

Figure 4. The lymph nodes contain clusters of epithelioid microgranulomata (hematoxylin-eosin, original magnification 200).

PATHOLOGIC FINDINGS

Grossly, the specimen consisted of a submandibular gland with surrounding soft tissue containing multiple enlarged lymph nodes and overlying skin, measuring 8 cm in aggregate measure. The lymph nodes were immobile within dense fibrous tissue, which was continuous with the dermis and formed a mass lesion. The salivary gland was adherent but not involved.

Microscopically, the tissue consisted of enlarged lymph nodes embedded in a dense collagenous stroma with scattered lymphocytes and occasional neutrophils. The periphery of some of the lymph nodes was obliterated by the sclerotic stroma (Figure 1). A dense lymphoid infiltrate extended to the overlying dermis and was mixed with neutrophils and occasional histiocytes (Figures 2 and 3). The surface of the skin was intact. Within the nodes, follicular hyperplasia was not prominent. The most striking finding was epithelioid microgranulomata with occasional multinucleated giant cells present throughout the nodes both within and in between follicles (Figure 4). No organisms were demonstrated on paraffin- embedded tissues subjected to special stains (periodic acid-Schiff, Gomori methenamine silver, acid-fast bacilli, Fite, and Giemsa). No necrosis was present.

Tissue was sent from the surgical bench to microbiology for fungal, mycobacterial, and bacterial cultures, and for flow cytometry. The bacterial culture grew H influenzae on chocolate agar, following inoculation in saline/MuellerHinton broth (to a 0.5 McFarland standard) and incubation at 35C with 5% carbon dioxide for 24 hours. No other organisms were identified by culture. Flow cytometry showed no evidence of a lymphoproliferative disorder.

COMMENT

The diagnosis of H influenzac lymphadenopathy is common in the setting of agammaglobulinemia, as these patients are prone to infections by encapsulated organisms. The Haemophilus species of bacteria are gram-negative, facultative anaerobic coccobacilli that normally reside in the upper respiratory tract of humans and other animals. The genus was first isolated in 1892 by Robert Pfeiffer with a strain of H influmzae. The bacillus was named for notably growing on blood agar media. The capsule in the type b organism contains polyribosylribitol phosphate, an antiphagocytic polysaccharide that is responsible for the bacteria’s virulence.4,5

Attempts at correlation of lymph node morphology and benign etiology appear throughout the literature. General groupings of these morphologies have resulted in the classification seen in the Table.6 The morphologic repertoire of a reactive lymph node is limited, and direct etiologic correlation is not definitive. It is useful, however, for the pathologist to give informed differential diagnoses when confronted with diagnostic lymph node biopsies. The lymph node sections in this case showed a distinct pattern of epithelioid microgranulomata and inflammation that were reminiscent of toxoplasmic lymphadenitis. However, follicular hyperplasia was not as prominent, and the dense sclerosis and extension to the dermis was also unusual. Twice the culture yielded H influenzas, which fit well with the patient’s history of XLA. This morphologic pattern would be best placed in the “Others” category of the Table.

A review of benign lymphadenopathies in children and adolescents by Segal et al6 found that diagnostic lymph node biopsies were performed only for chronic unexplained lymphadenopathy, lymphadenopathy unresponsive to antibiotics, massive or generalized lymphadenopathy, or worrisome clinical or laboratory findings. The most frequent cause of infectious lymphadenopathy was bacteria, specifically Staphylococcus species and Streptococcus species. These cases appeared morphologically as acute lymphadenitis with a prominent n\eutrophilic infiltrate. No patients with H influenzae lymphadenopathy or with a clinical history of agammaglobulinemia were included.

General Morphologic Correlates of Specific Disease Entities Causing Benign Lymphadenopathy (LA) in Children and Adolescents*

In a study by Freidig et al,7 the results of morphologiemicrobiologic correlation of 419 lymph node biopsies in all ages during a 5-year period were reviewed. No immunocompromised patients were included, and H influenzae was not found to be causative in these cases. Of the cases in the study by Freidig et al, 15.9% were diagnosed as infectious, with fungi and mycobacteria being the 2 most common causative agents. Bacteria were the third most common cause, with S anreiis as the most common isolate.

Cervical lymphadenitis caused by H influenzae, as well as by other Haemophilus species, has been reported.8-10 However, there is a relative paucity of pathologic and microbiologic descriptions of the affected cervical lymph nodes. While the etiologic agent for the adenopathy has been suspected to be H influenzae, no surgical biopsies were performed or described in these cases.

In his study of 72 pediatric patients presenting with epiglottitis from 1958 to 1975, Molteni9 found that 25% had associated cervical lymphadenitis. The patients’ immune status was not noted. Almost half of his cohort had H influenzae cultured from the blood, and that percentage increased to 70% when only his later cases were examined. He noted that no prior study had demonstrated the bacteria in cervical lymph nodes and admitted that he could not confirm the association, although the evidence of abscesses, ulcerations, and deep epiglottic cultures positive for H influenzae certainly supported the conclusion that local cervical adenitis was caused by the same organism.

One year later, Fishaut and Mokrohisky8 reported the first case of cervical adenitis caused by H influenzae, confirming prior speculation. They cultured H influenzae type b from a saline injection and needle aspirate of an enlarged tender cervical lymph node in a 4-year-old boy with a 5-day history of pharyngitis. Since the diagnosis was made on an aspirate, no pathologic description was able to be obtained. As far as we know, no further reports of H influenzae cervical adenitis have appeared in the literature, nor has anyone described H influenzae cervical adenitis occurring in a patient with XLA.

We present what we believe to be the first histopathologic description of H influenzae cervical adenitis in a patient with XLA. Although H influenzae infections are common in this disease state, to our knowledge no author has discussed the pathologic findings to date. In this case, the patient’s XLA predisposed him to H influenzae infection. Because the boy presented for treatment of a draining neck infection, management included excision of the involved mass and adjacent enlarged lymph nodes, providing the pathologist with the surgical specimen. Although the correlation of lymph node morphology with infectious etiology is not definitive, the grouping of common morphologies may help the pathologist give an informed differential diagnosis when confronted with a diagnostic lymph node biopsy.

References

1. Rich RR, Fleisher TA, Shearer WT, et al. Clinical Immunology: Principles and Practice. 2nd ed. London, England: Mosby; 2001.

2. Ochs HD, Smith CI. X-linked agammaglobulinemia: a clinical and molecular analysis. Medicine. 1996;75:287-299.

3. McClatchey KD. Clinical Laboratory Medicine. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002.

4. Hoeprich PD, Jordan MC, Ronald AR. Infectious Diseases: A Treatise of Infectious Processes. 5th ed. Philadelphia, Pa: J B Lippincott Co; 1994.

5. Schlossberg D. Current Therapy of Infectious Disease. 2nd ed. St Louis, Mo: Mosby Inc; 2001.

6. Segal CH, Perkins SL, Kjeldsberg CR. Benign lymphadenopathies in children and adolescents. Semin Diagn Pathol. 1995; 12:288-302.

7. Freidig EE, McClure SP, Wilson WR, Banks PM, Washington JA II. Clinicalhistologic-microbiologic analysis of 419 lymph node biopsy specimens. Rev Infect Dis. 1986:8:322-328.

8. Fishaut JM, Mokrohisky ST. Cervical lymphadenitis caused by Haemophilus influenzae type b. Am J Dis Child. 1977:131:925-926.

9. Molteni RA. Epiglottitis: incidence of extraepiglottic infection: report of 72 cases and review of the literature. Pediatrics. 1976:58:526-531.

10. White DR, Mukherji SK, Mangum ME, et al. Recurrent cervical lymphadenitis caused by Haemophilus aphrophilus. Clin Infect Dis. 2000;30:627629.

Candice Black, DO; Matthew B. Zavod, MD; Benoit J. Gosselin, MD, FRCSC

Accepted for publication August 30, 2004.

From the Departments of Pathology (Dr Black) and OtolaryngologyHead and Neck Surgery (Drs Zavod and Gosselin), Dartmouth Hitchcock Medical Center, Lebanon, NH. Dr Zavod is currently finishing the final year of his residency at Fletcher Alien Health Care, University of Vermont, Burlington.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Candice Black, DO, Department of Pathology, Dartmouth Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756 (e-mail: Candice.C.Black@hitchcock.org).

Copyright College of American Pathologists Jan 2005