An Exophytic Mass on the Mandible of an Immunocompromised Man - ANSWER

Figure 1.

Figure 2.

Diagnosis: Coexistent Cryptococcus neoformans and Kaposi sarcoma in a patient with AIDS.

Histopathologic examination revealed multiple budding yeast forms surrounded by a clear halo (Figure 1A).Grocott-methaminesilver and mucicarmine (Figure 1B) stains highlighted these organisms and their capsules, respectively. A proliferation of atypical spindle cells arranged in fascicles, associated with slit-like vascular spaces and extravasated red blood cells, was also identified (Figure 1A). Immunohistochemistry for human herpesvirus 8 demonstrated positive nuclear staining within these spindled cells (Figure 2). These findings were diagnostic for cutaneous Cryptococcus infection in the context of Kaposi sarcoma (KS).

The patient was treated with amphotericin B and flucytosine followed by fluconazole for his cryptococcal infection; emtricitabine, tenofovir, and raltegravir were initiated as therapy for AIDS. Doxorubicin therapy was initiated for probable multifocal KS. The patient’s cutaneous lesions have improved on this regimen, with concomitant resolution of his lower extremity swelling and improvement in breath sounds. His human immunodeficiency virus (HIV) load is currently undetectable.

Cutaneous disorders are estimated to affect approximately 64% of patients with HIV, with an increasing prevalence at lower CD4 counts. These conditions include common infections and malignancies such as Staphylococcus aureus and squamous cell carcinoma, as well as a variety of inflammatory dermatoses that are often more severe than in immunocompetent patients. Of particular concern are those opportunistic infections and neoplasms that are classified as AIDS-defining illnesses, including cryptococcosis and KS. Often these conditions have a protean presentation and may simulate one another. Nevertheless, the coexistence of Cryptococcus and KS in a single clinical lesion is an uncommon occurrence. Colocalization of these infections may be the presenting sign of AIDS in patients with known HIV or those who had been previously undiagnosed; it has also been associated with paradoxical immune reconstitution inflammatory syndrome (IRIS) following initiation of highly active antiretroviral therapy (HAART). 

The latter association is particularly noteworthy as significant morbidity and mortality are associated with KS-IRIS, particularly among patients with visceral KS.

KS-IRIS may be more difficult to treat than other forms of IRIS and has important prognostic implications. Cutaneous biopsy with meticulous histologic evaluation is therefore suggested in all HIV-infected patients with new or unusual skin lesions, even in the context of previously treated or active skin disorders. This practice guards against misdiagnosis of alternative or coincident disease. Multiorgan evaluation for cutaneous and visceral KS may be especially prudent in those patients who have also recently initiated HAART.

Rarely, KS can present with other viral, mycobacterial, or opportunistic fungal infections in the same lesion. In addition to cryptococcosis, other coincident infections include cytomegalovirus, molluscum, Candida albicans, Mycobacterium tuberculosis, Histoplasma capsulatum, and Mycobacterium aviumintracellulare. An instance of KS coexistent with both Cryptococcus and Mycobacterium avium-intracellulare has also been reported. The etiology of this phenomenon is unknown, and may represent a chance occurrence. It has alsobeen hypothesized that the vascular lesions of KS represent an ideal environment for the growth and protection of bloodborne opportunistic infections. 

Conversely, cryptococcal infection may induce a local inflammatory milieu that is hospitable to the development of KS, a concept known as inflammatory oncotaxis. These suppositions remain speculative, however, and the pathophysiologic mechanisms underpinning this unusual occurrence remain to be formally elucidated.

Clinical Infectious Diseases 2014;58(4):540

DOI: 10.1093/cid/cit711

A 59-Year-Old Woman With Chronic Skin Lesions of the Leg - ANSWER

Diagnosis: Acrodermatitis chronica atrophicans. 

The patient’s photograph of her skin rash taken 3 years ago, which clearly showed that she had erythema chronicum migrans (ECM) at that time, immediately prompted the diagnosis of Lyme disease in the form of acrodermatitis chronica atrophicans (ACA). The histology of the skin biopsy was compatible with this diagnosis, which was confirmed with serology and polymerase chain reaction (PCR). An enzyme-linked immunosorbent assay showed strongly elevated serum antibodies (immunoglobulin G [IgG]) to Borrelia burgdorferi (LiaisonDiaSorin; detection of immunoglobulin against B. burgdorferi, Borrelia afzelii, and Borrelia garinii; IgG >240 UA/mL). Western blotting (Biognost, Borrelia Euroline-WB) detected bands positive against VlsE, p83, p39, p30, and p21 antigens [1]. PCR on the skin biopsy sample (primer sets targeting 23S rDNA; TaqMan) was also positive. The patient was treated for 4 weeks with 100 mg of doxycycline twice a day. Six months later, she had no more lesions. Lyme borreliosis is caused by tick-transmitted spirochetes of the B. burgdorferi sensu lato complex. Although B. burgdorferi sensu stricto is the only species known to cause human disease in North America, at least 5 species can cause the disease in Europe: B. afzelii, B. garinii, B. burgdorferi sensu stricto, Borrelia spielmanii, and Borrelia bavariensis. The clinical symptoms vary widely and depend on the species; some have been described only in Europe [2]. ACA appears to be due only to B. afzelii [3]. This dermatological entity is a rare tertiary manifestation of Lyme disease, manifesting as inflammatory and trophic lesions on acral skin. After an early inflammatory stage with bluish-red discoloration and doughy swelling of the skin, a late atrophic stage appears a few weeks or months later. The skin becomes thin, wrinkled, dry, and transparent because of the loss of epidermal and dermal structures. Vessels may be easily visible, and telangiectasias can be observed. The diagnosis is suggested by dermatologic lesions and a clinical history of tick bites or other well-defined manifestations of Lyme borreliosis, such as ECM, shown in our patient’s picture. Confirmation of the diagnosis is obtained by serological testing (enzyme immunoassay and Western blotting). These methods might increase diagnostic accuracy over that of PCR, which has a sensitivity of about 50%, depending on primer set [4]. Treatment of ACA is usually based on a course of antibiotic treatment with ceftriaxone [5] or doxycycline [6] for 21–28 days. Complete disappearance of lesions is normally described [7, 8]. The absence of treatment can lead to fibrotic nodules and/or patchy or bandlike indurations that may limit joint movement without treatment.

Clinical Infectious Diseases 2013;57(12):1782

DOI: 10.1093/cid/cit667

A 59-Year-Old Woman With Chronic Skin Lesions of the Leg - QUIZ

Figure 1. Progressive atrophic and erythematous skin lesions on the left leg.

Figure 3. Asymptomatic skin rash on the back of the patient’s left ankle in July 2008.

Figure 2. Erythema with mild atrophy of the left foot.

A 59-year-old woman, a retired school director with no particular medical history, sought consultation because of chronic skin lesions on her left leg (Figures 1 and 2), which had been present for several months. Erythematous and minor atrophic lesions of the skin were seen. No infiltration was noted, and no other local symptom mentioned. The patient did describe pain in several joints. The physical examination found no other abnormalities. The patient also mentioned a history of a skin rash 3 years earlier, on the left ankle, which had appeared after a walk in a forest in southern France. A photograph she had taken then showed a large erythematous ring, which subsequently spread to the entire leg (Figure 3). No macular lesion was seen, and no pain at the time was reported. Laboratory analysis revealed a white blood cell count of 4420 cells/µL. Her C-reactive protein level was 3 mg/L (reference, <5 mg/L), and her fibrinogen level was 3 g/L (reference range, 2–4 g/L). Her liver enzyme and total complement activity levels were normal. The test for rheumatoid factor test was negative, but that for antinuclear antibodies was positive (1:200), with no specificity. The skin biopsy of a nonatrophic area showed cutaneous lymphoplasmacytic infiltration of interstitial tissue. 

What is your diagnosis?

Clinical Infectious Diseases 2013;57(12):1751

DOI: 10.1093/cid/cit661

An Exophytic Mass on the Mandible of an Immunocompromised Man - QUIZ

Figure 1. An exophytic mass of the mandible. A firm, 7-cm exophytic

and violaceous nodule surrounded by multiple agminated, violaceous

papules was present on the right mandible.

Figure 2. Punch biopsy of the mandible. A, Hematoxylin-eosin stain

(×100 magnification). B, Mucicarmine stain (×400 magnification).

A man in his thirties presented with a slowly growing, painful, swollen mass overlying his right mandible. He was diagnosed with human immunodeficiency virus 10 months prior and had not undergone treatment. The mass initially appeared as a “small bruise” that had enlarged over the preceding 6 months. 

The cutaneous lesion was accompanied by a nonproductive cough, dyspnea, weight loss, and progressive bilateral swelling of the patient’s lower extremities. Clinical examination revealed a firm, well-circumscribed, 7-cm exophytic and violaceous nodule on the right mandible. Superolateral to this lesion were multiple agminated, firm, and violaceous papules (Figure 1).

The skin underlying and between these lesions was thickened, hyperpigmented, and tender to palpation. The patient also had a thin purple-gray plaque on his right inner buccal mucosa extending to the margin of the lower lip. Breath sounds were absent with dullness to percussion on the left side of his lungs. His lower extremities were notable for pitting edema to the knees, most prominent over the dorsa of his feet. A punch biopsy of a mandibular papule was performed and sent for histologic evaluation (Figure 2A and 2B).

What is your diagnosis?

Clinical Infectious Diseases 2014;58(4):540

DOI: 10.1093/cid/cit711

A ManWith Unilateral Ocular Pain and Blindness - ANSWER

Figure 1. The molting larva of an Armillifer species. Note the 2 pairs of

chitinous claws (arrows) around the mouth (×10 magnification).

Diagnosis: Ocular pentastomiasis.

The parasite was identified as the larval form of an Armillifer species (Figure 1), a pentastomid. Brownish pigment in the gut is from consumed hemoglobin. It is clearly recognizable that the larva is in the middle of molting ( parts of the molted “skin” have been torn off during handling of the animal). Also well visible is the mouth of the larva, surrounded by the 2 pairs of claws on each side of the mouth (arrows) used for attachment.

In the first descriptions, these were also thought to function as separate mouths, hence the term Pentastomida, meaning “5 mouths.” The exact phylogenic position of these ancient parasites has long been debated until recent genetic evidences showed unequivocally that pentastomids are crustaceans.

The adult forms of Armillifer species live in the respiratory tract and paranasal sinuses of tropical reptiles. Human cases are almost exclusively caused by Armillifer armillatus. Of note, Linguatula serrata is a related pentastomid species that lives in the nasopharynx of temperate climate mammals. Ingestion of the eggs with the nasal secretion of the definitive host results in visceral invasion of larval Pentastomida in the intermediate host (rat, sheep, goat, camel).

Pentastomid species can infect humans as either accidental definitive or accidental intermediate hosts. Ingesting undercooked viscera (liver, lungs, spleen) of the intermediate hosts may result in nasopharyngeal infestation called halzoun or marrara, an illness caused by the adult form of L. serrata infecting the human paranasal sinuses where it feeds on blood and nasal secretions.

More commonly, in visceral pentastomiasis, humans serve as a dead-end intermediate host for the larvae. In most cases, it is caused by Armillifer species (eg, in our case). The ingested eggs hatch in the intestine; the larvae then penetrate the gut wall and migrate to parenchymal organs, surfaces of serous membranes, and soft tissues where they begin to molt and grow. They cause largely asymptomatic infestation of the liver, peritoneum, and lungs. The larvae usually die and calcify, leaving parts of their chitinous exoskeleton surrounded by a granuloma infiltrated with eosinophils. Larval pentastomiasis is usually a harmless condition accidentally found at autopsies. It is a rarity in developed countries, but still occurs in some parts of the world, for example, in Central Africa or in Malaysia. 

Infection of the eye is extremely rare. However, over a 3-year period, our ophthalmological examinations of 3000 patients in the Democratic Republic of Congo found 2 additional cases with macroscopically identical parasites, one of which was situated under the retina next to the papilla and the other one in the vitreous body, between a detached retina and the lens. Extended history revealed that all 3 patients came from the same region, where local eating habits include the consumption of various snakes, often raw. 

Due to the lack of any controlled data, the treatment of pentastomiasis is unclear, but surgical approach seems to be preferable in case of ocular localization. Differential diagnosis of ocular pentastomiasis includes myiasis and ocular larva migrans.

Clinical Infectious Diseases 2013;57(3):469–70

DOI: 10.1093/cid/cit316

Holoinspiratory Wheezing in a 46-Year-Old HIV-Seropositive Man - ANSWER

Figure 1. Computed tomographic scan of the chest revealing multiple cavitary pulmonary lesions (A) and tracheal subocclusion (B, arrow). C, Inset shows endoscopic appearance of tracheal subocclusion caused by papillomatous exophytic lesions extending over 4 cartilaginous rings. Air passage was possible only through a small hole (arrow).

Diagnosis: Respiratory papillomatosis of the trachea and lungs due to human papillomavirus infection. 

This patient presented with airway obstruction caused by tracheal papillomatous masses revealed on computed tomography and bronchoscopy (Figure 1). In addition, he had multiple bilateral cavitary lesions in his lungs (Figure 1A). Histological examination of tracheal biopsy samples showed respiratory papillomatosis with low-grade epithelial dysplasia (Figure 2) and koilocytotic atypia (Figure 3B). 

Immunohistochemical analysis for human papillomavirus (HPV) performed with antiHPV L1 (Cytoactiv Diagnostics GmBH, Pirmasens, Germany) showed positive nuclear staining of the koilocytes (Figure 3C). Even though lung nodules were not biopsied, other possible causes were ruled out in the bronchoalveolar lavage, including mycobacteria, bacterial organisms, and fungi. The patient was treated by rigid bronchoscopy with YAG (yttrium neodymium) laser therapy to relieve the tracheal obstruction, resulting in normalization of his arterial blood gas and amelioration of his respiratory symptoms. However, he experienced recurrence of the tracheal lesions and died of unrelated causes 20 months after the diagnosis. Recurrent respiratory papillomatosis (RRP) is a rare cause of benign tumors of the respiratory tract caused by HPV. Most commonly it involves the larynx and trachea, but rarely can spread distally to affect the bronchi and lung parenchyma. Although benign, it carries significant morbidity and occasional mortality, including life-threatening airway obstruction and a 3%–5% risk of malignant transformation. Pulmonary involvement heralds a poor prognosis and manifests in 1.8% of RRP patients, predominantly children, with multiple nodules and thin-walled cysts apparent on computed tomography. RRP has a bimodal age distribution: Juvenile-onset disease is thought to result from vertical transmission at the time of delivery, or, in some cases, from infection in utero; adult-onset disease may result from sexual or oral transmission. Its incidence in the United States has been estimated at 4.3/100 000 per year in children and 1.8/100 000 per year in adults. HPV is a nonenveloped double-stranded DNA virus, which replicates inside the nuclei of infected epithelial cells and is able to persist in basal cells as an episome. More than 100 types of HPV are known, but the majority of RRP is secondary to the low-risk types 6 and 11, with the latter being more virulent. Both the humoral and the cellular immune response may be compromised in patients with respiratory papillomatosis, and the patient’s degree of immunodeficiency may be associated with the clinical course of the disease. In particular, a compromised cell-mediated immune response has been associated with the development of RRP in children. In contrast to the link between HPV-mediated cervical and anogenital cancers with HIV infection, there is no known association of HIV with RRP. The condition is incurable. The mainstay of treatment is surgical debulking, predominantly through laser therapy or use of microdebriders. Multiple procedures may be necessary due to frequent, repeated recurrences. Various adjuvant treatments have been tried, including antivirals (mainly intralesional cidofovir) and immunomodulators (eg, interferon alfa), but highquality evidence to support their use is lacking. The advent of a quadrivalent HPV vaccine targeting types 6, 11, 16, and 18 is a promising development that could lead to prevention or even eradication of this condition in the long term.

Figure 2. Hematoxylin-eosin stain of tracheal biopsy material (×200 magnification).

Figure 3. A, Histopathological features of respiratory papillomatosis (hematoxylin-eosin stain, ×200 magnification). B, Arrows indicate the koilocytotic cells that show an intense immunoreaction for human papillomavirus (C, arrows). The koilocytes show well-defined perinuclear halos with a cookie-cutter border and cytoplasmic thickening; nuclei are enlarged (sometimes bi- or multinucleated with variation in nuclear size) with undulating (raisin-like) nuclear membrane.

Clinical Infectious Diseases 2014;58(1):134–5

DOI: 10.1093/cid/cit666

Holoinspiratory Wheezing in a 46-Year-Old HIV-Seropositive Man - QUIZ

Figure 1. Computed tomographic scan of the chest revealing multiple cavitary pulmonary lesions (A) and tracheal subocclusion (B, arrow). C, Inset showing endoscopic appearance of tracheal subocclusion caused by exophytic lesions extending over 4 cartilaginous rings. Air passage was possible only through a small hole (arrow).

A 46-year-old Italian man seropositive for human immunodeficiency virus (HIV) type 1 was admitted to our department with a 3-month history of nonproductive cough and progressively worsening dyspnea. The patient was a former heroin addict with liver cirrhosis caused by hepatitis C virus and previously treated visceral leishmaniasis and latent syphilis. He was on antiretroviral treatment consisting of emtricitabine, tenofovir, and fosamprenavir with an undetectable HIV load and a CD4 Tlymphocyte count of 180 cells/µL. On hospital admission, the patient was afebrile but short of breath at rest, with a heart rate of 110 beats per minute, respiratory rate of 35 breaths per minute, and oxygen saturation of 80% on room air. Physical examination revealed holoinspiratory wheezing. His oral cavity was unremarkable. Arterial blood gas showed an arterial pH of 7.48, an oxygen partial pressure of 56 mm Hg, and a carbon dioxide partial pressure of 28 mm Hg while breathing ambient air. A computed tomographic scan of the chest was performed showing multiple bilateral pulmonary lesions, some with a cavitary appearance (Figure 1). Bronchoscopy demonstrated tracheal subocclusion caused by irregular, friable rosy vegetations extending over 4 cartilaginous rings (Figure 1C). Biopsies were obtained (Figure 2). 

What is your diagnosis?

Clinical Infectious Diseases 2014;58(1):78

DOI: 10.1093/cid/cit660

A Man With Unilateral Ocular Pain and Blindness - QUIZ

A 25-year-old black man with unknown medical history presented at our ophthalmologic mobile outpatient clinic (District of Sankuru, East Kasai Province, Democratic Republic of Congo) with blindness and pain in his left eye. The examination showed a shrunken, nonfunctional left eye (phthisis bulbi), nonreactive to light, which, by slit lamp exam, revealed a large, blackish, crescent-shaped, worm-like foreign body wedged into the angle of the anterior chamber (Figure 1).

Much to our surprise, the foreign body began a peristaltic motion upon physical stimulation of the eye. The patient was otherwise in good health and free of general symptoms. Physical findings were unremarkable; thus, no further diagnostic tests were performed. The parasite was removed under local anesthesia, still alive and crawling (Figure 2). It was sent to the Hungarian Natural History Museum, Budapest, for further identification. The patient often consumed poorly cooked snakes. Despite the surgical procedure, the patient permanently lost vision in the left eye. 

What is your diagnosis?

Clinical Infectious Diseases 2013;57(3):418

DOI: 10.1093/cid/cit309

Rapidly Progressive Skin Lesions Requiring Admission in a Young, HIV-Infected Man - ANSWER

Diagnosis: Disseminated Cryptococcosis With Prominent Skin Involvement.

The patient’s serum cryptococcal antigen was strongly positive (titer >1:1024). After 96 hours of incubation, both blood and synovial fluid grew Cryptococcus neoformans. Cerebrospinal fluid (CSF) analysis showed no pleocytosis, and CSF cultures and cryptococcal antigen were negative. Skin biopsies revealed evidence of a granulomatous inflammation (arrow) in the dermis and subcutaneous tissue (Figure 1A). Round fungal organisms (arrowheads) were seen within the cytoplasm of histiocytes and multinucleated giant cells (Figure 1A-insert).

Grocott’s methenamine silver stain demonstrated abundant budding yeasts ranging in size from 5 to 15 μm in diameter (Figure 1B). The budding cells (arrowhead) had a narrow base (Figure 1B-insert). Mucicarmine stain revealed the characteristic pink-red capsule of Cryptococcus neoformans. (Figure 2).

The patient was treated with amphotericin lipid complex B and flucytosine. His highly active anti-retroviral therapy (HAART) regimen and trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis were continued. He was eventually discharged in overall better condition and with improved skin

lesions, with plans to complete the induction phase of antifungal therapy with oral fluconazole.

The final diagnosis was disseminated cryptococcosis with fungemia, joint and prominent skin involvement, and possible pulmonary involvement, but sparing the meninges, as well as an underlying HIV (human immunodeficiency virus) infection with a low CD4 cell count.

Skin lesions in the setting of human innumodeficiency virus (HIV) infection often present a diagnostic challenge, and newly found nodules and/or ulcers can be the dermal manifestation of infectious and non-infectious diseases. 

Among the latter, drug reactions, neoplasms (including but not limited to Kaposi’s sarcoma), and vasculitides should be considered. Potential infectious agents include viruses such as Molluscum

contagiosum, bacteria that include Treponema pallidum as well as non-tuberculous mycobacteria such as Pseudomonas aeruginosa (and associated ecthyma gangrenosum) and Bartonella spp. (causing bacillary angiomatosis), and fungi, including endemic fungi, and, as shown in our case, Cryptococcus neoformans.

Roughly 1 million new cases of cryptococcal meningitis occur annually worldwide, with the majority in the setting of HIV infection. The incidence of disseminated cryptococcosis, is when the organism is found in organs other than the meninges or lungs, is less well known. The recommended antifungal treatment is identical to that for meningitis. Skin lesions, seen in 10%–15% of disseminated cases, are classically described as umbilicated nodules, but can vary in appearance and sometimes resemble plaques, abscesses, sinus tracts, deep ulcers, and even cellulitis. At time of admission, our patient displayed the more typical lesions on his arms while more dramatic ulcerations were found on his face.

The appearance of deep confluent ulcers in our patient was unusual. It was likely due to a strong immune response to a high organism burden in the setting of immune reconstitution inflammatory syndrome (IRIS). IRIS typically occurs in younger patients with low pre-treatment CD4 cell counts and after the initiation of HAART. In the setting of C. neoformans infection, it can manifest in 2 ways, one of which is the paradoxical worsening of a patient’s clinical status with recurrence

of symptoms and signs resembling those of the initial opportunistic infection despite adequate antifungal therapy.

This occurs 1–3 months after HAART has been initiated and during maintenance treatment for cryptococcus. Our patient’s rather dramatic presentation with fungemia, joint involvement,

and rapidly worsening facial lesions was likely due to the second variant of IRIS. In this less common syndrome, unveiling of subclinical cryptococcal disease occurs within weeks of initiating treatment with HAART.

The World Health Organization recommends serum cryptococcal antigen screening in resource-limited settings for all HIV-infected patients with a CD4 cell count less than 100 cell/mm3 (regardless of skin findings) and subsequent pre-emptive treatment if the test is positive. We

believe that such a strategy would have helped prevent dissemination and IRIS-related, severe, ulcerating, facial skin lesions in our patient. We speculate that for certain highrisk populations (ie, younger patients with critically low CD4 cell counts), screening would be a cost-effective approach

even in the developed world because it may allow treatment with oral agents and obviate the need for hospitalization.

Regardless of screening strategies, newly developing, progressive skin lesions seen in patients with low CD4 cell counts have a broad differential diagnosis, and disseminated cryptococcosis should always be considered, especially when HAART has been recently initiated.

Clinical Infectious Diseases 2013;56(1):159–60

DOI: 10.1093/cid/cis667

Rapidly Progressive Skin Lesions Requiring Admission in a Young, HIV-Infected Man -QUIZ

A 28-year-old man was admitted to our hospital with worsening, ulcerating skin lesions on his face, arms and trunk. Six months prior, he had been diagnosed with HIV infection and hospitalized with Pneumocystis jiroveci pneumonia for which he received treatment with trimethoprim-sulfamethoxazole (TMP/SMX). Three intramuscular doses of penicillin benzathine were also administered for a positive RPR (titer 1:32).

Five months later, he was started on a highly active antiretroviral therapy (HAART) regimen, including emtricitabine, tenofovir, atazanavir, and ritonavir. Soon after, the patient noticed painless, non-pruritic, reddish nodules, initially on his face, later on his arms. A seven-day course of oral clindamycin had no effect. Instead, additional lesions appeared over his trunk and extremities and the facial lesions progressed in size, and ulcerated. In addition, he complained of fatigue, a dry cough and diffuse arthralgias. He denied travel, recent sick contacts, intravenous drug use, outdoor activities or animal exposures.

He identified himself as being homosexual and lived in an urban setting in the Northeast of the United States. 

On examination, the patient was in no distress, afebrile, normotensive, but tachycardic with a pulse rate of 127 beats/minutes. Scattered skin lesions, varying in size from 0.5 to 5 cm were present. Some were nodular and intact (Figure 1A); larger ones were ulcerated and/or crusted (Figure 1B). No mucosal involvement or adenopathy were noted. His right knee was moderately swollen without warmth, erythema or tenderness.

Routine laboratory testing revealed anemia, mild hyponatremia and mild hyperbilirubinemia. The RPR titer was unchanged. Blood cultures were obtained. His CD4 cell count had increased from 64 to 72 cells/mm3 (11% to 40%) and his HIV viral load had fallen one log from 214 570 to 19 009 copies/mL since initiation of HAART. A chest radiograph revealed scattered patchy opacities without effusions. Arthrocentesis of the right knee yielded 896 red blood cells/mm3 and 3380 white

blood cells/mm3 (88% neutrophils); fluid cultures were sent. A biopsy of the facial skin lesions was performed (Figure 2). 

What diagnosis best explains the patient’s progressive skin lesions?

Clinical Infectious Diseases 2013;56(1):117

A Man With Fever and Deranged Liver Function - ANSWER

Figure 1. A, Low-power view, bone marrow trephine. Several ring granulomata are shown in the trephine biopsy (arrows; hematoxylin-eosin stain, magnification ×200). B, High-power view, bone marrow trephine. Epithelioid histiocytes and neutrophils surround central lipid droplets forming a doughnut-shaped granuloma (arrows; hematoxylin-eosin stain, magnification ×400).

Diagnosis: Doughnut-shaped granuloma in a patient with acute Q fever.

Trephine biopsy showed a normocellular marrow with normoblastic erythropoiesis, active granulopoiesis, and adequate megakaryocytes. Numerous epitheloid granulomas with “doughnut-ring” appearance (Figure 1A and 1B) were found.

Special stains for mycobacterium and fungus were negative.

Serological examination for Coxiella burnetii antibodies by immunofluorescence assay (IFA) showed a rise of both phase II polyvalent IFA and immunoglobulin M titers from <25 to 200. The phase I polyvalent titers were both <25. 

Polymerase chain reaction (PCR) for C. burnetii performed on the first serum sample was also positive. The findings were compatible with acute Q fever. 

Transthoracic echocardiography showed no significant valvulopathy or vegetation. Our patient was treated with 14 days of doxycycline with good clinical response. 

Q fever is caused by C. burnetii, an obligate intracellular, gram-negative bacterium. It can infect humans and animals (eg. cattle, sheep, and goats). Humans can be infected when exposed to contaminated milk, excreta, and products of conception. Clinical presentation is highly variable, depending on host factors, bacterial virulence, and extent of exposure.

After exposure, 60% of the individuals are asymptomatic, whereas only 2%–5% of symptomatic patients require hospitalization because of severe diseases such as hepatitis, pneumonia,

and endocarditis.

Because of the heterogenous clinical presentation, prompt diagnosis requires a high index of suspicion. In this case, bone marrow aspiration and biopsy were performed to investigate

the cause of fever and thrombocytopenia. The doughnut-ring granuloma, together with the clinical presentation and epide-miological association, suggested Q fever as one of the differential diagnoses.

Doughnut-ring granuloma is characterized by a central vacuole surrounded by histiocytes, polymorphonuclear cells, macrophages, and eosinophils, while the ring of the granuloma consists of fibrin. Apart from bone marrow, doughnut-ring granuloma may also be found in liver; typically, bone marrow involvement is concurrent with liver disease. There is still no concrete explanation for the pathogenesis of ring-shaped granuloma in the bone marrow and liver. One possibility is the deposition of fibrin at the margin induced by macrophage with incorporation of lipid within the granuloma, which corresponds with the central vacuole. 

Font et al postulated focal vasculitis in liver due to immune complex deposition as a possible mechanism, and similar vasculitic changes have been previously described in the bone marrow.

Other histopathological features of Q fever in liver biopsies are focal hepatocellular necrosis, infiltrates by macrophages, lymphocytes, and polymorphonuclear cells. 

Skin involvement is rare. 

Pulmonary histopathological findings are nonspecific and consist of microscopic interstitial pneumonia and alveolar exudates.

Doughnut-ring granuloma is not pathognomonic of Q fever. It can also be found in acute typhoid fever, infections due to cytomegalovirus and Epstein-Barr virus, and leishmaniasis, as well as noninfectious diseases such as Hodgkin’s lymphoma, peripheral T-cell lymphoma, and drug hypersensitivity (eg, allopurinol). Some advocate the use of PCR detection of targeted gene fragments in bone marrow to provide direct evidence of C. burnetii infection. 

Serological testing remains the diagnostic tool of choice owing to poor sensitivity and availability of culture and molecular techniques. A 4-fold rise in titers of phase II antibody in paired sera indicates acute Q fever, and titers of ≥1:800 of phase I antibody are required for diagnosis of chronic cases.

Clinical Infectious Diseases 2012;55(11):1531

DOI: 10.1093/cid/cis652

A Man With Fever and Deranged Liver Function - QUIZ

Figure 1. Bone marrow biopsy specimen of the patient (hematoxylin-eosin stain, A: magnification ×200; B: magnification ×400).

A 55-year-old Chinese man presented with fever and jaundice for 4 days. There was also a 4-week history of progressive worsening of right upper quadrant abdominal pain. He reported a consumption of 10 bottles of goat milk during the 2 months before the onset of symptoms. Laboratory investigations revealed leukocytosis with atypical lymphocytes, thrombocytopenia, and deranged liver function with a cholangiohepatitic picture. 

Computed tomography of the abdomen showed normal biliary ducts and no bile duct stones, but multiple hemangiomata were found in the liver. 

Serological examination for viral hepatitis and brucellosis serology were negative. 

Tests for antinuclear, anti–smooth muscle, and antimicrosomal antibodies were negative. Microbiological cultures of blood, sputum, and urine were negative.

The patient was treated with broad-spectrum antibiotics including cefuroxime and then cefoperazone/sulbactam. In view of the persistent fever and abnormal blood film, bone marrow aspirate and trephine biopsy were performed (Figure 1A and 1B).

What is your diagnosis?

Clinical Infectious Diseases 2012;55(11):1531

DOI: 10.1093/cid/cis652

A 40-Year-OldWoman From a Native Indian CommunityWith Non- Hodgkin Lymphoma and Hemoptysis - ANSWER

Figure 1. High-resolution computed tomography scan showing a thinwalled cavity in the left superior lobe with a focal consolidation (arrow).

Figure 2. Ovoid-shaped egg of Paragonimus species, with a thick shell, with one end slightly flattened. At the large end, the operculum is clearly visible (arrow), and the opposite (abopercular) end is thickened. The eggs

are unembryonated when passed in sputum.

Diagnosis: pulmonary paragonimiasis.

The computed tomographic findings show a thin-walled cavity in the left superior lobe with a focal consolidation (Figure 1). A bronchoscopy was performed to rule out any involvement by opportunistic pathogens or neoplastic infiltration and to define treatment before the beginning of chemotherapy.

The direct evaluation of bronchoalveolar lavage fluid showed the presence of yellowish brown eggs, thick-shelled with an obvious operculum, characteristic of Paragonimus species (Figure 2). Based on the egg morphology, ovoid shape, eggshell and operculum, and epidemiology, the most likely species infecting this patient was Paragonimus mexicanus. Serological tests were not performed because they are not available in our country. The patient was treated with praziquantel 600 mg every 8 hours for 48 hours with resolution of the symptoms. Then the patient received R-CHOP (Rituximab - Cyclophosphamide, Hydroxydaunorubicin, Oncovin [vincristine], Prednisone) chemotherapy with significant reduction of the tumoral mass and at present is still receiving chemotherapy without infectious complications.

Paragonimiasis is a foodborne anthropozoonotic disease caused by the trematode Paragonimus species. Human infections have been reported in 39 countries, with 9 species identified that cause infections in humans. Paragonimus westermani is the most important and widely distributed of the many Paragonimus species that exist, and is frequently encountered in Southeast Asia and China, whereas P. kellicotti has been reported in North America. This is an expected condition in endemic tropical and subtropical countries of the Americas. In South America, paragonimiasis has been reported from Mexico to Brazil, and the species have been named according to the country where they have been identified, hence their names: P. mexicanus (Mexico), P. peruvianus (Peru), P. ecuadoriensis (Ecuador). In our country 5 endemic foci have been identified in the Embera Indian communities located on the Colombian Pacific coast.

Unfortunately, this population rarely seeks medical care and therefore the incidence of the disease is hard to establish and is underestimated. Even though the species Paragonimus caliensis has been identified in animals, and there are some studies in humans in our area, the species of Paragonimus has not been determined so the predominant species is unknown.

The infection in humans, an accidental host, occurs as a result of the ingestion of raw freshwater crabs, crayfish, and other crustaceans infected with the metacercariae. After the ingestion, the metacercariae hatch in the intestine and young worms penetrate the intestinal wall and the peritoneum, then the diaphragm and the pleura; finally reaching the lungs, where they produce the typical symptoms of the disease. A more unusual and atypical presentation results from ectopic involvement that results from erratic migration of the juvenile worms, with locations in the abdominal cavity, subcutaneous tissues, and brain.

Many patients with pulmonary P. westermani infections may have nonspecific signs and symptoms, usually with radiologic abnormalities such as lung infiltrates, nodules and cavities, airspace consolidation, or pleural effusions that may mimic tuberculosis. The diagnosis is made by direct visualization of the eggs in the sputum or bronchoalveolar lavage fluid; although the sensitivity of this test is low (30%–40%), repeated sputum examinations may increase the yield (54%–89%). The sensitivity of a stool examination is inferior to that of a sputum examination, with the sensitivity of a single stool examination being in the range of 11%–15%; examination of 3 stool specimens raises the sensitivity to 25%. Based on the egg morphology, in some instances, the species identification is possible.

For example, the eggs of P. kellicotti are bigger than those of P. mexicanus (average, 91.22 ± 3.60 μm in length with a mean width of 56.70 ± 1.78 μm vs 74.11 ± 3.28 μm in length with a mean width of 44.45 ± 1.97 μm, respectively), and the eggshells of P. kellicotti are thicker than those of P. mexicanus (average, 2.27 ± 0.26 μm vs 1.17 ± 0.19 μm, respectively). These features are important for differentiating P. mexicanus from P. kellicotti, both of which have a similar egg shape (broadest centrally) that is distinctly different from that of P. westermani, which is broadest near the operculum and has more distinct abopercular thickening.

Another tool especially useful regarding the extrapulmonary forms of the disease, in which diagnosis and isolation of the parasite is more difficult, is serological testing that allows the species to be differentiated; for example, enzyme-linked immunosorbent assay is highly sensitive (96%) and specific (99%) for P. westermani.

In general, paragonimiasis has a good prognosis and excellent clinical response to treatment if the diagnosis is made promptly. In our region, more public health interventions are needed to allow early detection and treatment of the population at risk.

Clinical Infectious Diseases 2013;57(5):765–6

A 40-Year-OldWoman From a Native Indian CommunityWith Non-Hodgkin Lymphoma and Hemoptysis - QUIZ

Figure 1. High-resolution computed tomography scan showing thinwalled

cavity in the left superior lobe with a focal consolidation.

Figure 2. Bronchoalveolar lavage fluid smear (original magnification,×40).

A 40-year-old woman from a native Indian community who lives in a rural area in Chocó, Colombia (a state on the northern Pacific coast of South America with an indigenous tropical rainforest) referred upon admission to our institution a positive epidemiological history of depending on handcrafted fishing for daily living. She presented to our institution with a 2-year history of a right submandibular tumor that had progressed over the past couple of months causing dysphagia with solid foods, limited mobility of the neck, and dyspnea. She subsequently complained of persistent cough with hemoptysis. 

Laboratory results were remarkable for anemia (8.3 g/dL) and eosinophilia (1.100 cells/μL). The patient had an excisional biopsy of the tumor on her neck and a tracheostomy because of airway compromise. The pathology report showed a diffuse large B-cell lymphoma. Systematic staging of the lymphoma included a computed tomographic scan of the thorax before the beginning of chemotherapy (Figure 1). A bronchoscopy was performed because of the hemoptysis, to rule out any infectious disease or neoplastic infiltration. The direct examination of the bronchoalveolar lavage fluid is shown in Figure 2.

What is your diagnosis?

Clinical Infectious Diseases 2013;57(5):711

Enlarging Ulcerated Plaques on Bilateral Arms of a 64-Year-Old Man - ANSWER

Figure 1. Skin biopsy showing several endospores acattered throughout the dermis (small arrows) with a tightly packed, morula-like sporangium (large arrow, hematoxylin-eosin stain, magnification x 400).

Diagnosis: Protothecosis.

Skin biopsy revealed several endospores (small arrows) scattered throughout the dermis with a tightly packed, morula-like sporangium (Figure 1). The fungal culture of the tissue confirmed the diagnosis of protothecosis. The patient was treated successfully with parenteral amphoteracin B followed by oral itraconazole. 

Prototheca is a type of green alga found worldwide in sewage, fresh water, trees, and soil. Infection is usually caused by Prototheca wickerhamii. Less commonly, infection occurs with Prototheca zopfii. Infection is quite rare despite frequent exposure. Patients are typically immunocompromised with a 

history of traumatic inoculation. The initial cutaneous lesion is typically a single localized eczematous nodule or plaque. An initial presentation with large extensive plaques or ulcers on bilateral forearms can be misleading for clinicians. Systemic  dissemination may rarely occur. Given that the infection is quite rare, there is currently no evidence-based protocol for the management of protothecosis. However, there are case reports in the literature indicating that the use of intravenous amphotericin B is effective in disseminated disease.

Clinical Infectious Diseases 2013;56(2):307

Enlarging Ulcerated Plaques on Bilateral Arms of a 64-Year-Old Man - QUIZ

Figure 1. Large confluent erythematous plaques with focal ulcers and scaling.

Figure 2. Several floret-like morula organisms in the dermis (hematoxylin-eosin stain, magnification x 400).

A 64-year-old retired farmer presented with a 3-month history of enlarging plaques of both upper limbs associated with several focal ulcers. Recent treatment with empirical oral and topical antibiotics had been ineffective. Apart from regular gardening, he denied contact with animals or use of nonprescribed topical agents, and had no history of malignancy.

Physical examination was notable for large nontender erythematous scaly plaques covering almost the entire forearms and upper arms with several healing ulcers (Figure 1). 

Histological examination of the skin biopsy is shown in Figure 2.

What is your diagnosis?

Clinical Infectious Diseases 2013;56(2):271.

A 68-Year-Old Man With Follicular Lymphoma Presenting With Fever and Chills - ANSWER

Figure 1. 

Anaerobiospirillum species Gram stain from blood agar plate incubated anaerobically showing Gram-negative, spiral-shaped bacteria (arrows). The organism grows as circular, translucent, nonhemolytic colonies up to 0.5 mm in diameter. They are motile by bipolar tufts of flagella. Useful biochemical markers include negative results for oxidase, catalase, indole, and nitrate reduction.

Diagnosis: Anaerobiospirillum species.

A preliminary diagnosis of Anaerobiospirillum species was made on the basis of the findings presented above, with definitive identification of Anaerobiospirillum succiniciproducens based on 16S ribosomal RNA (rRNA) sequencing. The patient was treated with a 14-day course of ertapenem with no growth on follow-up blood cultures. We believe his bacteremia was related to diverticular  disease in the setting of animal exposures. He continues to follow up with his oncologist for management of his follicular lymphoma.

Anaerobiospirillum species are Gram-negative, spiral-shaped anaerobic bacteria (Figure 1) that were first described by Davis et al in 1976. Despite their spiral shape, they are more closely related to the genus Aeromonas than to Treponema or Borrelia. They exhibit corkscrew-like motility and have bipolar multitrichous flagella and are part of the normal gastrointestinal flora of cats and dogs. Anaerobiospirillum species are a rare cause of bacteremia in humans; diarrheal illnesses have also been reported to be caused by A. succiniciproducens and Anaerobiospirillum thomasii.

The gastrointestinal tract is considered the usual route of entry. Patients typically present with gastrointestinal symptoms such as abdominal pain, nausea, and vomiting. Septicemia is mostly seen in patients with underlying medical conditions including alcoholism, malignancy (often gastrointestinal), diabetes, gingival disease, and atherosclerosis.

It is important to distinguish Anaerobiospirillum species from Campylobacter species, which have a similar Gram stain and colony morphology but are oxidase and catalase positive and grow in microaerophilic conditions. Although commercial biochemical tests may help, 16S rRNA sequencing is definitive. This is an uncommon infection, and optimal therapy has not been established. A. succiniciproducens is resistant to clindamycin and metronidazole, which are among the most commonly prescribed agents for anaerobic infections. A. succiniciproducens is reported to be susceptible to chloramphenicol, cephalosporins, fluoroquinolones, carbapenems, and penicillin/b-lactamase combinations.

Clinical Infectious Diseases 2012;54(1):148–9

A 68-Year-Old Man With Follicular Lymphoma Presenting With Fever and Chills - QUIZ

Figure 1. Gram stain from isolated colony from the blood agar plate (magnification 3 X 1000).

A 68-year-old man from southeast Ohio with a history of follicular lymphoma, diverticulosis, and sinusitis presented to our medical center in December 2010 with complaints of 3 weeks of productive cough, dyspnea, fever, and chills. He denied travel or exposure to sick contacts. He was  an avid hunter of deer and rabbits and owned hunting dogs. He had an annual gathering with other hunters where they ate numerous game meats including gator, bear, elk, moose, and deer. On examination, he appeared weak and fatigued. He was afebrile, tachypneic, tachycardic, and hypotensive with an oxygen saturation of 87% on room air. Pulmonary examination revealed bibasilar crackles. Initial chest x-ray showed a subtle air space disease in the left upper lobe concerning for evolving pneumonia. His peripheral white count was 30 200 cells/lL, with neutrophils 84%, lymphocytes 4%, and monocytes 10%. He was started initially on empiric vancomycin and piperacillin/tazobactam for sepsis secondary to pneumonia. He continued to improve in the hospital while on antibiotics. The anaerobic blood cultures drawn on admission and prior to antibiotic administration were positive. The Gram stain from the colonies growing in the blood agar plate incubated anaerobically is shown in the Figure 1. The motility based on the hanging drop test was positive. Based on the anaerobic growth, Gram stain, and the hanging drop test, what is your diagnosis? How would you treat this patient?

Clinical Infectious Diseases 2012;54(1):95