Case 1: Subacute cutaneous lupus erythematosus
By Rumman Langah, MD, FACP, and Noble Maleque, MD, FACP
A 43-year-old woman without significant medical comorbidity presented with acute and subacute pain, redness, and swelling of right lateral thigh and hip. Although her condition had been worsening over a four-day period at presentation, six weeks earlier she had had similar symptoms and was prescribed a seven-day course of oral clindamycin without improvement. Subsequently, she was treated with oral prednisone and ciprofloxacin for one week, resulting in some improvement for a few weeks. She was experiencing intermittent low-grade fevers and fatigue during this time.
On presentation, she was febrile (38.4 °C) and tachycardic (106 beats/min). Physical examination was pertinent for mild frontal alopecia, blanching, and an erythematous and tender rash (plaque-like) overlying a mildly swollen right lateral hip and thigh region (Figure 1). On laboratory testing, leukopenia (3.4 × 103 cells/µL) with relative lymphopenia (21%), mild anemia (hematocrit, 27.3%), and normal platelet count were noted. C-reactive protein level was 6.49 mg/L, and erythrocyte sedimentation rate was 38 mm/h. Aminotransferase levels were mildly abnormal: alanine aminotransferase (ALT) level, 79 U/mL, and aspartate aminotransferase (AST) level, 47 U/mL. Renal function, electrolytes, creatine phosphokinase level, thyroid-stimulating hormone level, and urinalysis results were unremarkable.
A presumptive diagnosis of cellulitis was made, and the patient was started on intravenous vancomycin. Meropenem was added by the third hospital day due to persistent fevers and rash extending beyond initially noted margins. MRI of the thigh showed skin thickening and soft-tissue edema without abscess or masses. Skin biopsy showed focal vacuolar interface alteration with associated dyskeratotic keratinocytes (Figure 2), raising concern for an immune-mediated connective tissue disorder. Further studies revealed positive anti-SSA/Ro Ab titer at 9.3 U/mL (normal range, <7 U/mL), positive antinuclear antibody at 1:320 dilution, and low-complement C3 and C4 levels at 36 mg/dL (normal range, 83 to 177 mg/dL) and 10 mg/dL (normal range, 15 to 45 mg/dL). Antibiotics were withdrawn and oral prednisone was initiated, with resolution of fever and noticeable improvement in rash within 48 hours. After discharge, the patient was treated in a rheumatology clinic, with resolution of rash and transition from prednisone to hydroxychloroquine.
Cutaneous lupus erythematosus involves a range of dermatologic manifestations, including this patient's diagnosis, an entity known as subacute cutaneous lupus erythematosus (SCLE). Although most patients with systemic lupus erythematosus (SLE) have cutaneous manifestations, cutaneous lupus erythematosus is a separate entity that is two to three times more prevalent than SLE. The American College of Rheumatology (ACR) criteria for SLE, which include four cutaneous signs, may lead to overdiagnosis of SLE in patients with predominantly cutaneous disease, as 50% of patients with SCLE meet the ACR criteria for SLE. Similar to systemic lupus, SCLE tends to occur in middle-aged women (ages 40 to 60 years) with a 4:1 female: male ratio. In contrast to SLE, SCLE is seen more frequently in white patients than in African-American patients due to its association with the HLA-DRE haplotype. SCLE is highly photosensitive, and the rash tends to be distributed in areas such as the upper thorax, upper back, and extensor surfaces of forearms. However, the rash of SCLE tends to spare the face and is rarely found below the waist. The rash can start as erythematous papules but later evolves into annular or papulo-squamous plaques. Immunologically, 70% of SCLE patients are anti-Ro (SS-A) positive, and overlap between Sjögren's syndrome and SCLE has been reported.
SCLE tends to have a milder course than SLE, with most patients experiencing arthralgia and myalgias. Only 10% to 15% of patients with SCLE develop visceral organ involvement (e.g., central nervous system or kidneys). A significant number of cases of SCLE are due to exposure to drugs such as tumor necrosis factor-alpha inhibitors, antiepileptic agents, antihypertensive drugs, or proton-pump inhibitors. The treatment of SCLE is similar to that of systemic lupus, with more emphasis placed on sun-protective strategies and topical therapies.
The diagnosis of SCLE is based mostly on clinical and histopathologic findings. In addition to the ACR criteria outlined above, SLE can be diagnosed on the basis of the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria (four clinical and immunological criteria and positive biopsy findings). The SLICC criteria have been reported to have a higher sensitivity than the ACR criteria with equivalent specificity. Regardless of diagnostic criteria, skin biopsy is usually required to differentiate SCLE from other rashes that may mimic cellulitis. The differential diagnosis for the rash seen in SCLE includes dermatomyositis, cutaneous T-cell lymphoma, tinea corporis, allergic drug eruption, granuloma annulare, and pemphigus.
- SCLE is a separate and more common disease entity than SLE, which tends to have a milder disease course and better prognosis.
- SCLE should be included in the differential diagnosis of “cellulitis mimics,” especially in patients with a rash in an unusual site, subacute course, and/or poor response to antibiotics.
Case 2: Disseminated histoplasmosis
By Aaron Gluth, MD, ACP Member; Rumman Langah, MD, FACP; and Dan Hunt, MD, FACP
A 33-year-old man with a recent diagnosis of HIV presented with a three-week history of fevers and painless diarrhea and a two-day history of a diffuse, pruritic rash. He was a veteran who had served in Iraq approximately 10 years prior but reported no other significant or recent travel. The patient said he did not use alcohol, tobacco, or recreational drugs but did report an extensive history of unprotected sex with multiple female partners. On presentation, he was febrile to 39.4 °C, tachycardic, and normotensive. On examination, he was diaphoretic and pale and had mild abdominal tenderness without rebound in the right lower quadrant. Tender bilateral axillary lymphadenopathy was also noted, as was an erythematous, blanching maculopapular rash, predominantly on the trunk and arms.
Initial labs revealed a creatinine level of 1.2 mg/dL, an AST level of 1,560 U/L, an ALT level of 393 U/L, normocytic anemia with a hemoglobin level of 10 g/dL, and a platelet count of 62,000/mm3. His CD4 count was 21 cells/mm3, triglyceride levels were elevated at 398 mg/dL, and ferritin level was markedly elevated at 70,170 ng/mL (reference range, 20 to 375 ng/mL). A CT scan of the chest, abdomen, and pelvis was remarkable only for splenomegaly and borderline lymphadenopathy in the axillae and mediastinum. A urine Histoplasma antigen test was positive. Subsequent skin and bone marrow biopsies revealed intracellular yeast-like microorganisms suggestive of histoplasmosis. The patient was given a 14-day course of IV amphotericin B and was discharged on oral itraconazole. The patient was nonadherent to his medications and was readmitted nine months later with lymphadenopathy in the neck and axillae. Lymph node biopsy demonstrated Histoplasma lymphadenitis. He was discharged, again on oral itraconazole, and was subsequently lost to follow-up.
This patient was diagnosed with disseminated histoplasmosis (DH). Histoplasmosis is an endemic fungal infection caused by Histoplasma capsulatum and is most prevalent within North and Central America. Within the United States, it is particularly common in the Ohio and Mississippi River valleys. The incidence of DH in HIV-positive patients is 2% to 5% in endemic areas. Most infections are asymptomatic or result in mild pulmonary infection, but manifestations can be severe and/or widespread, particularly in immunocompromised patients. When the condition is untreated, the mortality rate is greater than 80%. DH manifestations include but are not limited to the skin, central nervous system, pericardium, mediastinum, lungs, spleen, liver, bone marrow, gastrointestinal (GI) mucosa, and adrenal glands.
Urine and serum Histoplasma antigen are highly sensitive (urine antigen is 97% sensitive, blood antigen is 83% to 97% sensitive) for the diagnosis of DH in immunocompromised patients, although sensitivity declines in immunocompetent patients and those with a lower mycotic burden. Histopathology, cytology, antibody testing, and fungal cultures play a supportive role in diagnosis. Treatment of severe and/or disseminated histoplasmosis typically consists of amphotericin B induction therapy for one to two weeks, followed by itraconazole maintenance for at least one year.
Extreme hyperferritinemia, as noted in this case, has been linked to DH in the absence of hemophagocytic lymphohistiocytosis (HLH). While there were a number of clinical features suggestive of HLH in this case (cytopenias, hyperferritinemia, hypertriglyceridemia, transaminitis, splenomegaly, fever), bone marrow biopsy showed no active hemophagocytosis. An association between HLH and histoplasmosis has also been described.
- DH has been associated with HLH, as well as extreme hyperferritinemia in the absence of HLH, making ferritin a valuable diagnostic clue.
- Serum and urine Histoplasma antigen have good sensitivity in immunocompromised patients but are less sensitive in immunocompetent patients and those with less disease burden.
Case 3: Heyde's syndrome
By Mohamed Seedahmed, MD, FACP; Ketino Kobaidze, MD, PhD, FACP; Imre Bodo, MD, PhD; and James Stewart, MD
A 69-year-old man with a history of untreated rheumatoid arthritis, recurrent upper GI bleeding from known gastric arteriovenous malformations (AVMs), and recent mitral valve endocarditis presented with hematemesis and epistaxis. On physical examination, the patient's temperature was 36.5 °C, his blood pressure was 117/65 mm Hg, his heart rate was 105 beats/min, his respiratory rate was 18 breaths/min, and his oxygen saturation was 100% on room air. He was not in any distress. His heart auscultation detected regular tachycardia without rubs or gallops and a 4/6 systolic murmur at the right upper sternal border. He had no jugular venous distention. Lungs were clear on auscultation. Abdomen was soft without hepatosplenomegaly. Laboratory testing revealed a hemoglobin level on presentation of 5.1 g/dL (baseline, 8 to 10 g/dL). Two units of red cells were transfused, and bleeding ceased without intervention. Bedside flexible laryngoscopy by ENT was unremarkable. His last five esophagogastroduodenoscopies, two colonoscopies, and pill-camera endoscopy showed no alternative source of bleeding. The gastroenterology consultant recommended consideration of partial gastrectomy due to presumed recurrent hemorrhage from gastric AVMs, which had been cauterized multiple times during the preceding 18 months.
Transthoracic echocardiogram was also obtained and demonstrated a normal ejection fraction of 60%, elevated left ventricular outlet gradients of 60 to 80 mm Hg (normal range, <30 mm Hg), systolic anterior motion of the mitral valve leaflet with severe subaortic stenosis, and worsening severe mitral valve (MV) regurgitation. Transesophageal echocardiogram demonstrated a perforated mitral valve leaflet. Additional laboratory testing demonstrated a stable hemoglobin level and normal prothrombin time, partial thromboplastin time, and factor VIII activity. Fibrinogen was elevated to 618 mg/dL (reference range, 150 to 400 mg/dL) and von Willebrand factor (vWF) antigen was 550% (reference range, 70% to 200%), with absent distribution of vWF multimers. Peripheral blood smear revealed schistocytes, macrocytosis, and spherocytosis.
The patient underwent tissue mitral valve replacement and single-vessel bypass graft. Postoperative labs showed normalization of vWF multimer distribution. He had an excellent recovery without readmission or recurrent bleeding and ultimately did not require gastric resection.
This patient was diagnosed with Heyde's syndrome, with severe and recurrent bleeding from GI angiodysplasias in the setting of left ventricular idiopathic hypertrophic subaortic stenosis (IHSS). The syndrome was first described by Edward Heyde in 1958 in a case series of 10 patients with aortic stenosis and massive intestinal bleeding. IHSS and GI AVMs have also been described as a variant of this syndrome.
The mechanism of this syndrome is not clearly understood. vWF is a protein multimer of different sizes, with the largest multimers responsible for platelet adhesion and hemostasis. This is particularly important when bleeding occurs in locations with high-velocity blood flow, as found in small arterioles of the GI tract. Vascular abnormalities, such as aortic valve or left ventricular outflow obstructions, are thought to create high shear stress, which causes degradation of vWF multimers and impaired hemostasis. GI angiodysplasias or AVMs provide a source for such bleeding. The peripheral blood smear is not diagnostic, but may detect evidence of intravascular hemolysis via the presence of schistocytes.
To evaluate for Heyde's syndrome, testing should include echocardiography and vWF gel electrophoresis. Valve replacement to relieve the left ventricular outflow tract obstruction and pressure gradient is definitive therapy in such cases. Observational studies have found decreased GI bleeding after aortic valve replacement in patients with Heyde's syndrome.
- Consider screening for Heyde's syndrome in patients who present with recurrent bleeding from GI AVMs.
- To evaluate for Heyde's syndrome, testing should include echocardiography and vWF gel electrophoresis.
Case 4: Streptococcus sanguinis bacteremia
By Haritha Katakam, MD, ACP Member; Federico Palacio Bedoya, MD; David A. Krakow, MD; and Rumman A. Langah, MD, FACP
A 63-year-old man presented with a one-month history of severe lower back pain. He reported intermittent fevers and night sweats and estimated that he had lost 100 pounds over this period. His medical history was significant for a colonoscopy six weeks prior to admission during which he had multiple polyps biopsied, one of which revealed low-grade adenocarcinoma. On presentation, he was febrile to 38.4 °C and tachycardic. He was partially edentulous with mild periodontal disease. His physical exam revealed a systolic murmur heard at the apex and left sternal border. He had tenderness to palpation along his lumbar spine. He had an unremarkable neurologic examination. His labs demonstrated leukocytosis with neutrophilic predominance. Empiric antibiotics were started.
MRI of the spine showed vertebral endplate enhancement centered at the L1-L2 intervertebral disc, consistent with discitis and osteomyelitis. Transesophageal echocardiogram showed aortic valve vegetations with aortic valve perforation, severe aortic valve insufficiency, and mitral valve abscess with mitral valve perforation. Blood cultures grew Streptococcus sanguinis. The patient underwent aortic valve replacement and mitral valve repair with annuloplasty. He completed six weeks of intravenous ceftriaxone, and his back pain resolved. At three-month follow-up, the patient had a normally functioning bioprosthetic aortic valve and reported no functional limitations.
This patient had Streptococcus sanguinis bacteremia, complicated by aortic and mitral valve endocarditis, as well as L1-L2 discitis and osteomyelitis. S. sanguinis belongs to one of the five groups of the viridans group Streptococci. It is a part of the normal flora in the upper respiratory tract, female genital tract, and all regions of the GI tract. It is most prevalent in the oral cavity. The main clinical manifestations of S. sanguinis infection are bacteremia and endocarditis. In patients with S. sanguinis bacteremia, it is important to exclude oropharyngeal disease. Our patient did not have any recent dental procedures, and his oral exam revealed only mild periodontal disease, arguing against the oropharynx as the source of the bacteremia. In this case, the source of the bacteremia was presumably the colon, given the close timing of the colonoscopy and finding of colon cancer.
There is a well-established correlation of group D streptococci (Streptococcus gallolyticus) and colon cancer, which typically occurs secondary to bacterial translocation in areas of local inflammation due to the malignancy. Although S. sanguinis endocarditis is usually associated with oropharyngeal disease, multiple case reports demonstrate an association between colon adenocarcinoma and S. sanguinis bacteremia. Symptoms of fever and weight loss typically preceded the diagnosis of S. sanguinis bacteremia in these cases, and there was a temporal association with the discovery of an underlying GI malignancy.
- Subacute back pain in addition to constitutional symptoms including fever, night sweats, and weight loss should trigger an investigation into the possibility of bacterial endocarditis.
- In patients with Streptococcus sanguinis bacteremia, an underlying GI malignancy should be considered, particularly if an oral source for infection cannot be identified.
Case 5: Coccidioidal meningitis
By Zanthia Wiley, MD, and Karen Clarke, MD, FACP
An 18-year-old man presented to an outside facility with headache, fever, and gait imbalance. Three months prior to that presentation, he had developed a headache and was evaluated as an outpatient. He was diagnosed with sinusitis, and amoxicillin/clavulanate was prescribed. Despite this treatment, intermittent headaches continued and he developed fevers and gait imbalance that led to his presentation. On physical examination, he demonstrated aphasia, dysphagia, and left-sided weakness. His head CT scan was unremarkable, but his brain MRI revealed multiple infarcts. Lumbar puncture revealed a white blood cell (WBC) count of 492 cells/µL (normal range, 0 to 5 cells/µL) with lymphocytic predominance, low glucose level, and high protein level. Cerebrospinal fluid (CSF) mycobacterial, fungal, and bacterial cultures; viral studies; cytology; and paraneoplastic panel were all negative. He received empiric treatment for bacterial meningitis, symptom improvement was observed, and he was discharged.
Over the next three months, the patient reported recurrence of intermittent headaches, fevers, and neurologic deficits, and he presented to our institution for further evaluation. Additional history revealed that he currently resides in Florida but had lived in Arizona three years previously. On presentation, he was afebrile and his vital signs were unremarkable. He was drowsy but fully oriented. Motor strength was 4/5 in his left upper and lower extremities and 5/5 on his right side. Sensory exam and coordination were both unremarkable. Repeat lumbar puncture revealed a WBC count of 42 cells/µL, again with lymphocytic predominance, low glucose level, and high protein level. Serum coccidioidal antibodies were positive, and CSF coccidioidal antibody titers were elevated. Fluconazole was initiated, and the patient made a full clinical recovery within weeks. He was discharged on oral fluconazole with a plan for lifelong treatment.
This patient had disseminated coccidioidomycosis and coccidioidal meningitis. Coccidioidomycosis is caused by Coccidioides immitis and Coccidioides posadasii, which are endemic dimorphic fungi that lead to infection following spore inhalation. In the United States, there are approximately 150,000 primary infections each year, and most cases occur in southwestern states: 66% are reported in Arizona, while 31% are reported in California. Since coccidioidomycosis is most often subclinical, fewer than half of infections are recognized. Community-acquired pneumonia is the most common manifestation of a primary infection due to Coccidioides species, although disseminated disease is also possible. Dissemination of Coccidioides species occurs hematogenously and indicates progression of the primary infection. The skin, skeleton, and meninges are common sites of dissemination. Meningitis is the most serious diagnosis associated with coccidioidal infection and, if untreated, leads to death in 95% of patients within two years.
The diagnosis of coccidioidal meningitis is most reliably made by isolating Coccidioides from the CSF. However, in adults, the sensitivity for a positive CSF culture is low (approximately 25%). Therefore, in most instances a presumptive diagnosis is made by detecting coccidioidal antibodies in the CSF. In patients with newly diagnosed coccidioidal meningitis, the Infectious Diseases Society of America recommends high-dose oral fluconazole (400 to 1200 mg daily) as initial therapy for those with normal renal function. Lifelong treatment with an azole drug is recommended due to the high likelihood of relapse (which is potentially fatal) with treatment interruption.
- Coccidioidal meningitis is the most serious diagnosis associated with disseminated coccidioidomycosis and has a high mortality rate if untreated.
- Lifelong treatment is recommended due to the high likelihood of relapse (which is potentially fatal) with treatment interruption.