Physician editor: Christopher Sankey, MD, FACP
Deputy physician editor: Benjamin Galen, MD, FACP
Case 1: Atypical cystic fibrosis
By Patrick E. Prath, MD, ACP Resident/Fellow Member; Eyad Reda, MD, ACP Resident/Fellow Member; Benjamin M. Mulloy, MD, ACP Member; Faizan Shaikh, MBBS, ACP Member; and Damien R. Stevens, MD
A 24-year-old female health care worker presented with a 4-week history of fever and hemoptysis. She had been presumptively treated for acute bronchitis but did not improve with oral antibiotics. A more detailed history revealed that she had lifelong difficulty in gaining weight, allergic symptoms, and 3 years of intermittent hemoptysis. She had had a negative result on a purified protein derivative (PPD) within the past 4 years.
Upon presentation, temperature was 99 °F, pulse was 117 beats/min, respirations were 18 breaths/min, weight was 48 kg with a body-mass index of 19.3 kg/m2, and room air oxygen saturation of 99%. Chest examination revealed increased fremitus and egophony in the posterior right upper lung field. Initial laboratory evaluation was significant only for leukocytosis with neutrophilia, and chemistries were normal. Chest CT revealed diffuse tree-in-bud and nodular opacities with multiples areas of cavitation in parts of the right upper lobe.
Further evaluation revealed negative sputum culture, (1-3)-β-d-glucan assay, galactomannan, cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA), perinuclear antineutrophil cytoplasmic antibody (P-ANCA), anti-double-stranded DNA, anti-centromere antibody, anti-myeloperoxidase antibody, anti-glomerular basement membrane antibody, anti-Scl70, and serum immunoglobulin levels. Two separate sweat chloride levels were elevated at 75 mmol/L and 76 mmol/L (normal <60 mmol/L). Bronchoscopy evaluation showed purulent drainage in parts of the right upper lobe, with bronchoalveolar lavage culture positive for Staphylococcus aureus but negative for acid-fast bacilli (AFB) and fungal stains. She clinically improved and was discharged home on oral doxycycline and with specialty outpatient follow-up.
This patient's presentation with mild recurrent respiratory infections, inability to gain weight, and elevated sweat chloride levels is consistent with atypical cystic fibrosis. Cystic fibrosis (CF) is a multisystem disease that is characterized by mutations in the CFTR gene, which causes abnormal transport of chloride. There are more than 2,000 mutations listed in the current CFTR mutation database. Typical CF patients tend to present as children, with early-onset multiorgan involvement. However, patients with atypical CF are more likely to present as adults with milder disease, or disease limited to a single organ.
The criteria for atypical CF are clinical symptoms of CF in 1 organ and evidence of CFTR dysfunction. Gene dysfunction can be demonstrated either by sweat chloride levels greater than 60 mmol/L on 2 occasions, 2 disease mutations in the CFTR gene, or abnormal nasal potential difference testing. Adults with sweat chloride levels of 40 to 59 mmol/L should be referred for genetic testing. The diagnosis of atypical CF should warrant evaluation of other CF-related diseases, counseling regarding family planning, and supportive treatment for the organ involved. Patients with atypical CF will have longer life expectancies than typical CF patients, depending on the degree of organ dysfunction and the organ involved.
- Cystic fibrosis (CF) should be suspected in patients with the following symptoms: recurrent sinopulmonary infections, pancreatic insufficiency, failure to thrive, and infertility.
- Disease confined to a single organ in combination with elevated sweat chloride levels on 2 different occasions confirms the diagnosis of atypical CF; adults with intermediate levels should be referred for genetic testing.
Drs. Prath and Reda are affiliated with the internal medicine department and Drs. Mulloy, Shaikh, and Stevens are affiliated with the department of pulmonary and critical care at the University of Kansas Medical Center in Kansas City.
Case 2: Abdominal aortic aneurysm
By Fawwad Zaidi, MD, ACP Member
An 83-year-old man with a medical history of hypertension, systemic vasculopathy, obstructive lung disease, and former tobacco use presented with suprapubic pain. He reported a 7-day history of suprapubic discomfort with increased urinary frequency, during which time his primary care physician treated him with antibiotics for a presumed urinary tract infection. With persistent symptoms, he was referred for further evaluation.
The patient reported no subjective fever, chills, nausea, vomiting, or constipation. He was alert and oriented. His pulse was 100 beats/min, respirations were 22 breaths/min, and temperature, blood pressure, and oxygen saturation were normal. His cardiac, lung, prostate, and neurologic examinations were unremarkable. His abdominal examination was significant for periumbilical tenderness with a firm pulsatile mass. Laboratory assessment was noteworthy for an elevated creatinine level of 2.3 mg/dL with normal blood counts. A noncontrast CT of the chest/abdomen/pelvis (Figure 1) showed a severely atherosclerotic aorta with multiple fusiform aneurysms, including an 8.3-cm × 7.5-cm abdominal aortic aneurysm (AAA) and bilateral common iliac aneurysms. No leak or dissection could be identified.
Immediate open surgical repair of the aneurysm was recommended. However, considering his comorbidities and the substantial operative risk, the patient and family declined surgical repair. He developed hypotension and died that evening while awaiting transfer to hospice care.
AAA poses a significant diagnostic challenge, as most are asymptomatic until rupture. Symptoms (if any) vary and include nonspecific abdominal, back, flank, or groin discomfort. An enlarging AAA can cause local compressive symptoms such as urinary frequency, nausea, vomiting, or early satiety. A thorough physical exam, periodic screening, and a high degree of clinical suspicion are the keys to prevent a life-threatening AAA rupture. The majority of patients with ruptured AAA present without a prior diagnosis of AAA.
Ruptured AAAs lead to an estimated 15,000 deaths annually in the United States. Advanced age, male sex, hypertension, tobacco use, and family history of AAA are major risk factors for AAA development. Prognosis is extremely guarded once rupture occurs; more than half of patients with ruptured AAAs do not survive for surgical evaluation, and the survival rate declines by an estimated 1% per minute. The survival rate is marginally better for patients who do not present with shock and receive urgent expert surgical intervention.
The U.S. Preventive Services Task Force recommends one-time screening via abdominal ultrasound for men between the ages of 65 and 75 years with a smoking history. Following the diagnosis of AAA, periodic surveillance is required, with the interval depending on the size of the aneurysm. Treatment modalities for symptomatic or asymptomatic large AAA include open surgical or endovascular aneurysm repair (EVAR). The choice of intervention depends on the operative risk, surgeon's experience, anatomic location, and ease of outpatient follow-up. Elective repair of asymptomatic AAA is indicated if the AAA is at least 5.5 cm or expands more than 0.5 cm in 6 months. In comparison with open surgical repair, EVAR is associated with lower short-term morbidity, but larger trials are awaited to demonstrate significant difference in overall and aneurysm-related mortality.
- An abdominal aortic aneurysm (AAA) can present with nonspecific abdominal, back, or groin pain.
- Most patients who present with rupture do not have a previous diagnosis of AAA; rupture constitutes a surgical emergency and is associated with extremely high mortality.
Dr. Zaidi is affiliated with HSHS Medical Group at Saint John's Hospital in Springfield, Ill.
Case 3: Vasculitic neuropathy and eosinophilic granulomatosis with polyangiitis
By Vinit Oommen, MD; Mohit Shukla, MD; and Nureddin Almaddah, MD, ACP Resident/Fellow Member
A 56-year-old man with a history of severe recurrent chronic sinusitis, adult-onset asthma, and nasal polyposis presented with 2 days of left wrist and right foot weakness and paresthesias. On presentation, he had a blood pressure of 143/98 mm Hg, a heart rate of 116 beats/min, a respiratory rate of 20 breaths/min, and a room air oxygen saturation of 95%. Physical examination demonstrated a right foot drop, left wrist drop, and absent left Achilles tendon reflex. The remaining neurological exam was normal. No skin lesions were noted.
Laboratory examination was noteworthy for leukocytosis with marked peripheral eosinophilia (36%). Creatinine level was 1.13 mg/dL. Chest X-ray showed no acute findings, and a brain MRI was remarkable for pansinusitis without any acute intracranial process. The patient underwent lumbar puncture, and the cerebrospinal fluid was without pleocytosis or elevated protein. Perinuclear antineutrophil cytoplasmic antibody (P-ANCA) was positive, with antibodies to myeloperoxidase. Erythrocyte sedimentation rate was 27 mm/h (reference range, 0 to 20 mm/h), and C-reactive protein level was 9.4 mg/L (reference range, <8 mg/L).
The patient was treated with high-dose intravenous methylprednisone for 3 days and then subsequently started on cyclophosphamide and oral prednisone. His left wrist weakness and right foot drop improved over the following 3 days. Pneumocystis carinii pneumonia prophylaxis was initiated, and vaccinations for hepatitis and pneumococcus were given. Alendronate was also initiated to prevent glucocorticoid-induced osteoporosis. Following discharge, treatment was further supplemented by rituximab. Ultimately, the patient's eosinophilia resolved and immunosuppressive drugs were slowly tapered.
Eosinophilic granulomatosis with polyangiitis (EGPA) (previously known as “Churg-Strauss syndrome”) is an antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis first described in 1951. The disease typically manifests in 3 step-wise phases, though these phases are not always clearly recognizable: the allergic phase, characterized by nasal polyposis, rhinosinusitis, and asthma; the eosinophilic phase, characterized by peripheral and tissue eosinophilia; and the vasculitic phase, occurring in the third to fourth decade of life and often nearly 10 years after the diagnosis of asthma and involving nerves, skin, lungs, gastrointestinal tract, and heart. The diagnosis of EGPA is made with detailed history, physical examination and 4 or more of the following features: asthma, eosinophilia (>10% of white blood cell differential), mononeuropathy (including multiplex) or polyneuropathy, transient or migratory pulmonary opacities, paranasal sinus abnormality, and biopsy with histologic evidence of vasculitis, including extravascular eosinophils.
Mononeuritis multiplex (MNM) is the first manifestation of EGPA in 75% of cases. MNM is a peripheral neuropathy defined as damage to 2 or more peripheral nerves involving separate anatomical areas of the body. It is the most specific as well as the most common vasculitic neuropathy presentation leading to the diagnosis of vasculitis. Foot drop is the most common manifestation of MNM as the longest nerves in the body are affected first, and it can progress to symmetric or asymmetric polyneuropathy if untreated. EGPA vasculitis affects the small arteries supplying the nerves, leading to neuropathy, and it manifests as severe pain, numbness, tingling, or weakness.
The pathogenesis of ANCA in the development of neuropathy is unclear, as it is seen only in 40% to 60% of patients with EGPA. In a large cohort study, the most common EGPA manifestations at the time of diagnosis included weight loss (49.3%), MNM (46%), nonerosive sinusitis/polyposis (41.8%), skin lesions (39.7%), and lung infiltrates (38.6%). ANCA-positive patients were noted to have more peripheral neuropathy or renal involvement and less cardiomyopathy than ANCA-negative patients. Patients diagnosed with ANCA-positive vasculitis and MNM have a worse prognosis than those with ANCA-positive vasculitis only. The presence of MNM in ANCA-positive vasculitis often prompts immunosuppressive therapy in addition to glucocorticoids.
Induction therapy with high-dose glucocorticoids is recommended for patients diagnosed with EGPA. Multiorgan involvement usually prompts additional immunosuppressive agents, including but not limited to cyclophosphamide and rituximab.
- Mononeuritis multiplex can be an important clue in making the diagnosis of eosinophilic granulomatosis with polyangiitis, formerly known as “Churg-Strauss syndrome.”
- Prompt treatment with immunosuppressive medications is required to prevent progression of neuropathy and visceral organ involvement.
Drs. Oommen and Almaddah are affiliated with North Shore Medical Center in Salem, Mass. Dr. Shukla is affiliated with Cooper University Hospital in Camden, N.J.
Case 4: Tracheal chondrosarcoma
By Augustine Andoh-Duku, MD, ACP Member; Christian Ghattas, MD; Michael Agustin, MD; and Samaan Rafeq, MD
A 91-year-old man with history of coronary heart disease, a 25 pack-year smoking history, and pulmonary nodules was referred to a tertiary center for evaluation of an incidental tracheal abnormality found on chest CT. He had had chronic cough productive of clear sputum for several months. He also had difficulty with expectoration, hoarseness of voice, exercise intolerance, and dysphonia. He did not report stridor, wheezing, hemoptysis, dysphagia, odynophagia, or recent changes in weight or appetite.
Vital signs were unremarkable, and he had normal oxygen saturation without need for supplemental oxygen. Physical examination demonstrated no visible mass, no tracheal deviation, and no stridor or wheezing. The CT scan of the chest and neck (Figure 2) revealed a 17-mm × 11-mm partially calcified lesion of the trachea at the level of the clavicular heads. Direct laryngoscopy showed no abnormalities in the supraglottic areas and the vocal cords. Basic laboratory testing was normal. Rigid tracheoscopy allowed for visualization and removal of the mass (Figure 3) as well as inspection of the remainder of the airway, which did not reveal any additional endobronchial lesions. Histopathologic examination revealed a cartilaginous lesion most compatible with low-grade chondrosarcoma. The patient had an uneventful postprocedural course and was discharged home.
This patient had a chondrosarcoma of the trachea. The differential diagnosis for tracheal lesions includes chondroma, chondrosarcoma, squamous-cell carcinoma, endobronchial metastasis from another malignancy, and adenoid cystic carcinoma. Cartilaginous tumors of the trachea consist mainly of chondromas and chondrosarcomas, and patients from previous case reports are predominantly men with ages ranging from 32 to 87 years. Chondrosarcomas are more likely to present with extraluminal wall thickening and extratracheal extension. Clinical symptoms usually manifest when at least 75% of tracheal lumen is obstructed. In the largest available case series to date, most patients had tracheal resection, likely due to extratracheal extension of disease. Cartilaginous tumors of the trachea warrant removal due to the increased risk of recurrence, extratracheal extension, and malignant transformation. Endoscopic resection may be considered for those without local extension and/or those unable to tolerate surgical treatment, although local recurrence is more likely.
- Tumors of the trachea, while rare, are clinically consequential and can result in tracheal obstruction, extratracheal extension, and malignant transformation.
- Treatment is usually surgical, although bronchoscopic intervention can be considered in cases without local extension and/or in patients who are poor candidates for surgery.
Drs. Andoh-Duku is affiliated with Emory University Hospital in Atlanta. Drs. Ghattas, Agustin, and Rafeq are affiliated with St. Elizabeth Medical Center in Boston.
Case 5: Sarcoidosis presenting as recurrent nephrolithiasis
By Chris Mosher, MD, ACP Resident/Fellow Member; Ryan Boente, MD; and W. Graham Carlos, MD
A 26-year-old man with a history of nephrolithiasis presented with left flank pain for 1 day. The pain was colicky and associated with nausea and emesis. He reported no pulmonary symptoms, including pleuritic chest pain, cough, or dyspnea. Vital signs demonstrated only mild tachycardia. Physical examination was most notable for his apparent discomfort and left-sided costovertebral angle tenderness. Initial evaluation was remarkable for a creatinine level of 1.57 mg/dL (normal range, 0.67 to 1.17 mg/dL), normal serum calcium level, and urinalysis positive for blood without red blood cells. A CT of the abdomen and pelvis revealed a 9-mm obstructing stone with moderate hydronephrosis, along with multifocal airspace opacities in the lower lung fields.
CT of the chest revealed multiple nodular airspace consolidations with irregular margins and bulky mediastinal and hilar lymphadenopathy. Angiotensin-converting enzyme (ACE) level was noted to be elevated at 105 U/L (normal range, 9 to 67 U/L). The patient underwent bronchoscopy, with bronchoalveolar lavage (BAL) fluid with lymphocytosis of 49% (normal range, 2% to 12%) and a CD4:CD8 of 6.64 (normal range, 1.7 ± 1.0). Ultrasound-guided fine-needle aspiration of the mediastinal lymph nodes was confirmatory for noncaseating granulomatous inflammation. Kidney function returned to baseline following ureteral stent placement, and stone analysis revealed calcium oxalate nephrolithiasis. The patient was started on oral prednisone and discharged for outpatient follow-up.
This patient's diagnosis is nummular sarcoidosis with hypercalciuria resulting in calcium oxalate nephrolithiasis. Hypercalcemia and hypercalciuria are present in 10% to 20% and 30% to 50% of patients with sarcoidosis, respectively. Nephrolithiasis occurs in up to 14% of patients with sarcoidosis. A prospective study found that nephrolithiasis was the presenting feature of the disease in 4% of 204 consecutive patients with sarcoidosis. Hypercalcemia in sarcoidosis is due to excess conversion of calcidiol to calcitriol by activated macrophages in the lung and lymph nodes, which is independent of parathyroid hormone. Elevated calcitriol concentrations also result in increased intestinal calcium absorption. Nummular sarcoidosis is a rare radiographic variant occurring in less than 5% of patients and is characterized by multifocal ill-defined nodules that mimic airspace disease or malignancy.
Nummular sarcoidosis portends a more favorable prognosis than other forms of sarcoidosis and exhibits a similar degree of extra-pulmonary manifestations. ACE levels are sensitive but lack specificity, thus the diagnosis of nummular sarcoidosis is typically confirmed by a lymphocyte-predominant BAL with an elevated CD4:CD8 ratio and/or biopsy evidence of noncaseating granulomas. It is further recommended that all patients with a new sarcoidosis diagnosis be screened for cardiac involvement.
- Nephrolithiasis due to hypercalciuria can occur in sarcoidosis and can in rare instances be the presenting feature heralding the diagnosis.
- Nummular sarcoidosis is a rare radiographic presentation characterized by multifocal ill-defined nodules mimicking airspace disease or malignancy; it generally portends a more favorable prognosis than other forms of sarcoidosis.
Drs. Mosher, Boente, and Carlos are affiliated with the Indiana University School of Medicine in Indianapolis.
Case 6: Adult-onset Still's disease
By Camille Edwards, MD, ACP Resident/Fellow Member; Afua Kunadu, MD, ACP Resident/Fellow Member; Abdelhaleem Sideeg, MD, ACP Resident/Fellow Member; Amanda Sammut, MD; and Eldon A. Redwood, MD, FACP
A 42-year-old man with hypertension and diabetes presented with a 1-week history of intermittent fever, facial rash, and sore throat. He initially noticed itching around his nose and a rash that spread to his forehead and cheeks. Two days later, he developed intermittent subjective fevers, myalgia, and odynophagia. He did not report vomiting, abdominal pain, changes in bowel habits, urinary symptoms, joint pain, or weight loss. There was no history of outdoor activities or insect bites. Upon presentation, temperature was 97.3 °F, pulse rate was 83 beats/min, blood pressure was 133/83 mm Hg, and respiratory rate was 18 breaths/min. On physical examination, he appeared ill. Head and neck exam revealed tender submental and cervical lymphadenopathy. Oropharyngeal examination demonstrated a sub-centimeter ulcer on the uvula, oropharyngeal hyperemia, and petechiae on the hard palate. He also had a blanching salmon-colored maculopapular rash on the anterior and posterior upper torso and around the eyes, sparing the nasolabial folds. Cardiac, pulmonary, and abdominal exams were unremarkable. Initial joint exam was without synovitis.
Routine laboratory studies were noteworthy for a white blood count of 17,800 cells/mm3 (reference range, 4,000 to 11,000 cells/mm3) with 91.3% neutrophils, mild anemia (hemoglobin level 12.3 g/dL; reference range in men, 14.0 to 16.0 g/dL), and mildly abnormal liver tests (aspartate aminotransferase, 50 U/L [reference range, 0 to 35 U/L], alanine aminotransferase, 52 U/L [reference range, 0 to 35 U/L], alkaline phosphatase 176 U/L [reference range, 36 to 92 U/L], albumin, 2.1 g/L [reference range, 3.5 to 5.5 g/L]). The initial chest X-ray was normal.
On admission, empiric antibiotics were started for presumed cellulitis, and supportive care was provided. Blood, urine, and throat cultures were negative. HIV and hepatitis virus serologies were also negative. Testing for syphilis, Epstein-Barr virus, parvovirus B19, measles, mumps, rickettsia, Mycoplasma, malaria, and tularemia was unrevealing. Despite empiric antibiotics, the patient continued to spike daily fevers, with temperatures of up to 103.5 °F. A CT scan of the chest, abdomen, and pelvis was performed to rule out abscess, and it showed only a small right pleural effusion and mild splenomegaly. He later developed right knee and left elbow pain, swelling, and stiffness. Joint examination showed warmth, erythema, and painful range of motion with no palpable joint effusion.
Rheumatologic workup revealed markedly elevated erythrocyte sedimentation rate (105 mm/h; reference range in men, 0 to 15 mm/h) and ferritin level (5,346 ng/mL; reference range, 15 to 200 ng/mL), but anti-Smith, RNP antibody, perinuclear antineutrophil cytoplasmic antibody (P-ANCA), cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA) and rheumatoid factor were negative. Antinuclear antibody was positive in a speckled pattern at a titer of 1:160. The patient responded to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). His fever, upper respiratory tract symptoms, and joint pain resolved, and his rash almost completely subsided prior to discharge.
This patient's diagnosis is adult-onset Still's disease, often reached by exclusion of other more common entities. The Yamaguchi criteria are the most validated diagnostic criteria in the absence of infection. There are 4 major criteria: fevers, salmon-pink maculopapular rash, arthritis, and a white cell count greater than 10,000 cells/mm3 with predominance of neutrophils. Minor criteria include sore throat, lymphadenopathy, organomegaly, abnormal liver function, and negative antinuclear antibody and rheumatoid factor. In adult-onset Still's disease, fever often heralds the onset or worsening of the rash, which commonly involves the trunk, arms, and legs and may be “evanescent” (fading). The rash may also be atypical, persisting without direct correlation to the fever curve. Generally, arthralgia and arthritis involve the larger joints: knees, wrists, elbows, ankles, and shoulders. Most patients affected by adult-onset Still's disease also have significantly elevated ferritin levels, anemia, lymphadenopathy, and abnormal liver enzymes. The presence of an elevated ferritin level in a patient with unexplained fever despite a thorough evaluation can be an important clue in establishing the diagnosis of adult-onset Still's disease.
The goals of treatment are to control symptoms and signs and prevent end-organ damage. Approximately 20% of patients with mild disease (fever, rash, arthralgias, and mild arthritis) respond to NSAIDs alone. However, patients who do not respond to NSAIDs and those with moderate disease (severe joint disease or other organ involvement) generally require low-dose glucocorticoid therapy followed by long-term therapy with disease-modifying antirheumatic drugs. Patients with life-threatening organ involvement should be treated with high-dose glucocorticoids followed by steroid-sparing agents. The overall prognosis depends on the severity of the disease and response to therapy as patients with chronic joint involvement, more severe disease, or resistant disease have increased morbidity.
- A high index of suspicion for adult-onset Still's disease must be maintained when evaluating a patient with fever, rash, arthritis, and a negative infectious evaluation.
- Treatment of adult-onset Still's disease consists of nonsteroidal anti-inflammatory drugs and, in more severe cases, glucocorticoid therapy.
Drs. Edwards, Kunadu, Sideeg, Sammut, and Redwood are affiliated with Harlem Hospital and Columbia University Medical Center in New York.