Case 1: Undiagnosed hemoglobin SC disease
By Natalie Hale Wallace, MD, MPH; Tao Liu, MD; and Robert Nardino, MD, FACP
A 56-year-old man with a history of sarcoidosis and self-reported “sickle cell trait” presented with a two-day history of diffuse abdominal pain, vomiting, and shortness of breath. Initial vital signs were normal. Physical examination was notable for generalized abdominal tenderness, a prosthetic right eye, and nontraumatic amputations of several digits. Labs showed a stable normocytic anemia with a hemoglobin level of 11.3 g/dL and a new acute kidney injury with a creatinine level of 1.6 mg/dL (baseline 1.0 mg/dL). Peripheral blood smear showed target cells, but no sickled cells (Figure 1). Abdominal CT showed autosplenectomy and avascular necrosis of the femoral heads.
Shortly after admission, the patient reported chest pain and his oxygen saturation dropped acutely to 70%. He became unresponsive and was intubated. Post-intubation chest X-ray demonstrated new diffuse infiltrates. A CT of the head showed acute infarction of the right frontal and parietal lobes. Shortly thereafter, he became bradycardic, then asystolic, and died. High-performance liquid chromatography revealed a postmortem diagnosis of hemoglobin SC disease (HbSC). Autopsy revealed multiorgan sickle cell disease involvement, including renal infarcts, osteonecrosis of the lumbar spine and femoral heads, and an autoinfarcted spleen.
HbSC is a hemoglobinopathy related to homozygous sickle cell disease (HbSS). HbSC results when an individual inherits the hemoglobin S (HbS) gene from one parent and the hemoglobin C (HbC) gene from the other. HbSC occurs in 1 out of 833 African-American live births. The anemia observed in HbSC is less severe, with an average hemoglobin level of 10 to 13 g/dL, as compared to 6 to 9 g/dL in HbSS. Median survival is 65 years for HbSC, as compared to 45 years for HbSS. Common features of this disease include retinopathy (which occurs 10 times more frequently in HbSC than in HbSS), osteonecrosis, gallbladder disease, stroke, osteomyelitis, and sickle cell-related lung disease. Unlike in HbSS, splenic infarction occurs sporadically and often not until adulthood. In HbSC, peripheral blood smears often demonstrate target cells.
Our patient had been incorrectly identified as a carrier of the sickle cell trait. Sickle cell trait is generally a benign condition in which patients inherit a normal hemoglobin gene from one parent and the HbS gene from the other. Sickle cell trait is not associated with anemia, and red cell morphology is normal. Generally, carriers are asymptomatic, although there are some pathologic associations, including exertional heat illness and splenic infarction at high altitude. Universal neonatal screening for hemoglobinopathies was slowly implemented across the 50 states between 1983 and 2006, meaning that many adults, like our patient, have not been screened.
- While sickle cell trait is a benign carrier condition, HbSC is associated with many of the same complications as HbSS, including acute chest syndrome, vaso-occlusive crisis, stroke, autosplenectomy, avascular necrosis, and retinal disease.
- Neonatal screening for hemoglobinopathies was not universally instituted until 2006 across the United States; hence, a high degree of suspicion should be maintained in unscreened adult patients.
Dr. Wallace is a hematology/oncology fellow at Yale University in New Haven, Conn. Dr. Liu is an attending physician at Element Care in Lynn, Mass. Dr. Nardino is the internal medicine residency program director and an assistant professor of medicine at the University of Connecticut in Farmington, Conn.
Case 2: “Cotton fever”
By Daniel T. Mulcahy, DO, ACP Member, and Kim Soleymani, PA-C
A woman in her mid-20s with history of heroin use presented with severe back and flank pain, myalgias, vomiting, shaking chills, and palpitations. She said acute symptom onset occurred 30 minutes after she injected a heroin “cotton shot” intravenously. Her discomfort progressed, and she called a friend who found her face down on the couch, groaning in pain, and called emergency medical services.
On examination, the patient had a temperature of 101.5 °F (38.6 °C), tachycardia, and a blood pressure of 99/50 mm Hg. She was anxious, noncooperative, and writhing in pain. No heart murmurs were noted, and lungs were clear. No stigmata of infective endocarditis were seen.
Labs of note included normal leukocyte count with left shift, mildly elevated lactate level, and a toxicology panel positive for opiates only. Chest X-ray showed dependent ground-glass appearance in lung bases, attributed to atelectasis. Blood cultures were obtained. Fluids and broad-spectrum antibiotics were initiated, as was medication to treat symptoms. The patient improved clinically over the next 24 hours and left the hospital against medical advice. Blood cultures came back negative.
“Cotton fever” is a self-limited, painful, febrile illness associated with IV drug use, usually heroin. It occurs when the drug is filtered through cotton or, in the case of a “cotton shot,” when heroin residues are rinsed from the cotton filter and injected. The accepted pathophysiology is that symptoms are caused by endotoxin release by gram-negative bacteria such as Enterobacter agglomerans, which has been shown to regularly colonize cotton.
Cotton fever is marked by symptoms beginning 15 to 30 minutes after injection. They can include fever, chills, headache, extreme joint and muscle pain, abdominal pain, nausea, vomiting, tachycardia, and leukocytosis. Cotton fever typically lasts 6 to 12 hours but can last up to 48 hours. This is a diagnosis of exclusion, as cotton fever mimics sepsis and occurs in a high-risk population. Observation is recommended until negative cultures are obtained and symptoms have resolved.
There is a paucity of medical literature on cotton fever, but it is well known among people who use drugs and is increasingly evident in EDs and online teaching references. Cotton fever rarely requires extensive evaluation, and awareness of it may avoid costly evaluations and prolonged hospitalization.
- Cotton fever presents in patients who use IV drugs with fever, constitutional symptoms, and sometimes extreme joint and muscle pain.
- The illness is self-limiting, and treatment is supportive, assuming cultures remain negative and no additional signs or symptoms of acute infection arise.
Dr. Mulcahy and Ms. Soleymani are affiliated with Lehigh Valley Health Network-Muhlenberg in Bethlehem, Pa.
Case 3: Post-banding ulcer hemorrhage of the esophagus
By Yash Mittal, MD, ACP Resident/Fellow Member, and David C. Kunkel, MD
A 53-year-old woman with previously compensated cirrhosis due to alcohol and chronic hepatitis C presented acutely with hematemesis. On initial presentation, her heart rate was 113 beats/min and her blood pressure was 96/55 mm Hg. On physical examination, she was alert and fully oriented, jaundiced, and actively producing bright red vomitus. There was no ascites or asterixis. Her labs at admission were notable for a hemoglobin level of 6.1 g/dL, a platelet count of 135 × 103 cells/mm3, an international normalized ratio of 2.4, and total bilirubin level of 7.61 mg/dL (upper limit of normal, 1.2 mg/dL). No prior laboratory values were available for comparison.
Initial upper endoscopy demonstrated four columns of small varices without active bleeding, on which three bands were placed (Figure 2). Ongoing blood loss prompted repeat endoscopy, during which an additional five bands were placed and hemostasis was achieved. Due to profound volume overload and multifactorial encephalopathy, the patient was hospitalized for a prolonged period. On the hospital day 12, she developed recurrent upper gastrointestinal hemorrhage with tachycardia, bright red nasogastric tube output, and maroon stool. Her hemoglobin level decreased from 8.7 g/dL to 5.2 g/dL. Repeat upper endoscopy demonstrated post-banding ulcers with blood seen throughout the exam, but without active bleeding (Figure 3). No intervention was performed. Although the bleeding was controlled, the patient died within days due to infectious complications.
Post-banding ulcer hemorrhage (PBUH) is the recurrence of esophageal bleeding resulting from local tissue pressure from variceal bands, which cause tissue ischemia, necrosis, sloughing, and potentially recurrent hemorrhage. PBUH occurs in up to 8% of patients who receive variceal band ligation and has been encountered up to 29 days after hemostasis from initial banding procedure. Patients at highest risk for PBUH include those with Child class C cirrhosis and/or those who have had variceal band ligation for active bleeding as opposed to banding performed for bleeding prophylaxis. Mortality rates are up to 26% for patients who develop PBUH. Immediate medical management options for PBUH include proton-pump inhibitors and somatostatin analogues. Interventional options include attempting endoscopic hemostasis with epinephrine injection and hemoclips and transjugular intrahepatic portosystemic shunt (TIPS), though use of these techniques requires local expertise. Severity of illness and presentation should determine treatment, and the options should be carefully considered in collaboration with gastroenterology/hepatology subspecialists.
- PBUH may occur up to a month after variceal band ligation and carries a significant risk of death.
- Postprocedural hemorrhage is an emergency and should immediately be addressed with appropriate medical therapy as well as notification of interventional subspecialists.
Drs. Mittal and Kunkel are affiliated with the department of gastroenterology and hepatology at the University of California, San Diego.
Case 4: Acute myocarditis
By Christopher Murray, MD, ACP Resident/Fellow Member; Lukman Lawal, MD; and Tamanna Nahar, MD, ACP Member
A 54-year-old man with a history of hypertension, hyperlipidemia, and diabetes mellitus presented with three hours of left-sided chest pain. He described the pain as “pressing” and nonradiating, with no associated symptoms and no aggravating or relieving factors. He reported no palpitations, presyncope, or syncope. His initial vital signs were remarkable for a blood pressure of 170/110 mm Hg. His initial electrocardiogram (EKG) demonstrated normal sinus rhythm with left ventricular hypertrophy. Labs were most notable for an initial troponin I level of 1.93 ng/mL, with a repeated level of 2.42 ng/mL (normal range, 0.000 to 0.045 ng/mL). Brain natriuretic peptide (BNP) levels, electrolytes, blood counts, and urine toxicology were normal.
The patient was transferred to the coronary care unit due to concern for a non-ST-elevation myocardial infarction. A transthoracic echocardiogram (TTE) revealed a left ventricular ejection fraction (LVEF) of 20% to 25% with global hypokinesis. Cardiac catheterization revealed mild disease of the left anterior descending artery and a 20% right coronary artery stenosis, and no intervention was performed. Additional history obtained at this juncture revealed flu-like symptoms approximately five days prior to presentation. Chest pain persisted and troponins continued to rise despite adequate control of blood pressure. Logistical challenges prevented MRI, and the patient declined cardiac biopsy. Intravenous methylprednisolone, 30 mg/kg, was given empirically. During hospitalization, dramatic symptomatic and clinical improvement was noted. A repeated TTE 24 hours later showed an increase in LVEF, and a follow-up TTE at two weeks was normal.
The patient was diagnosed with acute myocarditis, likely caused by a virus. Myocarditis can have multiple infectious causes, including viral, bacterial, spirochetal, mycotic, rickettsial, protozoal, and helminthic. Additional causes include medications, illicit drugs, hypersensitivity reactions, and metabolic and autoimmune conditions. In the United States and other developed countries, viral causes are approximately four times as likely as other infectious causes in patients with acute myocarditis, though incidence varies by geographic location.
Acute myocarditis is definitively diagnosed by cardiac biopsy. A three-tiered clinical classification, developed by Sagar and colleagues and published in The Lancet in 2012, can be used to aid in the diagnosis. This categorizes cases into one of three diagnostic categories:
- 1. Possible subclinical acute myocarditis, defined by possible myocardial injury, without cardiovascular symptoms; in the absence of histologic confirmation, there is at least one of the following: elevated cardiac injury biomarkers, EKG findings suggestive of myocardial injury, or abnormal cardiac function seen on an echocardiogram or chest MRI.
- 2. Probable acute myocarditis, defined by the same factors, but with cardiovascular symptoms.
- 3. Definite myocarditis, defined by histologic or immunohistologic evidence of myocarditis, with no biomarker results required for diagnosis.
Treatment of myocarditis is typically supportive and includes therapies for heart failure and arrhythmias as appropriate. Immunosuppressive therapy is indicated in specific autoimmune disorders, such as giant-cell myocarditis and sarcoidosis. The use of corticosteroids for viral myocarditis remains controversial. In patients diagnosed with viral myocarditis and reduced LVEF, corticosteroids have not been shown to be routinely beneficial, although some effect has been reported over the first one to three months after initiation of treatment.
- Acute myocarditis has many potential etiologies, though studies suggest viral infections as the predominant cause in developed countries.
- Acute myocarditis is definitively diagnosed by biopsy, though clinical classification schema may prove useful in some patients.
Drs. Murray, Lawal, and Nahar are affiliated with the cardiology section at Harlem Hospital Center in New York City.
Case 5: Bannwarth syndrome
By Timothy Hunter, MD, ACP Resident/Fellow Member, and Julie M. Chen, MD, FACP
A 71-year-old woman with a history of stable chronic lymphocytic leukemia (CLL) presented to her primary care physician with a two-week history of fevers, chills, night sweats, myalgias, and fatigue. Symptoms included a new skin rash and severe bilateral lower extremity pain in both thighs. Her medical history was significant for CLL (Rai stage 0), and a prior infection with babesiosis. Her medications included atorvastatin, calcium/vitamin D, and topical estrogen. She lived with her husband in northern Virginia, was a nonsmoker, and drank alcohol socially.
On examination, the patient was afebrile with normal vital signs. Her physical exam was notable for multiple annular erythematous patches measuring from 5 to 12 cm in diameter and distributed over her upper and lower extremities as well as her trunk and back (Figure 4). Her laboratory studies were significant for a drop in leukocytes to 4,700 cells/µL (from a baseline of about 20,000 cells/uL) with 8% bands, new anemia with a hemoglobin level of 9.8 g/dL, and an elevated serum creatinine level of 1.23 mg/dL (baseline, 0.9 mg/dL). She had mild elevations in liver function tests, erythrocyte sedimentation rate, and C-reactive protein level. An electrocardiogram demonstrated no evidence of conduction system abnormality.
Upon admission, parenteral analgesia was required for leg pain and antibiotic treatment was initiated. On hospital day 3, the patient reported new left lower extremity weakness, and an MRI was significant for T1 post enhancement at the proximal caudal equina extending into the left lumbar plexus (Figure 5). A lumbar puncture demonstrated a lymphocytic pleocytosis, elevated protein, atypical lymphoid cells and negative flow cytometry. Both serum and cerebrospinal fluid (CSF) Lyme antibody and western blot returned positive. She completed the maximum recommended course of antibiotics: 28 days of 2 g of ceftriaxone daily. She subsequently developed weakness in the right lower extremity with MRI evidence of bilateral lumbar plexus involvement. At one year follow-up, the patient was markedly improved; however, she required the use of a cane for residual right-sided leg weakness.
This patient's constellation of symptoms and studies are consistent with Lyme neuroborreliosis, a lymphocytic meningoradiculitis also known as “Bannwarth syndrome.” Lyme disease causes roughly 300,000 annual infections in the United States, occurs in stages, and often presents with the characteristic skin finding of erythema migrans. Disseminated Lyme disease involves hematogenous spread of spirochete and can involve multiple organ systems including the heart, joints, and nervous system. Neurologic involvement in Lyme disease almost always occurs during the early disseminated stage and can consist of one or a combination of lymphocytic meningitis, cranial neuritis, and radiculoneuritis. Radiculoneuritis with motor weakness in the setting of a facial nerve palsy and CSF findings with a lymphocytic pleocytosis are consistent with the diagnosis of Bannwarth syndrome. Radiculoneuritis is an uncommon finding, seen in only 3% of the cases documented by the CDC.
The mechanism of nerve involvement is unclear. It is unlike other bacterial meningitides, in which nerve roots are compressed as they pass through an inflamed subarachnoid space. Proposed mechanisms involve direct damage to glial and neuronal cells from spirochetes or spirochetal products or induced inflammatory mediators such as IL-6, IL-8, and CCL-2. Pain, muscle weakness, and sensory involvement are the hallmark symptoms of Lyme radiculoneuritis. Early recognition of unusual manifestations of neuroborreliosis is important to ensuring the correct antimicrobial therapy and duration to provide the patient the best chance of recovery. Treatment with 2 g of IV ceftriaxone for 10 to 28 days remains the standard of care. There are no data to support the use of steroids in neuroborreliosis, as studies comparing antibiotics alone versus with corticosteroids have not shown a difference. Effectiveness of therapy is often judged by two measures: symptomatic improvement and resolution of CSF inflammation.
- Bannwarth syndrome is a lymphocytic meningoradiculitis caused by dissemination of Lyme disease to the nervous system.
- Neurologic involvement in Lyme disease almost always occurs during the early disseminated stage and can consist of one or a combination of lymphocytic meningitis, cranial neuritis, and radiculoneuritis.
Drs. Hunter and Chen are affiliated with the Walter Reed National Military Medical Center in Bethesda, Md.