Francisco M. Pherez

Diagnostic Importance of Relative Lymphopenia as a Marker of Swine Influenza (H1N1) in Adults

NOTE. The rapid influenza test was QuickS Influ A/B kit (Denka Seiken). Among patients with complete blood counts, 25 adults and 16 children tested positive for influenza A, and 3 adults and 2 children tested positive for influenza B. in HIV-infected patients with tuberculosis. Clin Infect Dis 2007; 44:141–4. 10. Manosuthi W, Tantanathip P, Prasithisirikul W, Likanonsakul S, Sungkanuparph S. Durability of stavudine, lamivudine and nevirapine among advanced HIV-1 infected patients with/without prior co-administration of rifampicin: a 144-week prospective study. BMC Infect Dis 2008; 8:136.

Swine influenza (H1N1): Diagnostic dilemmas early in the pandemic

Recognizing and diagnosing cases of influenza A in adults during the influenza season is relatively straightforward. This year, the swine influenza H1N1 pandemic began at the end of the usual influenza season (December 2008 March 2009). Swine influenza H1N1 appears to have started in Veracruz, Mexico, quickly spreading to other parts of Mexico, then to the USA, Europe and other parts of the world. In New York, the first recognized cases were at a school in New York City. The pandemic quickly spread to surrounding areas during April May 2009 [1]. A pandemic alert was declared by the Centers for Disease Control and Prevention (CDC) and hospitals in affected areas activated pandemic influenza plans, as we did at our hospital. Our institution mobilized its resources in accordance with the Health Department and CDC interim recommendations for emergency department (ED) triage for influenza A (QuickVue) screening. Specimens of respiratory secretions of patients that tested positive for influenza A were sent to the Health Department/CDC for reverse transcriptase polymerase chain reaction (RT-PCR) swine influenza H1N1 testing [2,3]. We implemented a prioritized response plan for the allocation of negative pressure and ventilator rooms, and devised plans for furloughing of employees who were sick or in contact with probable cases of swine influenza H1N1. Criteria were developed for oseltamivir (Tamiflu) prophylaxis/therapy [4,5]. A special multidisciplinary emergency task force was activated to handle the pandemic potential. In spite of these preparations, during the initial weeks of the swine influenza H1N1 pandemic, we found ourselves inundated with patients with influenza-like illnesses (ILIs) presenting to the ED for rapid influenza A testing. We experienced diagnostic difficulties related to rapid influenza A false negative screening tests. The other rapid influenza diagnostic tests (RIDTs), i.e., respiratory fluorescent antibody (FA) viral tests, did not agree with results of rapid influenza A testing. Without definitive RT-PCR results, difficulties with clinical diagnosis, i.e., overdiagnosing and misdiagnosing, quickly became apparent. Definitive testing for swine influenza H1N1 by RT-PCR was restricted resulting in a lack of definite diagnoses in most patients. Our initial experience with swine influenza H1N1 may be viewed as an learning experience and cautionary tale for a potential future wave (fall 2009 and/ or winter/spring 2010) of more virulence/severity, as occurred in the 1918 1919 influenza pandemic [6,7]. Our recent early experience demonstrated major problem areas with the laboratory and clinical diagnoses of swine influenza H1N1.

Severe cytomegalovirus (CMV) community-acquired pneumonia (CAP) in a nonimmunocompromised host.

Background Community-acquired pneumonia (CAP) in an immunocompetent host may be severe because of a variety or combination of host and microbial factors. In patients with severe cardiopulmonary dysfunction, even relatively avirulent pathogens, that is, Mycoplasma pneumoniae, Moraxella catarrhalis, may compromise borderline cardiac/heart function and present clinically as severe CAP. Alternately, patients with Streptococcus pneumoniae and impaired humoral immunity/splenic dysfunction may present as severe CAP. With the exception of Legionnaires disease, influenza, and adenovirus, pathogen virulence is not a key determinant of CAP severity. Methods Diagnostically, patients with severe CAP may be approached based on the pattern of infiltrates on chest x-ray together with the severity of hypoxemia (ie, increased A-a gradient: >35). Results We present the case of an immunocompetent adult who presented with severe CAP during peak influenza season. Direct fluorescent antibody testing of his respiratory secretions was negative for influenza, adenovirus, and other respiratory viruses. Diagnostic bronchoscopy was negative for bacterial and fungal pathogens. The only clues to the cause of his severe CAP was the presence of relative lymphopenia, atypical lymphocytosis and elevated serum transaminases. After influenza and adenovirus were ruled out, cytomegalovirus (CMV) CAP was considered. The diagnosis of CMV CAP was made serologically by demonstrating highly elevated IgM CMV titers. Because the diagnosis was made during the patients recovery late in hospitalization, he did not receive CMV antiviral therapy. Conclusion This case should remind clinicians that influenza and adenovirus are diagnostic considerations in patients presenting with severe CAP with diffuse bilateral interstitial infiltrates accompanied by severe hypoxemia in normal hosts. If influenza and adenovirus are ruled out, then CMV CAP, although rare, should be considered, particularly when viral CAP is accompanied by relative lymphopenia, atypical lymphocytosis and increased serum transaminases.

Fever of unknown origin (FUO) due to Rosai-Dorfman disease with mediastinal adenopathy mimicking lymphoma: diagnostic importance of elevated serum ferritin levels and polyclonal gammopathy.

Fever of unknown origin (FUO) characterizes febrile disorders that are accompanied by prolonged fevers of 101 degrees F or greater for 3 weeks or more that remain undiagnosed after comprehensive inpatient and outpatient diagnostic testing. At the present time, malignancies are the most common cause of FUOs. Among malignant FUOs, lymphomas are the most common. We present the case of a non-Asian young adult man who presented with FUO. He had no peripheral adenopathy or splenomegaly but was found to have anterior/superior mediastinal adenopathy and right paratracheal adenopathy. His diagnostic workup was negative for rheumatic/inflammatory and infectious diseases. Laboratory test results were unremarkable except for a highly elevated erythrocyte sedimentation rate and highly elevated serum ferritin level. Otherwise unexplained highly elevated serum ferritin levels in patients with FUOs suggest rheumatic and inflammatory disorders, for example, systemic lupus erythematosus flare or malignancy. The findings of mediastinal adenopathy combined with a highly elevated ESR and highly elevated serum ferritin levels indicate lymphoma as the most likely diagnosis. He also had polyclonal gammopathy on serum protein electrophoresis (SPEP). In a patient with FUO, negative blood cultures, and a heart murmur, polyclonal gammopathy on SPEP suggests atrial myxoma. Lymphomas are often associated with elevated alpha(1)/alpha(2) globulins on SPEP. Lymph node biopsy of the mediastinal nodes was negative for lymphoma but did not show characteristic emperiopolesis, pathognomonic of Rosai-Dorfman disease, a benign lymphoproliferative disorder. Rosai-Dorfman disease usually presents with massive bilateral cervical adenopathy but may present with lymph node involvement in other sites, as in this case. In patients with lymphadenopathy and a negative FUO workup, clinicians should consider the possibility of Rosai-Dorfman disease, particularly if accompanied by an otherwise unexplained highly elevated serum ferritin levels and polyclonal gammopathy on SPEP.

Severe swine influenza A (H1N1) versus severe human seasonal influenza A (H3N2): Clinical comparisons

At the beginning of the swine influenza (H1N1) pandemic in the spring of 2009, there were still stories of human seasonal influenza A circulating in the New York area. Adult patients admitted with influenza-like illnesses (ILIs) (fever > 102°F, dry cough, and myalgias) presented diagnostic problems. First, clinicians had to differentiate ILIs from influenza, and then differentiate human seasonal influenza A from H1N1 in hospitalized adults with ILIs and negative chest films (no focal segmental/lobar infiltrates). Human seasonal influenza A was diagnosed by rapid influenza diagnostic tests (RIDTs), but H1N1 was often RIDT negative. Reverse transcriptase-polymerase chain reaction for H1N1 was restricted or not available. The Winthrop-University Hospital Infectious Disease Division developed clinical diagnostic criteria (a diagnostic weighted point score system) to rapidly and clinically diagnose H1N1 in patients with negative RIDTs. The point score system was modified and shortened for ease of use, that is, the diagnostic H1N1 triad (any 3 of 4) (ILI, see above) plus thrombocytopenia, relative lymphopenia, elevated serum transaminases, or an elevated creatine phosphokinase. Our clinical experience during the pandemic allowed us to develop the swine diagnostic H1N1 triad. In the process, similarities and differences between human seasonal influenza A and H1N1 were noted. We present 2 illustrative cases of severe influenza, one due to human seasonal influenza A and one due to H1N1, for clinical consideration reflective of our experiences early in the H1N1 pandemic in 2009.

Swine influenza (H1N1) and acute appendicitis

BACKGROUND During the swine influenza (H1N1) pandemic that began in 2009, many hospitalized adults had gastrointestinal symptoms. The most common symptoms associated with swine influenza (H1N1) were nausea, vomiting, or diarrhea. In the experience of the authors, swine influenza was not complicated by abdominal pain. There are a wide variety of infectious and non-infectious disorders that may present with a pain in the right lower quadrant, mimicking appendicitis, ie, pseudoappendicitis. Influenza predisposes to some types of bacterial infection, eg, influenza pneumonia may be complicated by simultaneous Staphylococcus aureus community-acquired pneumonia or subsequent community-acquired pneumonia due to Haemophilus influenzae or Streptococcus pneumoniae. It remains unclear if there is direct involvement of the appendix, ie, pseudoappendicitis as occurs with measles or if influenza itself somehow predisposes to increased frequency/severity of bacterial appendicitis. German clinicians first noted an increased incidence of acute appendicitis in children/young adults with influenza. The American and British cases of influenza and acute appendicitis compared to age-matched controls with more severe and of delayed onset/complicated by appendicial perforation/abscess. These reports noted an increased incidence/severity of acute appendicitis during influenza. METHODS AND RESULTS A 15-year-old girl presented to the hospital with an influenza-like illness and right lower quadrant abdominal pain. Acute appendicitis was diagnosed by a computed tomography scan and the patient underwent emergency appendectomy. Subsequently, it was noted that she did not have leukocytosis and, in fact, had borderline leukopenia. Her differential white blood cell count also revealed relative lymphopenia. Neither leukopenia nor relative lymphopenia are features of acute bacterial appendicitis. These two findings in the setting of an influenza-like illness indicate the underlying presence of influenza. Post-operatively, respiratory secretion samples were sent for swine influenza (H1N1) testing. Both her respiratory florescent antibody (FA viral panel) was positive for influenza A, as was her RT-PCR for swine influenza (H1N1). The authors believe that this is the first case of swine influenza (H1N1) and acute bacterial appendicitis. Direct involvement of the appendix by swine influenza (H1N1) virus could not be demonstrated. CONCLUSIONS The authors conclude that during the swine influenza (H1N1) pandemic clinicians should be alert to the possibility of an increased incidence/severity of acute bacterial appendicitis in patients with swine influenza (H1N1) infection.

Adult Kawasaki's disease with myocarditis, splenomegaly, and highly elevated serum ferritin levels

Kawasakis disease is a disease of unknown cause. The characteristic clinical features of Kawasakis disease are fever≥102°F for≥5 days accompanied by a bilateral bulbar conjunctivitis/conjunctival suffusion, erythematous rash, cervical adenopathy, pharyngeal erythema, and swelling of the dorsum of the hands/feet. Kawasakis disease primarily affects children and is rare in adults. In children, Kawasakis disease is more likely to be associated with aseptic meningitis, coronary artery aneurysms, and thrombocytosis. In adult Kawasakis disease, unilateral cervical adenopathy, arthritis, conjunctival suffusion/conjunctivitis, and elevated serum transaminases (serum glutamic oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) are more likely. Kawasakis disease in adults may be mimicked by other acute infections with fever and rash, that is, group A streptococcal scarlet fever, toxic shock syndrome (TSS), and Rocky Mountain Spotted Fever (RMSF). Because there are no specific tests for Kawasakis disease, diagnosis is based on clinical criteria and the syndromic approach. In addition to rash and fever, scarlet fever is characterized by circumoral pallor, oropharyngeal edema, Pastias lines, and peripheral eosinophilia, but not conjunctival suffusion, splenomegaly, swelling of the dorsum of the hands/feet, thrombocytosis, or an elevated SGOT/SGPT. In TSS, in addition to rash and fever, there is conjunctival suffusion, oropharyngeal erythema, and edema of the dorsum of the hands/feet, an elevated SGOT/SGPT, and thrombocytopenia. Patients with TSS do not have cervical adenopathy or splenomegaly. RMSF presents with fever and a maculopapular rash that becomes petechial, first appearing on the wrists/ankles after 3 to 5 days. RMSF is accompanied by a prominent headache, periorbital edema, conjunctival suffusion, splenomegaly, thrombocytopenia, an elevated SGOT/SGPT, swelling of the dorsum of the hands/feet, but not oropharyngeal erythema. We present a case of adult Kawasakis disease with myocarditis and splenomegaly. The patients myocarditis rapidly resolved, and he did not develop coronary artery aneurysms. In addition to splenomegaly, this case of adult Kawasakis disease is remarkable because the patient had highly elevated serum ferritin levels of 944-1303 ng/mL; (normal<189 ng/mL). To the best of our knowledge, this is the first report of adult Kawasakis disease with highly elevated serum ferritin levels. This is also the first report of splenomegaly in adult Kawasakis disease. We conclude that Kawasakis disease should be considered in the differential diagnosis in adult patients with rash/fever for≥5 days with conjunctival suffusion, cervical adenopathy, swelling of the dorsum of the hands/feet, thrombocytosis and otherwise unexplained highly elevated ferritin levels.

Fever of unknown origin (FUO) caused by Kikuchi's disease mimicking lymphoma

Fever of unknown origin (FUO) refers to infectious, neoplastic, or rheumatic/inflammatory disorders that present with fevers of 101 degrees F or greater for 3 weeks and that remain undiagnosed after an intensive in-hospital or outpatient workup. The noninfectious causes of FUO in adults are most often lymphomas or rheumatic/inflammatory disorders. Among the rare causes of rheumatic/inflammatory FUOs is Kikuchis disease. Kikuchis disease (Kikuchi-Fujimoto disease) is also known as histiocytic necrotizing lymphadenitis, a benign, self-limited disorder usually in middle-aged women of Asian descent. Cervical adenopathy is typical and often accompanied by leukopenia. In middle-aged adults patients presenting with an FUO, the presence of otherwise unexplained cervical adenopathy should suggest the possibility of lymphoma or, rarely, Kikuchis disease.

Mycoplasma pneumoniae community-acquired pneumonia (CAP) in the elderly: Diagnostic significance of acute thrombocytosis

The most common cause of nonzoonotic atypical community-acquired pneumonia (CAP) is Mycoplasma pneumoniae. M. pneumoniae CAP is most common in young adults but may occur at any age. Like other atypical CAPs, M. pneumoniae is associated with a characteristic pattern of extrapulmonary organ involvement and nonspecific laboratory tests. M. pneumoniae CAP is frequently accompanied by gastrointestinal manifestations (eg, loose stools/diarrhea), nonexudative pharyngitis, or skin involvement (ie, erythemamultiforme). Central nervous system involvement with M. pneumoniae is rare and accompanied by highly elevated cold agglutinin titers. Cardiac, hepatic, and renal involvement are not features of M. pneumoniae CAP. Because M. pneumoniae CAP is most frequent in ambulatory young adults, it is an easily overlooked diagnosis in elderly patients hospitalized with CAP. The hallmark clinical finding of M. pneumoniae CAP is protracted nonproductive cough. The characteristic nonspecific laboratory test finding uniquely associated with M. pneumoniae CAP is elevated cold agglutinin titers. Seventy-five percent of patients with M. pneumoniae infection have elevated cold agglutinin titers. However, the absence of elevated cold agglutinin titers does not argue against the diagnosis of M. pneumoniae. If cold agglutinins are present in a patient with CAP, the higher the cold agglutinin titer is (>1:64), the more likely the cold agglutinins are due to M. pneumoniae. Q fever is the only other atypical CAP that is rarely associated with cold agglutinins. We present a hospitalized patient with CAP in whom all microbiologic and serologic diagnostic test results were negative during the first week of her hospitalization. M. pneumoniae CAP was not suspected because of her age. Her initial M. pneumoniae immunoglobulin-M and cold agglutinin titers were negative. During the second week of hospitalization, an increased platelet count was noted. It is a common misconception that acute thrombocytosis is an acute phase reactant. Her acute thrombocytosis increased and persisted. The diagnostic clue to the cause of this hospitalized patient with CAP was acute thrombocytosis. In a patient with CAP, acute thrombocytosis is usually associated with Q fever pneumonia and less commonly with M. pneumoniae. If Q fever can be excluded on the basis of a recent/proximate zoonotic vector contact history, then acute thrombocytosis is an important clue to M. pneumoniae CAP. Acute thrombocytosis due to M. pneumoniae and Q fever occurs during weeks 1 and 2 of the infection. In patients with CAP, acute thrombocytosis that occurs during weeks 1 and 2 of the illness should suggest M. pneumoniae in patients without recent zoonotic vector contact history.

Fever of unknown origin (FUO) due to a solitary cavitary lung lesion: The deadly ferritin-laced doughnut

Fever of unknown origin (FUO) is the clinical designation for patients who have fevers >101F that have persisted for >3 weeks that remain undiagnosed, after an intensive ambulatory/in-hospital workup. Fevers of unknown origin may be due to wide variety of infectious, neoplastic, or rheumatic/inflammatory disorders. The most common causes of FUOs in elderly patients are infectious and neoplastic diseases. With FUOs, the clinical presentation and routine laboratory tests are usually sufficient to narrow differential diagnostic possibilities. We present a case of an elderly Italian woman who presented with an FUO and a solitary, thick-walled cavitary lesion on chest x-ray (CXR). The infectious disease differential diagnosis of her FUO included lung abscess, M. tuberculosis (TB), systemic mycoses, and echinococcal-cyst (or hydatid-cyst) disease. The malignancy and neoplastic differential diagnosis included bronchogenic carcinoma, lymphoma, and metastatic carcinoma. Her nonspecific laboratory tests indicated a highly elevated erythrocyte sedimentation rate (ESR) >100 mm/hour, chronic thrombocytosis, relative lymphopenia, and highly elevated serum ferritin levels. Excluding highly elevated serum ferritin levels, the differential diagnosis of her FUO with a solitary, thick-walled cavitary lesion was lung abscess vs tuberculosis. However, her highly elevated serum ferritin levels proved to be the critical diagnostic clue in predicting the diagnosis of squamous-cell carcinoma. We conclude that serum ferritin levels are an important part of the laboratory workup. As with other nonspecific laboratory tests, the diagnostic significance of highly elevated ferritin levels depends associated clinical features in the clinical presentation.